Volume 70Number 5

May 2017

THE JOURNAL OF THE SOUTH DAKOTA STATE MEDICAL ASSOCIATION

Annual LeadershipConference

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Sioux Falls, South Dakota

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Volume 70 lNumber 5May 2017

The Journal of the South Dakota State Medical Association

ContentsPresident’s Comments195 Thank You – Tom Hermann, MD

Editorial197 Inguinal and Femoral Hernioplasty: Anatomic Repair – Keith Hansen, MD

The Journal199 Point-Counterpoint: Genotype-Guided Opioid Therapy

– Wenjie Jessie Lu, PhD; Sreekanth Chavour, MD

203 Superior Ophthalmic Vein Thrombosis: The Role of Anticoagulation – Samuel Thomsen, MD; Eric Larson, MD; Michael Greenwood, MD

207 Atypical Presentations of Tularemia – Karah Odegaard, MSIV; Kristin Hockhausen, MSIV; Beth Boersma, LPN; James M. Keegan, MD

211 Pre-Guideline Trends Associated with Radiograph Usage for Pediatric Community-Acquired Pneumonia in Emergency Department Settings – Eric W. Jones, MSIV; Benjamin Meyer, MD; Aaron M. Berg, MD; Benson S. Hsu, MD, MBA

217 Laparoscopic Pediatric Inguinal Hernia Repair: Overview of “True Herniotomy” Technique and Review of Current Evidence – Brendan P. Feehan, MSIV; David S. Fromm, MD

Primers in Medicine225 Genetics of Alcoholism – Ena C. Zhu, BS; Yueshan Hu, PhD;

Timothy J. Soundy, MD

Pharmacology Focus229 Pharmacotherapy Review of Ceftazidime-Avibactam – Amber Yaeger, PharmD;

John Kappes, PharmD, BCCCP

Special Features232 Quality Focus: Antimicrobial Stewardship: Cultural Change Continuing Challenge

– Stephan D. Schroeder, MD

234 Board News – Margaret B. Hansen, PA-C, MPAS

235 Patient Education: The Story of a Badly Sprained Ankle – Richard P. Holm, MD

236 2017 SDSMA Foundation Donations

Member News237 For Your Benefit: Providing Solutions for Your Practice

Registration Deadline Approaching – 2017 SDSMA Annual Leadership Conference

238 Physician Burnout is Topic of SDSMA PAC Lunch

Membership Mixer is Networking Opportunity

Join Us for Awards Banquet & Scholarship Recognition

Legal Brief Highlight: Venereal Disease

239 The Issue Is…AMA, Other Organizations Send Letters to Trump & Congressional Leaders

Advertisers In This Issue240 Physician Directory

Office of Publication2600 W. 49th Street, Suite 200Sioux Falls, SD 57105605.336.1965Fax 605.274.3274www.sdsma.org

EditorKeith Hansen, MD

SDSMA PresidentTom Hermann, MD

Chief Executive OfficerBarbara A. Smith

SDSMA Vice PresidentMark East, MS

Staff Editor Elizabeth Reiss, MS–ereiss@sdsma.org, 605.336.1965

Advertising RepresentativeElizabeth Reiss, MS–ereiss@sdsma.org, 605.336.1965

South Dakota Medicine(ISSN 0038-3317)Published 12 times per year with one special issue by the South Dakota StateMedical Association.

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195May 2017

President’s Comments

Thank You By Tom He rmann , MD

SDSMA P r e s i d e n t

As my year representing you as your South DakotaState Medical Association (SDSMA) presidentcomes to a close, many thoughts come to mind of

whom to thank. I want to tell you all what an amazing anddedicated team of leaders you have chosen to work foryou, and yes, I wish to express my appreciation to all ofyou for the honor to serve you this past year.

First of all, I thank my wife, Terry, for her enduring supportand effort to help me time manage and for her remindersto get things done.

A special thanks to our SDSMA staff, and leader, BarbSmith, for doing everything that this special group does.They run our office and guide us in serving physicians,they organize our efforts, and all the memos and commu-nications to stay on top of things – accolades.

To my dedicated Executive Committee team, high fives allaround for participating diligently and thoughtfullyregarding everything that’s needed to guide our associa-tion through the complex matters that invariably comeforward.

Thank you to my clinic and hospital leadership and mypractice partners, for allowing me the time away.

Thank you to my patients and my Sturgis families who letme know how special it was for them to have me representmedicine in our state, and to our University of SouthDakota Sanford School of Medicine leadership and stu-dents who delight and challenge me to be a better teacherand colleague. To our SDSMA past presidents and leader-ship on the Council of Physicians and district medicalsocieties across the state – thank you. Your interest andinput are invaluable regarding our advocacy efforts andthe heart and soul issues surrounding the practice of med-icine going forward. Thank you to our teachers for theirefforts in our medical school and for their support for SouthDakota Medicine as they continue to strive for and produceexcellence in scholarship and guidance to our medicalcommunity.

Thank you to our American Medical Association (AMA)delegates Mary Carpenter, MD, and Rob Allison, MD, fortheir passion and commitment representing us and their

work to guide our students who attend to learn aboutnational advocacy, political issues, and the democraticprocess of our AMA.

This year we have seen the transition of our SDSMA froma guiding ownership interest and role involvingDakotacare to a transition of new ownership by Avera andthe necessary separation of business services and officearrangements long shared between Dakotacare, SDSMA,and the South Dakota Foundation for Medical Care.

Our association’s governance has taken on new bylaws,and this June the Executive Committee will become aboard of directors. Our former Council of Physicians willbecome a Policy Council, responsive to issues and policyguidance, providing quick feedback to our board of direc-tors. This new structure accomplishes and supports themission of our SDSMA. Our membership will see theleadership listening and functioning well on their behalf.I have confidence in our team.

Some of my previous columns have mentioned our “circlesof care being unbroken” and “our cups of medical practicebeing more than half full” as we together strive to adapt tochanges in the future of the business of medicine whilemaintaining the special ideals of the patient-physicianrelationship and the profession of medicine.

We are all honored to serve our patients. As we do so, welikewise honor our teachers and mentors before us. As wecontinue to support our SDSMA, we share a special unityof commitment to the quality of medicine and practice.As such, our AMA and SDSMA House of Medicine seekto include all our specialty societies so important to all ofus for education; shared insights into practice issues; andpolicies facing our practices, clinics and hospital systems.Together we have a stronger voice, and this unity makesour shared advocacy efforts more meaningful and successful. We will not always be right, but as a team wewill listen, strive to get it right, and represent you well.Please continue to support each other as physicians bysupporting your SDSMA.

Thank you again for the privilege to have served you asyour SDSMA president this past year. I know I was justpart of your amazing leadership team.

196

197May 2017

Welcome to this issue of South Dakota Medicine,where we have a number of interesting manuscripts for your review.

Chester B. McVay, MD, developed an open surgical technique for repairing an inguinal hernia which hasbecome one standard method of repairing these hernias.In this issue of the journal, Brendan Feehan, a currentfourth-year University of South Dakota Sanford School ofMedicine (USD SSOM) student, reports on a “laparo-scopic pediatric inguinal hernia repair: overview of ‘trueherniotomy’ technique and review of current evidence,”which was awarded the 2016 South Dakota Chapter of theAmerican College of Surgeons Chester B. McVay, MDAward. Mr. Feehan matched in anesthesiology at theUniversity of Alabama Medical Center in Birmingham.

In this issue, we continue the pharmacogenomic seriesexpertly arranged by Russell A. Wilke, MD, chair of theDepartment of Internal Medicine at the USD SSOM. Dr.Wilke has arranged several fascinating articles exploringthe effects various genes can have on the effectiveness andside effects of different medications. In this issue, WenjieJessie Lu, PhD, and Sreekanth Chavour, MD, explore theimportant area of opioid pharmacogenomics.

Tying in nicely with Lu and Chavours’ manuscript,Timothy Soundy, MD, and co-authors explore the genetics of alcoholism. In this manuscript, the authorsdiscuss the metabolism of alcohol and how genes canaffect this metabolism and potentially increase the risk ofdependence. They discuss major and minor genetic factors as well as interactions with the environment whichmay affect the risk of developing dependence on alcohol.

This issue also has a couple of case reports which areenlightening on superior ophthalmic vein thrombosis andtularemia. Superior ophthalmic vein thrombosis is a rarecondition with significant morbidity. This article reviewsthe management of a case of superior ophthalmic veinthrombosis and discusses the controversy surrounding theneed for anticoagulation. In the case report of an unusual presentation of tularemia, the authors note thatthere has been an increase in the number of cases oftularemia and many of them have atypical presentations.

Editorial

Inguinal and Femoral Hernioplasty:Anatomic Repair1

By K e i t h Han s e n , MDEd i t o r, S o u t h D a k o t a M e d i c i n e

REFERENCES1. McVay CB. Inguinal and femoral hernioplasty: anatomic repair. Arch Surg.

1948;57(4)524-30.2. McVay CB Surgical Anatomy. 6th ed. Philadelphia, Pa WB Saunders Co. 1984.

“We are like dwarfs seated on the shoulders of giants. If we see more and further than they, it is not due to our own clear eyes or tall bodies, but because we are raised on high and upborne by their gigantic bigness.”2

198

One Number Accesses Our Pediatric Surgical Specialists, Any Problem, Anytime.

1.855.850.KIDS (5437) PHYSICIANS’ PRIORITY LINE

Your 24-hour link to pediatric specialists for physician-to-physician consults, referrals, admissions and transport service.

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199May 2017

Point-Counterpoint: Genotype-Guided Opioid Therapy By Wen j i e J e s s i e Lu , PhD ; and S r e ek an th Chavou r, MD

Earlier this year, South Dakota Medicine began publishing a series of monthly articles dedicated toreviewing the pros and cons of gene-based drug

dosing.1 The first article in this series was a point-counter-point by local content experts exploring the utility ofCYP2C19 genotyping for patients taking clopidogrel.2 Wenow present the fifth point-counterpoint article in thisseries – a discussion about CYP2D6 genotyping forpatients taking opioids.

Wenjie Jessie Lu, PhD: “CYP2D6 genotyping reducestherapeutic failure with opioids” Pain medications are among the most commonly prescribedmedications in the United States.3 Despite the commonuse of this important class of drugs, effective pain management is still widely recognized as inadequate inmany settings. Prescription drug misuse and risk for overdose are a concern with all pain medications but particularly with the most potent: the opioid class ofdrugs. Codeine efficacy in particular has wide variabilityacross the general population. This is in part due to thefact that codeine is a prodrug.

The efficacy of codeine is strongly related to the activityof each patient’s liver enzyme CYP2D6. In a person withpoor activity of CYP2D6, not enough codeine is convertedto active drug and therefore codeine will often not work aswell for this person. In a person with very high activity,codeine is converted too rapidly, and that person may beat risk of complications due to overdose. Clinical forms ofopioid toxicity include nausea, vomiting, dry mouth, con-stipation, and respiratory depression. The vast variabilityin patient response to medications makes it challenging todetermine in advance which prescribed medications willactually be effective in any individual.

The trial-and-error approach to opioid prescribing is verycostly and it may put patients at risk for undue sufferingthat results from delays in effective care, inappropriate orunnecessary medication use, and adverse drug reactions.Among the tools available to implement a more

personalized approach that has greater precision, pharmacogenetics has emerged as a practical means ofdetermining interindividual differences in the efficacy andtoxicity of medications that result from inherited geneticvariation in drug-metabolizing enzymes, transporters,receptors, and other drug targets. Genotyping for variationin CYP2D6 holds great promise to reduce therapeutic failure with opioids. The impact of CYP2D6 genotype onseveral opiod analgesics is explored below.

Codeine

Codeine is an opioid with mild to moderate analgesicproperties and mild sedative effects. It also acts centrallyto suppress cough, and as an antidiarrheal, and is widelyused for both. There is substantial evidence linkingCYP2D6 genotype to variability in codeine efficacy andtoxicity, since the analgesic effects of the drug appear to beprimarily mediated by its more potent metabolite, morphine,which is approximately 200 times more potent4 and whoseformation is highly dependent on metabolism byCYP2D6. Individual patients who are poor metabolizers ofCYP2D6 may experience markedly less pain relief whencodeine is used to treat their pain, whereas severe or life-threatening toxicity can occur after normal doses ofcodeine have been administered to ultrarapid metabolizers.A large body of literature has contributed to the ClinicalPharmacogenetics Implementation Consortium (CPIC)guideline for the use of pharmacogenetic testing duringtreatment with codeine.5 Recent data include a populationsimulation of 320,000 individuals in which the dominantrole of CYP2D6 activity in morphine exposure was reproduced.6

Public discussions have focused on the dangers that theultrarapid CYP2D6 genotype poses to children takingcodeine. Codeine-related fatality and severe respiratorydepression cases were reported after tonsillectomy in chil-dren who were later identified to be rapid metabolizers. Asa result, the Food and Drug Administration announced itsstrongest and new black box warning against codeine use

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to manage postoperative pain in children following tonsillectomy. The codeine product label also informspatients about the increased risk of morphine overdose inbreastfed infants whose mothers are taking codeine andare ultrarapid metabolizers. Multiple genes in the pathways of drug absorption, distribution, metabolism,and elimination may impact tissue drug levels. One studyfound that genetic testing for CYP2D6 and ABCB1 (anATP cassette binding protein that acts as a tissue specifictransporter) predict 81 percent of the cases of codeine-induced CNS depression in breastfed infants and theirmothers. When genetic testing was combined with clinical factors, the accuracy rose to 87 percent with a sensitivity of 80 percent and a specificity of 87 percent.7

Tramadol

Tramadol is a narcotic analgesic indicated for the treatmentof moderate to severe pain. It is widely used to treat postoperative, dental, cancer, and acute musculoskeletalpain and as an adjuvant to other nonsteroidal anti-inflam-matory drugs in patients with osteoarthritis. Like codeine,tramadol is metabolized by CYP2D6 to an active metabolite, (-)-O-desmethyl-tramadol that contributesimportantly to its action.8 More than a dozen studies haveconsistently shown a positive association between tramadol pharmacokinetics and CYP2D6 genotype. A totalof nine studies in 978 patients documented tramadol-induced changes in either pupillary miosis, efficacy oradverse effects, all associated with CYP2D6 genotype. Thedata available indicate that patients who carry poormetabolizer genotypes have a four-fold lower response rateto tramadol, and lower adverse effects.9 Therefore, a largenumber of opiate analgesics are available to patients asalternatives to tramadol if CYP2D6 genotype indicates alow chance of response.

Hydrocodone

Hydrocodone is metabolized to hydromorphone byCYP2D6 enzymes, and hydromorphone has a 10- to 33-fold greater affinity for binding to �-opioid receptors thanhydrocodone.10 Pain relief has been correlated with plasmaconcentrations of hydromorphone in these patients, andnot with hydrocodone.11 In a CYP2D6 poor metabolizer,hydrocodone may not be effectively metabolized intohydromorphone, and therefore the patient may havealtered analgesic response.

In summary, pharmacogenetic testing may help optimizethe choice of effective opioid analgesics while minimizingside effects. The availability of CYP2D6 genotyping makes

it clear that there are few practical impediments to obtaining testing: the challenge therefore is how to bestuse the available tools to improve pain control. As alreadydiscussed, CPIC released guidelines on codeine use basedon CYP2D6 genotype test results, along with theCanadian Pharmacogenomics Network for Drug Safety.5,12

The Pharmacogenetics Working Group of the RoyalDutch Association for the Advancement of Pharmacy hasalso established gene-based therapeutic (dose) recommen-dations for 53 medications, including codeine, oxycodone,and tramadol.13 Organized and consistent pharmacogenetictesting may become more widely adopted in clinical painmanagement given the recent publication of guidelines onthis topic.

Sreekanth Chavour, MD: “Genotype has a limited rolein guiding opioid therapy”

As noted by Wenjie Jessie Lu, PhD, gene-based drug selection may enhance our ability to prescribe medicationsmore safely.1 However, the utility of this approach variesfrom one drug class to another.2,14 Opioid analgesics arecommonly used in routine medical practice, and opioidefficacy is highly variable, making this class of drugs anattractive target for exploring the potential utility of gene-based dosing strategies.

The liver enzyme CYP2D6 helps convert codeine and tramadol to more potent metabolites morphine and O-desmethyltramadol.15 The impact of CYP2D6 on otheropioids varies drug by drug, with CYP2D6 having littledirect effect on hydromorphone and fentanyl.

The idea that, if we know each patient’s “activity level”ahead of time, we can make predictions about opioidselection that will improve pain control and avoid toxicity seems intriguing. While this idea sounds simple,there are many things that need to be considered beforewe can put this principle to practical use. Several challenges are outlined below.

Issue # 1: Genetic complexity

More than 100 alleles (alleles are variants of enzymes) forCYP2D6 have been identified by genetic testing.Phenotype (how the person actually responds if he/she hasthese alleles) has not been fully characterized for all thesegenotypes. Most of the information that we get fromassessing and evaluating the genetic tests is predicted bymodels/theories. Further, there have been no randomizedcontrolled trials to prospectively assess the strength of thisrelationship.

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201May 2017

Issue # 2: Phenotypic diversityBased on the activity of the CYP2D6 enzyme, people canbe classified as “poor metabolizers” (activity level 0),intermediate metabolizers (activity level 0.5), extensivemetabolizers (activity level 1-2) and ultra-rapid metabolizers(activity level greater than 2). The percentage of poormetabolizers in the general population is anywhere from 0to 10 percent and ultra-rapid metabolizers are 0 to 29 percent. Therefore, 60 percent of the general population(intermediate and extensive metabolizers) may not benefit from this testing.10,15 Further, activity ofcytochrome P 450 enzymes in general can be increased ordecreased by other medications that the person might betaking. For instance, if an intrinsic ultra-rapid metabolizerof CYP2D6 (with an activity level of enzyme greater than2) is taking other medications that inhibit the activity ofthe enzyme then the enzyme activity score would decreasefrom greater than 2 to less than 2, depending on thedegree of inhibition is (strong versus moderate versus weakinhibition of the enzyme) and how many other medications he/she is taking which have similar effect onthe enzyme. Thus, there is a dynamic interaction betweenthe genetic blueprint and the phenotype, and this interaction can make it difficult to interpret the geneticinformation.16

Issue # 3: Bioinformatic issuesUnlike some laboratory test results that we routinelyorder, genetic test results can impact decision making fora patient many years later. These results need to be reportedaccurately and placed in a person’s chart in a way thatfacilitates easy access to the information. For most practices,electronic medical records are not yet equipped to facilitatesuch a process longitudinally. At present, providers wouldhave to dig in the chart to find genetic results and thencross check all of the patient’s medications before they initiate a prescription or facilitate further medication reconciliation. In a health care system where time spentwith a provider is at a premium, and waiting lists to see aprovider are getting longer and longer, this seems impractical.

Overall, the idea that genetic testing can be used to guideopioid therapy is exciting, but given our limited knowledgeabout how best to interpret and use these results, manyremaining obstacles make gene-based opioid selection andgene-based opioid dosing quite challenging. Given theburgeoning cost of health care, and current lack of clarityabout insurance coverage regarding this approach, gene-based opioid selection does not seem like an optimal

approach at this point of time. Using pharmacogenetictests to make routine health care decisions is less appealingfor opioids than for some other agents. The old adage“start low and go slow” still seems to be the most economical and the most practical way to prescribe opioids at this time.

REFERENCES1. Wilke RA. Genes that predict drug response. SD Med. 2017;70(1):13.2. Larson EA, Miller NJ. Point-counterpoint: CYP2C19 genotyping for clopidogrel.

SD Med. 2017;70(1):13-5.3. IMS Institute for Healthcare Informatics. Medicine use and shifting costs of

healthcare: a review of the use of medicines in the United States in 2013. April 2014.

4. Mignat C, Wille U, Ziegler A. Affinity profiles of morphine, codeine, dihydrocodeine and their glucuronides at opioid receptor subtypes. Life Sci. 1995;56(10):793-9.

5. Crews KR, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC)guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6)genotype. Clin Pharmacol Ther. 2012;91(2):321-6.

6. Eissing T, et al. Pharmacogenomics of codeine, morphine, and morphine-6-glucuronide: model-based analysis of the influence of CYP2D6 activity, UGT2B7activity, renal impairment, and CYP3A4 inhibition. Mol Diagn Ther. 2012;Feb1;16(1):43-53.

7. Sistonen J, et al. Prediction of codeine toxicity in infants and their mothers usinga novel combination of maternal genetic markers. Clin Pharmacol Ther. 2012Apr;91(4):692-9.

8. Dayer P, Desmeules J, Collart L. [Pharmacology of tramadol]. Drugs, 1997;53Suppl 2:18-24.

9. Stamer UM, et al. Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacol Ther. 2007Jul;82(1):41-7.

10. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical PharmacogeneticsImplementation Consortium guidelines for cytochrome P450 2D6 genotype andcodeine therapy: 2014 update. Clin Pharmacol Ther. Apr 2014;95(4):376-82.

11. Stauble ME, Moore AW, Langman LJ, et al. Hydrocodone in postoperative personalized pain management: pro-drug or drug? Clin Chim Acta. 2014;429:26-9.

12. Madadi P, Amstutz U, Rieder M, et al. Clinical practice guideline: CYP2D6 genotyping for safe and efficacious codeine therapy. J Popul Ther Clin Pharmacol.2013;20(3):e369-96.

13. Swen JJ, et al. Pharmacogenetics: from bench to byte--an update of guidelines.Clin Pharmacol Ther. 2011 May;89(5):662-73.

14. Lu WJ, Miller NJ. Point-counterpoint: genotype-guided warfarin therapy. SD Med.2017;70(2):54-6.

15. Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. TheCYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin. Pharmacol. Ther. 2008;83:234-42.

16. Eckhardt K, Li S, Ammon S, Schänzle G, Mikus G, Eichelbaum M. Same incidenceof adverse drug events after codeine administration irrespective of the geneticallydetermined differences in morphine formation. Pain. 1998;76:27-33.

About the Authors:Wenjie Jessie Lu, PhD, Department of Internal Medicine, University of South DakotaSanford School of Medicine.Sreekanth Chavour, MD, Department of General Internal Medicine, Sanford Health,Fargo, North Dakota.

Journal

IntroductionIsolated orbital vein thrombosis is a rare disease that canresult in significant morbidity and mortality. Most morbidity and mortality arises due to the involvement ofthe cavernous sinus. Cavernous sinus thrombosis (CST)can result in significant consequences such as residual cranial nerve weakness and blindness.1 The role of antico-agulation in the treatment of CST is controversial butappears to reduce morbidity if initiated early.2 The role ofanticoagulation in isolated orbital vein thrombosis is notclear. In this article, we present a case of isolated orbitalvein thrombosis and review the evidence for and againstanticoagulation.

Case ReportAn 88-year-old patient presented to their local hospitalwith a one-week history of intractable headache, nausea,vomiting, and failure to thrive. The headache wasdescribed as a 10/10 in severity and involved the left

frontal area. They also noted fevers. They denied any history of cough or sore throat but complained of sinusdrainage and left posterior neck and ear pain. The patientwas afebrile, but upon examination, it was noticed thatthe left eye was edematous and erythematous, with matting of the eyelids. There was also injection of the leftconjunctiva. Visual acuity was recorded as intact, withpupils equal and reactive to light and accommodation andextraocular muscles displaying the full range of movement.The patient’s neck was supple, with tenderness to palpa-tion over the posterior musculature of the cervical spine.No focal neurological deficits were noted. Laboratoryevaluation demonstrated a leukocytosis (15.7 K/uL) witha left shift, and blood cultures were drawn. The compre-hensive metabolic panel was normal. A computed tomog-raphy scan of the brain showed no signs of a mass, acutebleeding, or stroke. There was, however, evidence of acuteon chronic right sphenoid sinusitis. The patient wasadmitted to the hospital due to hypovolumeia and for

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Superior Ophthalmic Vein Thrombosis: The Role of Anticoagulation By S amue l Thomsen , MD ; E r i c L a r s on , MD ; and M i cha e l G r e enwood , MD

Abstract

Purpose: To report a case of superior ophthalmic vein thrombosis (SOVT) and review the available literature toassess if anticoagulation is warranted in all cases of SOVT.

Observations: The patient presented to an outside hospital facility with a severe headache involving the leftfrontal temporal area. This progressed to left-sided ptosis and facial droop. Magnetic resonance imaging revealeda left SOVT secondary to sphenoid sinusitis. Treatment was initiated with vancomycin and cefepime, and thepatient was transferred to our tertiary care center for further management. Upon arrival at our facility, her symp-toms had significantly improved compared to prior documented findings.

Conclusions and Importance: Due to the rarity of SOVT, large clinical studies assessing the necessity of anticoag-ulation are not likely to be conducted. A review of the literature suggests the use of anticoagulation is deter-mined on a case-by-case basis, taking into account symptom severity. Our case demonstrates that a resolution ofsymptoms is possible without anticoagulation. The decision to initiate anticoagulation will continue to requirea clinician to perform a detailed physical examination to determine if the patient is responding to antibiotictreatment alone.

treatment of sinusitis. Empiric ceftriaxone was initiatedfor the sinusitis, and tobramycin eye drops were startedwith warm compresses for the left eye conjunctivitis.

Over the next day, the patient’s headache and leukocytosisresolved. However, the patient developed a left eye ptosisand left facial droop. Magnetic resonance imaging (MRI)was performed and revealed acute on chronic sphenoidalsinusitis, meningitis, and left superior ophthalmic veinthrombosis with extension to the left cavernous sinus(Figure 1). The MRI findings raised questions of a fungaletiology for the sinusitis due to the subtle, bony destructionof the basisphenoid bone. A lumbar puncture was performed but was negative for meningitis. Vancomycinwas initiated, and the ceftriaxone was switched tocefepime for Pseudomonas coverage. The patient was thentransferred to our facility due to the possibility of cavernous sinus thrombosis and the need for coordinatedcare from various specialties.

Upon presentation to our hospital, the patient hadmarked improvement compared to prior documented findings. An ophthalmologic examination showed thepatient’s visual acuity was 20/100 in the right eye and20/30 in the left eye. Pupils were equally round and reactive to light without a relative afferent pupillarydefect. Intraocular pressure was 14 in the right eye and 13in the left eye as measured with Tono-Pen tonometry.Confrontational visual fields were full, and the patient wasable to count fingers with both eyes. Extraocular movements in both eyes were full without pain. An external examination revealed normal eyelids and eyelashes. The anterior segment exam of both eyes showed

the following: the conjunctivae and sclera were white; the anterior chambers were deep without signs of inflam-mation; the corneas were clear; and both irises were flatwith no evidence of neovascularization. There was thepresence of age-appropriate cataracts in both eyes. A funduscopic examination showed a normal optic nervewith a normal cup-to-disc ratio in the right eye and somepallor of the left optic nerve with a normal cup-to-discratio. Blood vessels in both eyes appeared normal. In addition to these findings, dry age-related macular degeneration was noted to be greater in the right eye thanthe left, which likely represents the decreased visual acuity noted above.

Vancomycin and cefepime were continued, and metron-idazole was added for anaerobic coverage. The patientcontinued to improve dramatically, and this was attributedto the empiric antibiotic therapy. MRI results werereviewed again, and this confirmed the findings of thrombosis of the left superior ophthalmic vein, but thefindings of left cavernous sinus thrombosis were equivocal.Therefore, with the patient’s dramatic improvement inclinical status, combined with imaging being not definitive for the diagnosis of cavernous sinus thrombosis,anticoagulation was held.

A bilateral sphenoidectomy with cultures was performedto rule out a fungal etiology. The bilateral nares culturesgrew Penicillium species. An infection with this species isusually opportunistic and only impacts people infectedwith human immunodeficiency virus (HIV). Because ourpatient tested negative for HIV and improved significantlywith therapy, the antifungal treatment was not added. An

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Figure 1. T1 and T2 axial images showing hypointensity and dilatation (arrow) involving the left superior ophthalmic vein (A and B).T1 coronal fat suppressed with contrast image showing filling defect (arrow) of the left superior ophthalmic vein (C).

aerobic culture from the left nares did have light growth of Cornybacterium jeikeium, which tends to cause opportunistic infections in bone marrow transplantpatients. However, no adjustment of therapy was requiredsince it was susceptible to vancomycin. All blood cultureswere negative.

The patient had complete resolution of the left eye edemaand erythema. The left eye vision remained stable at20/30. They were discharged to a long-term care facilitywith plans to continue treatment with vancomycin,cefepime, and metronidazole for a total of six weeks.

DiscussionTreatment of superior ophthalmic vein thrombosis(SOVT) is guided by physician experience and judgment,as large-scale studies have not been done and are notforthcoming due to the condition’s rarity. In the case ofSOVT secondary to infection, the rationale for anticoagulation is clear and involves clot stabilization andcanalization of the thrombus, facilitating the penetrationof antibiotics into the infected clot. It is also surmised thatanticoagulation may prevent extension to CST.3 However,due to the rarity of SOVT, use of anticoagulation is stilldebated because though it may prevent extension to CST,there is the possibility of it causing septic emboli or hemorrhage.4 If treatment recommendations for CST canbe extrapolated for SOVT, then it is reasonable to base theuse of anticoagulation on a patient’s response to initialmedical management.3 If the patient is improving and notshowing decreases in visual acuity, proptosis, focal neurological deficits, or other signs of extension into thecavernous sinus, anticoagulation can be held. However, ifthe patient is not responding to therapy and havingincreased deficits attributable to SOVT, it may be reason-able to initiate anticoagulation after a risk-benefit analysishas been reviewed with the patient.5 If there are no con-traindications to anticoagulation and the clinical settingsuggests that further intervention is needed, it should beinitiated within seven days of diagnosis. Early anticoagu-lation combined with antibiotics compared to late antico-agulation with antibiotics appears to be more effective indecreasing morbidity.4,6 In conclusion, the decision ofwhether or not to anticoagulate patients with SOVT willcontinue to be based on a patient’s clinical course and thephysicians’ experience and judgment due to the lack ofevidence-based approaches.

Acknowledgements: We thank Catherine Hensley for editing assistance.

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REFERENCES1. Southwick FS, Richardson EP, Swartz MN. Septic thrombosis of the venous dural

sinuses. Medicine (Baltimore). 1986;6582-106.2. Ebright JR, Pace MT, Niazi AF. Septic thrombosis of cavernous sinus. Arch Intern

Med. 2001;161(22):2671-6.3. Kumar JB, Colon-Acevedo B, Liss J, Fekrat S, Scott I. Diagnosis and management

of superior ophthalmic vein thrombosis. EyeNet. 2015;19(5):35-6.4. Desa V, Green R. Cavernous sinus thrombosis: current therapy. Journal of Oral

and Maxillofacial Surgery. 2012;70(9):2085-91.5. Lim LH, Scawn RL, Whipple KM, Oh SR, Lucarelli MJ, Korn BS, Kikkawa DO.

Spontaneous superior ophthalmic vein thrombosis: a rare entity with potentiallydevastating consequences. Eye. 2014;28(3):348-51.

6. Cumurcu T, Demirel S, Keser S, Bulut T, Cavdar M, Dogan M, Sarac K. Superiorophthalmic vein thrombosis developed after orbital cellulitis. Semin Ophthalmol.2013;28(2):58-60.

About the Authors:Samuel Thomsen, MD, University of South Dakota Sanford School of Medicine.Eric Larson, MD, University of South Dakota Sanford School of Medicine.Michael Greenwood, MD, Vance Thompson Vision, Sioux Falls, South Dakota.

206

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207May 2017

Journal

Atypical Presentations of Tularemia By Ka r ah Odeg a a r d , MS IV; K i r s t i n Hockhau s en , MS IV;

B e th Boe r sma , LPN , C IC ; and J ame s M . Ke e g an , MD

AbstractFrancisella tularensis is a gram-negative coccobacillus that causes a condition commonly referred to as tularemia.There has been a dramatic increase in tularemia cases reported in South Dakota, many of which were challenging to diagnose due to atypical clinical manifestations. We describe an interesting case of pneumonictularemia and summarize six similar cases, several of which presented with lung nodules suggestive of malignancy. According to the literature, this is only the third outbreak of pneumonic tularemia reported in theU.S. We believe it is important for clinicians to be aware of the increased incidence of tularemia in the area andto be vigilant in the diagnosis and management of these atypically presenting cases.

IntroductionFrancisella tularensis is a gram-negative coccobacillus thatcauses a condition commonly referred to as tularemia.Although tularemia is seen throughout the world, it ismost prevalent in the Northern Hemisphere.1 Flea andtick bites and exposure to rabbits, cats, rodents or contaminated animal products are common modes oftransmission. The majority of tularemia cases in the U.S.occur in Arkansas, Kansas, South Dakota, Missouri,Nebraska, and Oklahoma.2 There has been a dramaticincrease in tularemia cases reported in South Dakota,shifting from an average of seven cases per year over thelast five years to a reported 25 cases in 2015.3 There has notbeen an outbreak like this in South Dakota since 1984,when Lower Brule and Crow Creek Indian reservationsendured an outbreak of tick-borne tularemia.4

Tularemia classically presents with a sudden onset of fever,chills, headache, malaise, anorexia, and fatigue, and isoften accompanied by cough, myalgia, chest discomfort,vomiting, sore throat, abdominal pain, and diarrhea.Patients with tularemia typically have a fever greater than101 degrees Fahrenheit that lasts for several days.1 Thefever often diminishes for a short time and later returns asthe disease progresses. There are several presentations oftularemia, the most common being ulceroglandulartularemia.1 This is the most easily recognized form as it

initially presents with localized, tender lymphadenopathyand a red, painful papule that develops into a tender ulcerwith a raised border.

Another presentation of tularemia, pneumonic tularemia,is only seen in 7 to 20 percent of cases and is characterizedby fever, cough, minimal sputum production, pleuriticchest pain and pulmonary infection.1 Of the eight casestreated at Rapid City Regional Hospital, seven of thepatients presented with pneumonic tularemia. Atypicalclinical manifestations made these cases difficult to diagnose, thereby making treatment decisions more challenging. It is important that clinicians be aware of theincreasing prevalence of this disease and recognize thepossibility of tularemia in patients with abnormal respiratory findings.

Case ReportA 58-year-old Caucasian male with a previous history ofsquamous cell carcinoma of the vocal cords presented toan emergency department in Wyoming with symptoms ofgeneralized ache, malaise, cough with production of grey-brown sputum, and fever with sweating and chills.He also complained of new onset pleuritic chest pain. Hewas prescribed amoxicillin-clavulanate, but showed noimprovement in symptoms over the following five days.The patient recalled recent exposure to many old,deceased rabbits while working in a field and also

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sustained multiple insect bites during this time.

On the sixth day of symptoms, the patient was transferredto Rapid City Regional Hospital. At this time, he wasfound to have a temperature of 37 degrees Celsius, pulse of77 beats per minute, respiratory rate of 16 breaths perminute, blood pressure of 126/72 mmHg, and pulse oximetry of 94 percent. Physical exam revealed occasionalrespiratory crackles and an absence of adenopathy. Hislaboratory studies showed a leukocyte count of 10,100/mL(4,500-10,500/mL) and a normal white cell count differential. The patient was also noted to have abnormalliver function tests, including aspartate aminotransferaselevel 112 IU/L (normal range of 0-37 IU/L), alanineaminotransferase 198 IU/L (normal range of <78 IU/L),and alkaline phosphatase 258 IU/L (normal range of 55-142 IU/L). The patient was also nonreactive to hepatitis B surface antigen, hepatitis B core antibody andhepatitis C antibody.

The chest radiograph on initial presentation in Wyomingwas negative. However, a computed tomography angiogra-phy of the chest obtained to rule out a pulmonaryembolism revealed a spiculated, 2.5 x 2 cm nodule and asmaller, nonspecific density, both located in the left lowerlobe with hilar lymphadenopathy. These findings weresuspicious for malignancy. A CT-guided biopsy was performed. Histology from the larger nodule showedinflammation, necrosis, fibrin without granulomatous tissue, and reactive pneumocytes. Special staining did notreveal fungi or acid-fast organisms. Blood cultures were

negative, however lung tissue grew gram-negative coccobacilli. The patient was started on antibiotic therapy with intravenous gentamicin and ceftriaxone.The culture was sent to the South Dakota Department ofHealth and confirmed as Francisella tularensis. On thesixth day of the gentamicin therapy, the patient felt hisbreathing had improved and the pleuritic chest painrelieved. He was discharged with a plan to finish a 10-daycourse of gentamicin, followed by a two-week course oforal ciprofloxacin.

As previously stated, there were multiple cases of pneumonic tularemia treated at Rapid City RegionalHospital in 2015, which were similar to the case presented.All cases, including the case report (Case 1), are summarizedin Table 1. Most of these cases presented with the classicfindings of pneumonic tularemia including fever, cough,and pleuritic chest pain. They also had the classic radiographic findings of pleural effusions, subsegmental orlobar infiltrates and hilar lymphadenopathy. However, asseen in Table 1, five patients also presented with pulmonarymasses or nodules, which raised suspicion for malignancyas opposed to an infectious process. Diagnosis was made inall cases either by pleural fluid culture, lung tissue biopsyand culture, or blood cultures. Upon diagnosis, patientswere treated with either single or combination antibiotictherapy with ciprofloxacin, gentamicin, or doxycyclineand all had positive outcomes.

For all cases of pneumonic tularemia, patient exposure history was obtained and is reviewed in Table 2.

Table 1. Comparison of Clinical Presentation, Pulmonary Radiographic Findings, Diagnostic Method and Treatment

DiscussionAccording to the literature, this is only the third outbreakof pneumonic tularemia reported in the U.S., with theprevious outbreaks both occurring in Massachusetts onMartha’s Vineyard in the years 1978 and 2000.5 ThoughSouth Dakota did have an outbreak in 1984 with 20 definite and eight probable cases reported, the clinicalpresentation suggested a glandular type of tularemia, withticks as the primary vector.4 Of the eight cases seen in2015, seven have been characterized as the pneumonictype. Though two cases had sustained insect bites, nonespecified any history of tick exposure. However, four casesreported prior exposure to cats, two to rabbits, and one torodents, as seen in Table 2. Three patients also stated thatthey mow their own lawns. The outbreak of primary pneumonic tularemia in Martha’s Vineyard revealed common exposures of lawn-mowing and brush-cutting asrisk factors for development of the infection.5 Without significant evidence supporting vector transmission inthese cases of pneumonic tularemia, this raises the question of possible transmission through a respiratoryroute and suggests that aerosolization of the bacteria couldbe a potential risk factor in the environment, though person-to-person transmission is not well-documented.5,7

Classically, pneumonic tularemia presents with pleuraleffusions, subsegmental or lobar infiltrates, and hilar lymphadenopathy.1 Though six cases did present withthese particular findings, there were four cases that alsorevealed lung nodules or masses and one case that presentedwith only a pulmonary nodule, all of which were concerningfor the possibility of malignancy (see Table 1). One ofthese cases had a 15-mm nodule in the left upper lobe withno other pulmonary findings. Lung biopsies were performedon four of the cases that presented with lung nodules ormasses to rule out malignancy. Culturing of these biopsiesled to the positive diagnosis of F. tularensis in three of thefour cases. Three cases were identified as tularemia viapleural fluid culture confirmed by direct fluorescence antibody testing and one case was found to have a positiveblood culture.

All seven of the pneumonic cases were treated as eithercommunity-acquired or hospital-acquired pneumonias,but did not respond to common antimicrobials such as ceftriaxone, vancomycin, azithromycin, piperacillin-tazobactam, ampicillin-sulbactam, ceftazadime, and nafcillin. Because patients did not respond to the typicaltreatments of pneumonia, they were started on less commonempiric therapies including acyclovir, amoxicillin-clavulanate, and metronidazole. Three of the sevenpatients were also considered immunocompromised at thetime of presentation, which may have also influencedtheir initial treatment. Each patient was placed on at leastone antimicrobial prior to their diagnosis of tularemia,with an average of 3.75 antimicrobials used before initiating tularemia-specific therapy. This ultimatelydelayed targeted treatment as these patients spent time inthe hospital on other antimicrobials prior to startingeither individual or combination therapy with gentamicin,ciprofloxacin, or doxycycline, the recommended antibioticsfor tularemia. All patients had good outcomes, as theyreceived appropriate treatment. However, in the pre-antibiotic era, the mortality rate was as high as 60 percent,compared to the current national mortality rate of lessthan 2 percent.6,7 Due to the difficulty of diagnosis of thiscondition, there were likely more cases of tularemia notidentified. Early clinical suspicion is critical, especially forthe protection of our laboratory workers who have a highrisk of tularemia exposure from processing of laboratoryspecimens. Therefore, we believe that awareness to theseatypical presentations and the increasing incidence ofpneumonic tularemia in South Dakota is important forclinicians to consider in order to avoid delayed diagnosisand treatment.

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Table 2. Comparison of Known Patient Exposures

Journal

REFERENCES1. Penn RL. Francisella tularensis (tularemia) [Chapter 224]. In: Bennett JE, Dolin R,

Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice ofInfectious Disease. 3rd ed. Philadelphia, PA: Elsevier Churchill Livingston; 2005.

2. Centers for Disease Control and Prevention. Surveillance reported cases by state– tularemia, 2004-2013. Statistics. 2014.

3. South Dakota Department of Health. (2015) South Dakota infectious disease summary 2015. Retrieved from www.doh.sd.gov/documents/statistics/ID/HealthDiseaseSummaryAug2015.pdf.

4. Markowitz LE, Hynes NA, de la Cruz P, Campos E, Barbaree JM, Plikaytis BD, etal. Tick-borne tularemia: an outbreak of lymphadenopathy in children. JAMA.1985;254(20):2922-5.

About the Authors:Karah Odegaard, MSIV, University of South Dakota Sanford School of Medicine.Kirstin Hockhausen, MSIV; University of South Dakota Sanford School of Medicine.Beth Boersma, LPN, CIC, Department of Infection Control, Rapid City RegionalHospital, Rapid City, South Dakota.James Keegan MD, Clinical Associate Professor University of South Dakota SanfordSchool of Medicine; Infectious Diseases, Rapid City, South Dakota.

Please note: Due to limited space, we are unable to list all references. You may contact South Dakota Medicine at 605.336.1965 for a complete listing.

211May 2017

Pre-Guideline Trends Associated with ChestRadiograph Usage for Pediatric Community-AcquiredPneumonia in Emergency Department SettingsBy E r i c W. J o n e s , MS IV; B en j am i n Me y e r, MD ; Aa r on M . B e r g , MD ;

B en s on S . H s u , MD , MBA

Introduction

U.S. health care costs totaled $3 trillion in 2014, accountingfor 17.5 percent of the overall U.S. economy.1 Reducinghealth care cost is essential for long-term sustainability. It has been estimated that 30 percent of health care spending in 2009 was wasted on unnecessary medical services.2 Decreasing unnecessary services reduces spendingwithout compromising patient care.

Pneumonia is a leading cause of hospitalization in children,and currently available diagnostic studies are relativelyinsensitive.3 Specifically, chest radiograph has been shown

not to improve clinical outcome in an ambulatory setting,yet approximately $189-496 million each year is spent onchest X-ray (CXR) for diagnosis of community-acquiredpneumonia (CAP) in an outpatient setting.4,5,6 Moreover,substantial disagreement exists in the interpretation ofCXR to diagnose CAP,7 suggesting that it is an unreliablediagnostic tool.

Given the cost of CXR and inconsistency of evidence todemonstrate improved outcomes, the use of CXR is apromising area for the application of clinical guidelinesaimed to encourage consistency and reduce unnecessarycost. In 2011, the Infectious Disease Society of America

Journal

AbstractBackground: Health care spending in the U.S. totaled $3 trillion in 2014 and continues to increase rapidly.Minimizing waste through clinical guidelines is a promising strategy to reduce spending without compromisingpatient care. In 2011, clinical guidelines recommended against the use of chest X-ray (CXR) for diagnosis ofcommunity-acquired pneumonia (CAP) in pediatric ambulatory settings. However, use of CXR has not changedpost-guideline. Thus, understanding the drivers of CXR utilization prior to guideline implementation couldimprove guideline adherence.

Methods: Retrospective study using 2009 Nationwide Emergency Department Sample data set consisting of arepresentative sample of all emergency room admissions. Inclusion criteria consisted of: 18 years of age oryounger and the diagnosis of outpatient CAP. Population was segmented by the presence of a CXR obtained during the visit. Socioeconomic status was determined by quartile classification of the estimated median household income based on patient ZIP code.

Results: In 2009, children living in wealthier ZIP codes presenting to the emergency department (ED) who werediagnosed with CAP were more likely to receive diagnostic CXR. The use of chest radiograph was not statistically correlated to gender, weekday versus weekend admission, number of diagnoses at discharge, or totalED charges.

Conclusion: The research demonstrates a strong correlation between socioeconomic status of the pediatricpatient and use of chest radiograph for CAP in the ED setting prior to 2011 guideline publication. Furtherresearch to determine the reason for this correlation could give rise to focused efforts to successfully encourageadherence to clinical practice guidelines.

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(IDSA) along with the Pediatric Infectious DiseaseSociety (PIDS) published guidelines for the managementof CAP for infants and children older than 3 months ofage.8 According to guidelines, CXR is not necessary toconfirm CAP in an ambulatory child who is otherwisehealthy. Instead, CXR is recommended for patients withhypoxemia, significant respiratory distress, or after failedantibiotic treatment to confirm the presence or absence ofcomplications such as parapneumonic effusions, necrotizingpneumonia, or pneumothorax.

Despite consensus among experts on best practice, implementation of these guidelines was not successful inchanging physician behavior. 9 Before guideline imple-mentation, no studies were published to determine groupsof children who receive CXR most often. Given the difficulty of producing clinical guidelines effective inchanging physician behavior, more information on pre-publication trends and patterns of behavior wouldprovide useful insight to tailor implementation plans.While these patterns may not describe reasons why emergency department (ED) physicians make decisions,they can provide useful insight into how to better encourage adherence to the published guidelines. Thepurpose of this study is to examine pre-publication trendsin physician practice in the setting of pediatric outpatientpneumonia in order to identify patterns correlated withnon-adherence to clinical guidelines with the hope thatthis knowledge may provide insight and direction intosuccessfully encouraging adoption of clinical guidelines.

MethodsStudy Design and Data Source

We performed a retrospective study of hospitalized children utilizing the 2009 Nationwide EmergencyDepartment Sample (NEDS), a part of the HealthcareCost and Utilization Project sponsored by the Agency forHealthcare Research and Quality (AHRQ). This data setis available every three years with the 2009 sample beingthe most recent data set available prior to the implemen-tation of the new IDSA/PIDS consensus guideline on themanagement of pediatric CAP.

Due to the de-identified nature of the patient data, theproject received exempt status from the institutionalreview boards of Sanford Health and University of SouthDakota Sanford School of Medicine.

Case Definitions

Patients 18 years or younger with CAP were identified

through the use of a previously validated InternationalClassification of Disease, Ninth Revision, ClinicalModification (ICD-9-CM) algorithm.10,11 Patients wereidentified with CAP if they had a primary ICD-9-CMdiagnosis of pneumonia (480-483 and 485-486) or a primary diagnosis of a pneumonia-related symptom suchas fever or cough (780.6, 786.0, 786.2-5, 786.7) and a secondary ICD-9-CM diagnosis of pneumonia, empyema(510), or pleurisy (511.0-1 and 511.9). Outpatient statuswas based on discharge from facility following treatment.All outpatients 18 years or younger with a diagnosis ofCAP in the emergency setting identified by this algorithmmet the inclusion criteria. All others were excluded.

Socioeconomic status was determined by a quartile classification of the estimated median household incomeof residents in the patient’s ZIP code as provided byAHRQ. In 2009, the quartile ranges were: $1-$39,999,$40,000-$49,999, $50,000-$65,999, and $66,000+.Descriptive characteristics evaluated include the patients’age and gender, whether or not the hospitalization wasweekend versus weekday, number of diagnoses at discharge, and total ED charges.

Statistical Analysis

All statistical analyses were conducted using STATA/IC12.1 (Stata Corporation, College Station, Texas). Giventhe complex sampling of survey data present in KID, weutilized the weighted analysis function (“syv” command)in STATA/IC to determine the mean and 95 percent confidence intervals. Tests to compare the mean valueswere performed using the adjusted Wald test. All valuespresented are based on weighted analysis. Statistical significance was established at p value <0.05.

ResultsThere were 99,814 observations in the sample populationmeeting the criteria of CAP within NEDS. These observations represented an overall population of445,078. Overall demographics showed that 45 percent ofthe population received CXR while 55 percent of the population did not. There was little difference noted inage or gender. Clinically, the two populations did not differ in the number of diagnosis at discharge or whetherthe ED visit occurred on a weekend (Table 1).

From a view of charges, total charges were higher for thosewho did not receive a CXR at $1,516 (95 percent confidence interval of $1,500 to $1,532) versus those whoreceived a CXR at $1,498 (95 percent confidence interval

of $1,486 to $1,510). This was not statistically significantwith the p value being 0.08.

In respect to socioeconomic status, pediatric patients living in ZIP codes with the lowest estimated medianhousehold income quartile were the least likely to receiveCXR for a diagnosis of community-acquired pneumoniawhile pediatric patients living in ZIP codes with the highest estimated median household income quartile were

the most likely to receive CXR for a diagnosis of CAP(Figure 1).

DiscussionIn 2009, children living in wealthier ZIP codes presentingto the ED who were diagnosed with CAP and dischargedhome were more likely to receive diagnostic CXR thantheir less wealthy peers. The use of chest radiograph didnot correlate with statistically different total ED charges,

gender, weekday versus weekend, or number of diagnoses at discharge.

Health care costs are currently a major concern inthe U.S., and minimizing waste is a promising strategy to reduce spending without compromisingpatient care. Clinical guidelines which achieve thispurpose in the setting pediatric CAP were publishedin 2011. These guidelines discourage the use of CXRfor diagnosis of CAP in ambulatory children on thebasis that CXR has been shown not to improvepatient outcome and has been shown to be an unreliable diagnostic tool. Eliminating CXR usagefor children who are treated outpatient for CAPcould potentially save hundreds of millions of dollars each year in the U.S.

Despite expert guidelines discouraging use of CXR fordiagnosis of CAP in an ambulatory patient, studies havenot shown a resultant change in physician practice. Arecently published study examined pediatric patients witha diagnosis of CAP who were discharged from the ED in asample of children’s hospitals. This study demonstratedthat the rate of CXR usage over the years 2008 to 2014,three years before and three years after publication,remained unchanged.12 Similarly, use of other unnecessarydiagnostic testing such as blood culture, CBC, CRPchanged minimally, resulting in only modest cost reduction. Researchers noted wide variations in diagnostictesting between hospitals before and after guideline publication. Similarly, the Etiology of Pneumonia in theCommunity (EPIC) study reported significant variation indiagnostic testing between hospitals, and that hospitalistdiagnosis of CAP differed from ED physician for 47 percent of admissions. 13

The lack of adoption of guidelines is not specific to CAP.The 2004 guidelines for the management of acute otitismedia (AOM) allow for watchful waiting instead ofimmediate antibiotic treatment in certain cases. Thisguideline was based on evidence that resolution of AOMoften occurs with or without antibiotic treatment and that

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Table 1. Demographics of Sample Population (n = 444,705)

Received CXR Did Not Receive CXR p value(95% Confidence Interval) (95% Confidence Interval)

Age 4.3 4.37 0.05(Years) (4.27 – 4.35) (4.33-4.41)

Gender 44.7% 44.9% 0.71(% Female) (44.3% - 45.2%) (44.4% - 45.3%)

Diagnosis 2.07 2.07 0.84at Discharge (2.06 – 2.09) (2.06 – 2.09)

(#)

Weekend 32.5% 32.7% 0.57ED Visit (%) (32.1% - 33.0%) (32.3% - 33.2%)

Figure 1. Median Household Income (ZIP Code) on CXR Use

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watchful waiting does not increase the incidence of serious sequelae.14 Practicing according to these guidelinesreduces spending on antibiotics, decreases the chance ofadverse side effects from antibiotics, and prevents antibiotic resistance.15 Despite these virtues, this recommendation did not result in an increase of management of AOM without antibiotics.16 Interestingly,a 2012 study showed that neither ethnicity, race, norinsurance status significantly influenced antibiotic prescribing practices of doctors.17 Socioeconomic statuswas not analyzed.

With strong evidence to support guideline recommenda-tions, it can be puzzling why guidelines often are not successful in changing physician practice.18 Reasonsbehind non-adherence to guidelines have been exploredin the literature, with exploration mostly focusing oninstitutional organizations and physician perceptions.19 A2016 study exploring reasons preventing doctors fromswitching antibiotics from IV to oral found that the threemain factors were consumerism (i.e., fear of litigation ordissatisfying patients), hierarchy of medical team, and per-ception that IV antibiotics were more potent.20 A study inSaudi Arabia found that organizational barriers and lackof implementation strategy led to doctor non-complianceto pediatric asthma guidelines.21

Our study, in pointing out the correlation between socioe-conomic status and physician practice patterns, supportsprior research that consumerism and organizational barriers may impact non-adherence to guidelines. It mightbe reasonable to assume that a child from lower socioeconomic status is more likely to receive chest radiograph because ED physicians assign a likelihood ofproper follow-up (due to possible financial, transportation,or time constraints) in making the decision for a CXR.However, our data show that in 2009 the opposite wastrue. The exact reason for this difference is unclearthrough our research, but consumerism and organizationbarriers offer a possible explanation.

Consumerism may drive doctors to order other testing,thus explaining why total ED charges were not statisticallydifferent between those patients who received CXR andthose who did not. Doctors may also be hesitant to do toolittle for fear of dissatisfying the patient’s parents. Finally,fear of litigation as a basis of our health care system structure shows the role of organization barriers to guide-line adherence. The unexpected correlation betweensocioeconomic status and use of CXR highlights the

impact that patient characteristics may play a role inwhich diagnostic studies doctors order, and calls for futureresearch to determine if the relation is causal and why therelationship exists.

Limitations of this study include that the sample consistedonly of U.S. children from a single year, the sample wasnot broken down further by child’s race or geographicarea, and socioeconomic status of the child was deducedby ZIP code instead of actual family income (although thispractice is well-established in public health literature).22,23,24

Furthermore, this study was not able to identify exact reasonsdriving provider decisions to order chest radiograph forchildren living in wealthier ZIP codes. Lastly, this studyfocused on patient characteristics, and did not delve intophysician or hospital characteristics that may be correlatedwith use of CXR in the ambulatory patient with suspectedCAP.

Strengths of the study include a large sample size and avery strong correlation (p<0.001) of CXR use in CAPwith children living in wealthy ZIP codes. Six separatevariables including age, gender, weekend versus weekday,number of diagnoses at discharge, total ED charges, andmedian household income based on median householdincome quartiles for ZIP code were examined for correlation.Most importantly, this study explores the novel idea thatexamining trends in physician practice prior to guidelinepublication may lead to improved implementation andthat patient characteristics may influence physicianadherence to clinical guidelines.

Future studies should seek to determine if there are financial, demographic, or racial biases in the health caresystem that led to disparity in use of CXR between children living in wealthier neighborhoods. By identifyingreasons driving physician adherence to clinical guidelinessuch as socioeconomic status, targeted interventions canbe developed focused on improving guideline implemen-tation acceptance.

ConclusionUnderstanding underlying patterns of physician practiceprior to guideline release would likely aid in successfullyimplementing guidelines. Somewhat unexpectedly, thispaper demonstrates a strong correlation between socioeco-nomic status of the pediatric patient and use of chest radiograph for CAP prior to guideline publication in 2011which discourages ordering CXR in the outpatient setting.Further research is needed to determine the exact reason

215May 2017

About the Authors:Eric W. Jones, MSIV, University of South Dakota Sanford School of Medicine.Benjamin Meyer, MD, PGY-1, Department of Internal Medicine, University of South Dakota Sanford School of Medicine.Aaron M. Berg, MD, Clinical Assistant Professor, Department of Neurosciences, University of South Dakota Sanford School of Medicine. Benson S. Hsu, MD, MBA, Associate Professor, Department of Pediatrics, University of South Dakota Sanford School of Medicine.

REFERENCES1. National Health Expenditure Accounts. National health expenditures 2014 high-

lights. 2015 Dec 3. Retrieved from www.cms.gov/research-statistics-data-and-systems/statistics-trends-and-reports/nationalhealthexpenddata/downloads/high-lights.pdf

2. Smith MD, Saunders R, Stuckhardt L, McGinnis JM, editors. Best care at lowercost. Washington DC: The National Academies Press; 2013.

3. Jain S, Williams DJ, Arnold SR, Ampofo K, Bramley AM, Reed C, et al.Community-acquired pneumonia requiring hospitalization among U.S. children. N Engl J Med. 2015; 372:835-45.

4. Parikh K, Hall M, Blaschke AJ. Aggregate and hospital level impact of nationalguidelines on diagnostic resource utilization for children with pneumonia at chil-dren’s hospitals. J Hosp Med. 2016 May;11(5):317-23.

5. Federal Interagency Forum on Child and Family Statistics. America’s children: keynational indicators of well-being, 2015. Washington, DC: U.S. Government PrintingOffice.

6. Swingler GH, Hussey GD, Zwarenstein M. Randomised controlled trial of clinicaloutcome after chest radiograph in ambulatory acute lower-respiratory infection inchildren. Lancet. 1998;351:404-8.

7. Novack V, Avnon LS, Smolyakov A, Barnea R, Jotkowitz A, Schlaeffer F.Disagreement in the interpretation of chest radiographs among specialists andclinical outcomes of patients hospitalized with suspected pneumonia. Eur J InternMed. 2006;17:43-7.

8. Bradley JS, Byington CL, Shah SS, Alverson B, Carter ER, Harrison C, et al. Themanagement of community-acquired pneumonia in infants and children older than3 months of age: clinical practice guidelines by the pediatric infectious diseasessociety and the infectious diseases society of America. Clin Infect Dis. 2011;53:e25-76.

9. Parikh K, Hall M, Blaschke AJ, Grijalva CG, Brogan TV, Neuman MI, et al.Aggregate and hospital-level impact of national guidelines on diagnostic resourceutilization for children with pneumonia at children’s hospitals. Journal of HospitalMedicine. 2016;00:1-7.

10. Kronman MP, Hersh AL, Feng R, Huang YS, Lee GE, Shah SS. Ambulatory visitrates and antibiotic prescribing for children with pneumonia, 1994– 2007.Pediatrics. 2011;127:411-8.

11. Whittle J, Fine MJ, Joyce DZ, Lave JR, Young WW, Hough LJ, et al. Community-acquired pneumonia: can it be defined with claims data? Am J Med Qual.1997;12:187-93.

12. Parikh K, Hall M, Blaschke AJ, Grijalva CG, Brogan TV, Neuman MI, et al.Aggregate and hospital-level impact of national guidelines on diagnostic resourceutilization for children with pneumonia at children’s hospitals. Journal of HospitalMedicine. 2016;00:1-7.

13. McCulloh RJ, Patel K. Recent developments in community-acquired pneumonia.Curr Infect Dis Rep. 2016;18:14.

14. Subcommittee. Diagnosis and management of acute otitis media. Pediatrics.2004;113(5):1451-65.

15. McCormick DP, Chonmaitree T, Pittman C, Saeed K, Friedman NR, Uchida T,Baldwin CD. Nonsevere acute otitis media: A clinical trial comparing outcomes ofwatchful waiting versus immediate Antibiotic Treatment. Pediatrics2005;115(6):1455-65.

16. Coco A, Vernacchio L, Horst M, Anderson A. Management of acute otitis mediaafter publication of the 2004 AAP and AAFP clinical practice guideline. Pediatrics.2010;125(2):214-20.

17. Sidell D, Shapiro NL, Bhattacharyya N. Demographic influences on antiobiotic prescribing for pediatric acute otitis media. Otolaryngol Head Neck Surg.2012;146:653-8.

18. Timmermans S, Mauck A. The promises and pitfalls of evidenced-based medicine. Health Affairs. January 2005;24:118-28.

19. Cabana MD, Rand CS, Powe NR, Wu AW, Wilson MH, Abboud PA, Rubin HR.Why don’t physicians follow clinical practice guidelines? A framework forimprovement. JAMA. 1999 Oct 20;282(15):1458-65.

20. Broom J, Broom A, Adams K, Plage S. What prevents the intravenous to oralantibiotic switch? A qualitative study of hospital doctors' accounts of what influences their clinical practice. J Antimicrob Chemother. 2016;71 (8):2295-9.

21. Wahabi HA, Alziedan RA. Reasons behind non-adherence of healthcare practitioners to pediatric asthma guidelines in an emergency department in Saudi Arabia. BMC Health Services Research. 2012;12:226.

22. Krieger N, Chen JT, Waterman PD, Rehkopf DH, Subramanian SV. Race/ethnicity,gender, and monitoring socioeconomic gradients in health: a comparison of area-based socioeconomic measures — the public health disparities geocodingproject. Am J Public Health. 2003 Oct; 93(10):1655-71

23. O’Lenick CR, Winquist A, Mulholland JA, Friberg MD, Chang HH, Kramer MR, et al. Assessment of neighborhood-level socioeconomic status as a modifier of air-pollution — asthma associations among children in Atlanta. J EpidemiolCommunity Health. 2016;0:1-8.

24. Guglani L, Booza J, Havstad SL, Joseph CLM. Usefulness of a home affluencescale administered to urban adolescents with asthma to estimate the family’ssocioeconomic status. Ann Epidemiol. 2015;25:855-60.

motivating providers to order CXR for children residing inwealthier ZIP codes and to determine what other factorsmay be associated with non-adherence to guidelines. With

this knowledge, focused efforts addressing specific patternsof behavior could be undertaken to more successfullyencourage adherence to clinical practice guidelines.

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AbstractInguinal hernia repair is one of the most commonly performed operations in the pediatric population. While themajority of pediatric surgeons routinely use laparoscopy in their practices, a relatively small number prefer alaparoscopic inguinal hernia repair over the traditional open repair. This article provides an overview of thethree port laparoscopic technique for inguinal hernia repair, as well as a review of the current evidence withrespect to visualization and identification of hernias, recurrence rates, operative times, complication rates, post-operative pain, and cosmesis. The laparoscopic repair presents a viable alternative to open repair and offers anumber of benefits over the traditional approach. These include superior visualization of the relevant anatomy,ability to assess and repair a contralateral hernia, lower rates of metachronous hernia, shorter operative times inbilateral hernia, and the potential for lower complication rates and improved cosmesis. This is accomplishedwithout increasing recurrence rates or postoperative pain. Further research comparing the different approaches,including standardization of techniques and large randomized controlled trials, will be needed to definitivelydetermine which is superior.

Laparoscopic Pediatric Inguinal Hernia Repair:Overview of “True Herniotomy” Technique and Review of Current EvidenceBy B r e n d an P. F e e h an , MS IV; a n d D a v i d S . F r omm , MD

IntroductionInguinal hernia repair remains one of the most commonlyperformed procedures in the pediatric population.1 It isestimated that inguinal hernia occurs in 1 to 5 percent ofall newborns and in 9 to 11 percent of premature newborns.2

Boys experience an incidence three to four times higherthan in girls.3 The incidence is highest during the first yearof life, with peak incidence occurring in the first month.3

Despite the rise of laparoscopy and minimally invasivesurgical techniques in the realms of general and pediatricsurgery over the last 20 years, many pediatric surgeonsremain reluctant to employ laparoscopy in the repair ofinguinal hernias. In a recent survey of 187 pediatric surgeons in 46 different countries, 79 percent (148 out of187) of respondents routinely employed laparoscopy intheir practice.1 However, only 17 percent (32 out of 187)of respondents preferred laparoscopy in the repair of

inguinal hernia. Concerns cited by these surgeons includeless risk of recurrence, less abdominal organ injury, lessvas/vessel injury, and faster operative times with the traditional open approach. Of the 17 percent of respondentsthat preferred laparoscopy, stated benefits of the techniqueincluded less metachronous contralateral hernias, bettercosmesis, easier technique, less vas/vessel injury, and lesspostoperative pain. Proficiency with the technique can beachieved in 10 to 25 procedures, according to 80 percentof the polled surgeons. Despite this reluctance to employ alaparoscopic repair, a review of current literature on thetechnique does find several advantages, including superiorvisualization of the relevant anatomy, ability to assess thecontralateral inguinal ring and repair a contralateral herniaif present, lower rates of metachronous hernia, shorteroperative times, low complication rates, and excellentcosmesis. This article provides an overview of the three-

Editor’s note: This manuscript is the winner of the 2016 Chester B. McVay, MD, Award from the South Dakota Chapter of the American College of Surgeons.

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port “true herniotomy” laparoscopic technique for repairof pediatric inguinal hernias as well as a review of the current evidence on the laparoscopic approach with comparison to the standard open technique.

Overview of TechniqueThe procedure is set up with the patient supineon the operating table. The table is positioned ina manner that the surgeon stands at the head ofthe table. Patient is prepped and draped in theusual manner. After administration of local anesthetic, a small stab incision is made alongthe superior rim of the umbilicus. Veress needleis inserted and the abdomen is inflated withmaximum pressure of 6-10 mmHg. The Veressneedle is removed and a 5 mm port is positionedthrough the opening. A 5 mm 30 degree laparo-scope is used for visualization while two additional3 mm ports are placed along the left and rightanterior axillar lines slightly cephalad with ahorizontal axis of the umbilicus.

The laparoscope is used to identify and assess thehernia (Figure 1). Contents such as omentum orbowel are reduced if needed. The peritoneumlateral to the internal inguinal ring is grasped andincised with laparoscopic scissors. The peritoneumis then mobilized in a circumferential fashion atthe internal ring (Figure 2). The laparoscopicview provides excellent magnified visualizationof the relevant anatomy, especially the vas deferens, testicular artery, and testicular vein.These structures are identified and protectedthroughout the procedure. The hernia sac isreduced using gentle hand-over-hand dissectionfrom the spermatic cord. The posterior aspect ofthe hernia sac is mobilized using sharp scissor dissection from the vas deferens as well as thetesticular artery and vein. The hernia sac isretrieved through the 3 mm ports and submittedfor pathology review. 4-0 nonabsorbable braidedsuture is introduced and used to close the internal ring in a multiple figure-of-eight fashion(Figure 3). This is consistent with high ligationof the hernia sac. The process is repeated on theopposite side if bilateral hernia is present.

Following completion of the repair, the laparo-scopic ports are removed and the pneumoperi-toneum is evacuated. The fascia at the umbilicusis closed with 3-0 absorbable synthetic braided

suture in an inverted interrupted fashion. 5-0 monofila-ment synthetic absorbable suture is used in a running sub-cuticular fashion to approximate skin edges. Dermabondsolution is used to reinforce the skin closure.

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Figure 1. Identification of a large, right-sided indirect inguinal hernia defect in a 4-month-old boy. The testicular artery, testicular vein, and

vas deferens are easily identified.

Figure 2. Circumferential dissection of the posterior hernia sac.

Figure 3. Completed repair of indirect inguinal hernia following figure-of-eight suture closure.

219May 2017

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Evidence for the Laparoscopic ApproachSuperior Visualization and Evaluation of ContralateralInguinal Ring

One of the biggest advantages to the laparoscopic techniqueis the superior visualization of the relevant anatomy. Theinternal inguinal ring is presented in a close-up, magnifiedview from inside the abdomen that is indisputably superiorto the visualization provided by the classic open technique.This allows the surgeon to identify hernias that are notclinically apparent.

Schier4 described 129 pediatric patients with 153 inguinalhernias that were pre-operatively diagnosed. Of these, 15percent (19 out of 129) of patients had an unexpectedcontralateral internal ring open on the left, while 22 percent (28 out of 129) of patients had an unexpectedcontralateral internal ring open on the right.Additionally, Schier found multiple instances of clinicallydiagnosed hernia that were in contradiction with whatwas visualized with the laparoscope. In the largest series ofits kind, Valusek et al.5 studied 1,676 patients clinicallydiagnosed with unilateral inguinal hernia by performinglaparoscopy to evaluate the contralateral side. Beforelaparoscopic visualization was performed, patients wereexamined under general anesthesia by an attending pediatric surgeon. Following these exams, it was predictedthat 28 percent (470) of these patients would have a contralateral patent processus vaginalis (PPV). Afterlaparoscopic exam, 40 percent (670) of the patients had acontralateral PPV. In patients that did not have a contralateral PPV on exam, 39 percent did in fact have acontralateral PPV after laparoscopic visualization. Anadditional study by Mollen and Kane6 has noted that visualizing the anatomy through a laparoscope at the transumbilical position is superior to clinical exam orextension of pneumoperitoneum into the scrotum.

Additionally, discovery of bilateral hernia is easily remediedwith the laparoscopic technique, as the contralateralinternal ring can be closed without additional incisions oraccess. The evidence for routinely closing open internalrings in the absence of clinical symptoms of hernia is controversial. However, metachronous hernia rates arelower when any open inguinal ring that is discovered isroutinely closed, according to Schier.7 In fact, the laparoscopic approach has a lower rate of metachronoushernia, likely due to its ability to easily identify and closean open internal ring.8,16 The ability of the laparoscopicapproach to discover an undiagnosed hernia and

subsequently close it provides a benefit not seen with theconventional open technique.

Recurrence Rates

An important measure for success in inguinal herniarepair is the rate of recurrence. Laparoscopic techniquehas been criticized as an inferior procedure due toincreased inguinal hernia recurrence.1 Direct comparisonof recurrence rates in laparoscopic pediatric inguinal hernia repair is difficult due to variation in techniques.Additionally, defining recurrence is often difficult andvaries between surgeons and studies. Schier7 suggests thatpediatric hernias and their recurrences exist on a spectrum,ranging from a partially open internal inguinal ring to “all-the-way-down-into-the scrotum open processes.”However, when comparing the laparoscopic approaches tothe conventional open technique in the pediatric population, the available evidence suggests that there isno significant difference in recurrence rates between procedures.7-10,16,22

Yang et al.8 conducted a meta analysis of three randomizedcontrolled trials and four observational clinical studiescomparing 1,543 laparoscopic repairs to 657 open repairs.The authors reported that inguinal hernia recurrence ratebetween the two procedure techniques was not significantlydifferent. An additional randomized controlled trial byShalaby et al.9 involving 125 patients undergoing laparo-scopic repair and 125 patients undergoing open repairfound an inguinal hernia recurrence rate of 0.8 percent(one out of 125) in the laparoscopic group compared to2.4 percent (three out of 125) in the open group over amean follow-up period of 24 months. No statistically significant difference was noted. Philippe et al.10 conducteda retrospective series involving 385 patients with 525 herniarepairs that had four indirect hernia recurrences (0.76 percent of repairs); three at one month post-operativelyand one at two years post-operatively. A prospectivereview by Dutta et al.13 of 275 laparoscopic hernia repairsin 187 children found a recurrence rate of 1.5 percent(four out of 275) with two or more years of follow-up. Aretrospective study involving 884 children documented aninguinal hernia recurrence in 28 children, at a rate of 3.2percent.7 In a prospective series involving 712 laparoscopicinguinal hernia repairs in 542 children age 4 days to 14years, Schier reported a slightly higher inguinal herniarecurrence rate of 4.1 percent (29 out of 712 repairs) withmedian follow-up of 39 months.11 However, this recurrencerate was reported to decrease as experience with the

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technique was gained. In a large multicenter study, Schier,Montupet, and Esposito13 performed 933 repairs in 666children age 3 weeks to 14 years (median 3.2 years). Thereported inguinal hernia recurrence rate was 3.4 percent(32 out of 933 repairs) with follow-up time ranging fromtwo months to seven years. In an additional large multicenter study in Japan, Takehara et al.14 performed 972laparoscopic inguinal hernia repairs in 711 children age 18days to 19 years. The reported recurrence rate with fivemonths to 10 years of follow-up was 0.73 percent (sevenout of 972 repairs). A retrospective analysis conducted bySaka et al.17 reported 326 laparoscopic repairs and 162open repairs with no significant difference noted in recurrence rates. Parelkar et al.15 in another retrospectiveanalysis of laparoscopic repair of 437 children undergoing576 laparoscopic inguinal hernia repairs described a recurrence rate of 2.4 percent (14 out of 576). The published recurrence rates in open inguinal hernia repairrange from 0 to 4.7 percent.8,10,23 The published recurrencerates for laparoscopic repair do not vary significantly fromthose for open repair. However, a direct comparison ofrecurrence rates between the two approaches is difficult.There are a variety of techniques currently employed inlaparoscopic repair, and each technique is updated andchanged as surgeons gain experience with them. Theadoption of a standard technique for laparoscopic repairwould allow for a more direct comparison to the openrepair.

Operative Times

An additional concern limiting the adoption of laparoscopicrepair is longer operative times.1 Current evidence suggeststhat the operative time for laparoscopic repair is no differentfor unilateral hernia, and possibly superior in bilateral hernia.8-10,15,16 Shalaby et al.9 reported that laparoscopicrepair was significantly shorter in children with a unilateralhernia (p<0.001) and in children with a bilateral hernia(p<0.001). Philippe et al.10 note mean operation times of26.2 minutes for unilateral laparoscopic inguinal herniarepair and 34.5 minutes for bilateral laparoscopic herniarepair. Schier12 documents a median operating time of 22minutes with laparoscopic repair. Mean operating time ina retrospective review of 437 children undergoing laparo-scopic repair was 23 minutes for unilateral hernia and 29minutes for bilateral hernia.15 The meta-analysis conductedby Yang et al.8 notes no significant difference in operatingtimes between procedures for unilateral hernia; however,there was a significantly shorter operating time (p=0.02)in laparoscopic bilateral hernia repair. Another randomized

controlled trial by Celebi et al.16 compared a laparoscopicprocedure to open repair in bilateral hernias of 62 boysranging in age from 6 to 14 years. The authors found theoperative time for laparoscopic repair to be slightly shorter,although the difference was not statistically significant.The limiting factor for operative times in laparoscopicrepair is generally the familiarity and skill withlaparoscopy of the surgeon, and operating times tend todecrease with experience performing laparoscopic herniarepair.12 As reported above, proficiency with laparoscopicrepair can generally be attained in 10 to 25 procedures.1

Reported operative times for laparoscopic unilateralinguinal hernia repair range from as little as seven minutesfor a surgeon experienced in laparoscopic repair up to 55minutes for a trainee or surgeon inexperienced withlaparoscopic repair.10,12 Overall, a surgeon experienced inlaparoscopy and proficient in the laparoscopic repair ofinguinal hernias should have comparable operative timesto a surgeon performing the standard open technique. Inthe case of bilateral hernias, the laparoscopic approachmay be superior.

Complication Rates

Possible complications with both the laparoscopic andopen repair include injury to cord structures, injury tonerves, hydrocele, testicular atrophy, testicular injury, andtesticular malposition. Laparoscopic repair adds additionalrisk of major blood vessel or abdominal viscera injuries,most frequently due to insertion of trocars or Veress needleto establish pneumoperitoneum.18,19 While pediatric-specific data is sparse, data from the population at largesuggests that these events are rare. Major blood vesselinjury occurs at a rate between 0.03 and 0.3 percent, withan average rate of 0.1 percent.18-20 Abdominal viscerainjuries, the vast majority of which are small or largebowel, occur at rates of 0.05 to 0.3 percent.18-20 The openrepair is generally regarded as a safe procedure with lowcomplication rates,21,23 but the current evidence suggeststhat the laparoscopic approach does not increase the riskof complications.8,9,13,17,22,24-27 This may be a result oflaparoscopy eliminating the need to manipulate the vascular structures of the testes.10 Philippe et al.10 note a 0percent rate of testicular atrophy or testicular malposition,compared to published rates of up to 2.7 percent for eachin open repair. A prospective review by Dutta et al.13 of275 laparoscopic hernia repairs indicated no spermaticcord injuries, no testicular atrophy, and no symptoms ofilioinguinal nerve injury. Overall, a number of studieshave found that the safety and testicular complication

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rates of laparoscopic repair are no different when comparedto the open technique.8,9,11,12,14,17,22,24 One randomized controlled study by Shalaby et al.9 reported a significantlylower rate (p<0.049) of iatrogenic ascent of the testes.Hydrocele and testicular atrophy occurred at rates thatwere not statistically different between procedures. Whenincarcerated tissue or bowel is present, laparoscopy may besuperior to the open approach in the removal and evaluationof incarcerated tissue due to its excellent magnified viewproviding direct visual control, the ability to simultane-ously apply external manual pressure while internallypulling, and the avoidance of dissecting an edematous hernia sac.25-27 The complication rates of laparoscopicrepair remain at the same low level as the traditional openrepair in the available literature. When incarcerated hernia is present, the complication rate of laparoscopymay be lower.

Postoperative PainAnother consideration when evaluating laparoscopicrepair versus open repair is the presence and degree ofpostoperative pain. One of the benefits of other laparo-scopic and minimally invasive procedures is the potentialfor reduced postoperative pain. A randomized controlledtrial by Chan et al.29 evaluated pain scores using theChildren and Infants Postoperative Pain Score and theChildren’s Hospital of Eastern Ontario Pain Score in 97children older than three months undergoing laparoscopicand open inguinal hernia repair. The authors noted higherpain scores in the open repair group as well as significantlymore analgesic doses required (p=0.032). Celebi et al.16

evaluated a visual analog scale of pain scores related tobilateral inguinal hernia repair. Pain scores were signifi-cantly higher (p=0.036) in the open repair group than thelaparoscopic repair group at one hour postoperatively.During other recorded time frames, there were no significant differences in pain scores. Additionally, theauthors showed no difference in requested or deliveredanalgesic doses per 24 hours. These findings are similar tothe randomized controlled trial conducted by Bharathi etal.28 involving 85 children undergoing unilateral inguinalhernia repair that found no difference in postoperativepain. The meta analysis by Yang et al.8 found no significant difference in postoperative pain betweenlaparoscopic and open repairs. In contrast, a prospectivestudy of 89 children by Koivusalo et al.30 found that a significantly higher portion of the laparoscopic repairgroup required rescue analgesia postoperatively (79 versus42 percent, p<0.05). Additionally, the laparoscopic grouphad a significantly higher median pain score on the second

postoperative morning (p<0.05). This did not affect timeto return to normal activity, the primary outcome of thestudy. The evidence for postoperative pain followinglaparoscopic and open repair of inguinal hernia presents amixed picture. As a whole, it appears that there is no difference in postoperative pain between the two groups.

CosmesisOne benefit of laparoscopic surgery over traditional opentechniques is its ability to produce superior cosmesis. Anumber of studies indicate that the cosmesis achievedwith laparoscopic repair of pediatric inguinal hernia issuperior compared to the open approach.9,15,28 Koivusalo et al.30 indicated that the cosmesis provided by each technique is similar due to the location of the incision inthe open approach. Philippe et al.10 asked patients andfamilies to rank the residual scars following laparoscopicrepair. Forty-five percent were considered “not visible”while an additional 49.4 percent were considered “barelyvisible.” When Celebi et al.16 compared bilateral inguinalhernia repair, parents of patients scored the wound appear-ance of laparoscopic repair significantly better than that ofopen repair (p<0.05). Overall, it is difficult to definitivelysay that the cosmesis provided by laparoscopic repair issuperior to open repair, although there is evidence to suggest that it is, especially in the case of bilateral hernias.

ConclusionsLaparoscopic repair of pediatric inguinal hernias presentsa viable alternative to the standard open repair. Whilepediatric surgeons are reluctant to adopt the use of thetechnique at a widespread level, there are several advantagesto laparoscopy. These include superior visualization of therelevant anatomy, ability to assess and repair a contralateralhernia, lower rates of metachronous hernia, shorter operative times with surgeons experienced in laparoscopy,lower potential complication rates, and better cosmesis.There is similar recurrence rate and postoperative painwhen comparing laparoscopic and open techniques. Themajor limitation in comparing open hernia repair tolaparoscopic hernia repair is the lack of a single acceptedbest method for laparoscopic repair. Randomized controlled trials and large multicenter studies are lackingin the pediatric population. In order to definitively conclude that one technique is superior to the other, a single laparoscopic technique will need widespreadacceptance and additional large randomized trials willneed to be performed.

Acknowledgements: Special thanks to Dr. Sue Davies, PhD for her assistancein editing this article.

223May 2017

REFERENCES1. Eaton S, Hoellwarth M, Puri P, Tovar J. Fasching G, Bagolan P, Zani A.

Management of pediatric inguinal hernias in the era of laparoscopy: results of aninternational survey. European Journal of Pediatric Surgery. 2014;24(01):9-13.

2. Grosfeld JL. Current concepts in inguinal hernia in infants and children. WorldJournal of Surgery. 1989;13(5):506.

3. Pan ML, Chang WP, Lee HC, Tsai HL, Liu CS, Liou DM, Sung YJ, Chin TW. A longi-tudinal cohort study of incidence rates of inguinal hernia repair in 0- to 6-year-oldchildren. Journal of Pediatric Surgery. 2013;48(11):2327-31.

4. Schier F. Laparoscopic surgery of inguinal hernias in children — initial experience.Journal of Pediatric Surgery. 2000;35(9);1331-5.

5. Valusek P, Spilde T, Ostlie D, Peter S, Iii W, Iii J, Iii G. Laparoscopic evaluation forcontralateral patent processus vaginalis in children with unilateral inguinal hernia.Journal of Laparoendoscopic & Advanced Surgical Techniques. 2006;16(6):650-3.

6. Mollen K, Kane T. Inguinal hernia: what we have learned from laparoscopic evalu-ation of the contralateral side. Current Opinion in Pediatrics. 2007;19(3):344-8.

7. Schier F. The laparoscopic spectrum of inguinal hernias and their recurrences.Pediatric Surgery International. 2007;23:1209-13.

8. Yang C, Zhang H, Pu J, Mei H, Zheng L, Tong Q. Laparoscopic vs open herniorrha-phy in the management of pediatric inguinal hernia: a systemic review and meta-analysis. Journal of Pediatric Surgery. 2011;46(9):1824-34.

9. Shalaby R, Ibrahem R, Shahin M, Yehya A, Abdalrazek M, Alsayaad I, Shouker M(2012). Laparoscopic hernia repair versus open herniotomy in children: a con-trolled randomized study. Minimally Invasive Surgery. 2012;2012:484135

10. Giseke S, Glass M, Tapadar P, Matthyssens L, Philippe P. A true laparoscopicherniotomy in children: evaluation of long-term outcome. Journal ofLaparoendoscopic & Advanced Surgical Techniques. 2010;20(2):191-4

11. Schier F. Laparoscopic inguinal hernia repair – a prospective personal series of542 children. Journal of Pediatric Surgery. 2006;41(6):1081-4.

12. Schier F, Montupet P, Esposito C. Laparoscopic inguinal herniorrhaphy in children:a three-center experience with 933 repairs. Journal of Pediatric Surgery.2002;37(3):395-7.

13. Dutta S, Albanese C. Transcutaneous laparoscopic hernia repair in children: aprospective review of 275 hernia repairs with minimum 2-year follow-up. SurgicalEndoscopy. 2008;23:103-107.

14. Takehara H, Yakabe S, Kameoka K. Laparoscopic percutaneous extraperitonealclosure for inguinal hernia in children: clinical outcome of 972 repairs done in 3pediatric surgical institutions. Journal of Pediatric Surgery 2006;41(12):1999-2003.

15. Parelkar S, Oak S, Gupta R, Sanghvi B, Shimoga P, Kaltari D, Bachani M.Laparoscopic inguinal hernia repair in the pediatric age group — experience with437 children. Journal of Pediatric Surgery. 2010;45(4):789-92.

16. Celebi S, Uysal A, Inal F, Yildiz A. A single-blinded, randomized comparison oflaparoscopic versus open bilateral hernia repair in boys. Journal ofLaparoendoscopic & Advanced Surgical Techniques. 2014;24(2):117-21.

17. Saka R, Okuyama H, Sasaki T, Nose S, Yoneyama C. Safety and efficacy of laparo-scopic percutaneous extraperitoneal closure for inguinal hernias and hydroceles inchildren: a comparison with traditional open repair. Journal of Laparoendoscopic& Advanced Surgical Techniques. 2014;24(1):55-8.

18. Philips P, Amaral J. Abdominal access complications in laparoscopic surgery.Journal of the American College of Surgeons. 2001;192(4):525-36.

19. Bhoyrul S, Vierra M, Nezhat C, Krummel T, Way L. Trocar injuries in laparoscopicsurgery. Journal of the American College of Surgeons. 2001;192(6):677-83.

20. Fuller J, Scott W, Ashar B, Corrado J. Laparoscopic trocar injuries: a report from aU.S. Food and Drug Administration (FDA) Center for Devices and RadiologicalHealth (CDRH) Systematic Technology Assessment of Medical Products (STAMP)committee: FDA Safety Communication. 2003.

21. Potts WJ, Riker WL, Lewis JE. The treatment of inguinal hernia in infants andchildren. Annals of Surgery. 1950;132:566-76

22. Çelebi S, Yıldız A, Üçgül A, Karadağ Ç, Sever N, Akın M, Dokucu A. Do openrepair and different laparoscopic techniques in pediatric inguinal hernia repairsaffect the vascularization of testes? Journal of Pediatric Surgery. 2012;47(9):1706-10.

23. Ein SH, Njere I, Ein A. Six thousand three hundred sixty-one pediatric inguinal her-nias: A 35-year review. Journal of Pediatric Surgery. 2006;41:980-86.

24. Parelkar S, Oak S, Bachani M, Sanghvi B, Prakash A, Patil R, Patel J.Laparoscopic repair of pediatric inguinal hernia — is vascularity of the testis atrisk? A study of 125 testes. Journal of Pediatric Surgery. 2011;46(9):1813-6.

25. Kaya M, Hückstedt T, Schier F. Laparoscopic approach to incarcerated inguinalhernia in children. Journal of Pediatric Surgery. 2006;41(3):567-9.

26. Nah S, Giacomello L, Eaton S, Coppi P, Curry J, Drake D, Pierro A. Surgical repairof incarcerated inguinal hernia in children: laparoscopic or open? European Journalof Pediatric Surgery. 2010;21(1):8-11.

27. Zhou X, Peng L, Sha Y, Song D. Transumbilical endoscopic surgery for incarcerat-ed inguinal hernias in infants and children. Journal of Pediatric Surgery.2014;49(1):214-7.

28. Bharathi RS, Arora M, Baskaran V. Pediatric inguinal hernia: laparoscopic versusopen surgery. Journal of the Society of Laparoendoscopic Surgeons.2008;12(3):277-81

29. Chan KL, Hui WC, Tam PKH. Prospective randomized single-center, single-blindcomparison of laparoscopic vs open repair of pediatric inguinal hernia. SurgicalEndoscopy and Other Interventional Techniques. 2005:19(7):927-32.

30. Koivusalo A, Korpela R, Wirtavuori K, Piiparinen S, Rintala R, Pakarinen M. A sin-gle-blinded, randomized comparison of laparoscopic versus open hernia repair inchildren. Pediatrics. 2009;123(1):332-7.

About the Authors:Brendan P. Feehan, MSIV, University of South Dakota Sanford School of Medicine.David S. Fromm, MD, Rapid City Medical Center, Rapid City, South Dakota; Associate Professor of Surgery, University of South Dakota Sanford School of Medicine.

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AbstractConsuming excessive amounts of alcohol has the potential to modify an individual’s brain and lead to alcoholdependence. Alcohol use leads to 88,000 deaths every year in the U.S. alone and can lead to other health issuesincluding cancers, such as colorectal cancer, and mental health problems. While drinking behavior varies dueto environmental factors, genetic factors also contribute to the risk of alcoholism. Certain genes affecting alcohol metabolism and neurotransmitters have been found to contribute to or inhibit the risk. Gene-environment interactions may also play a role in the susceptibility of alcoholism. With a better understandingof the different components that can contribute to alcoholism, more personalized treatment could cater to theindividual. This review discusses the major genetic factors and some small variants in other genes that contribute to alcoholism, as well as considers the gene-environmental interactions.

Genetics of Alcoholism By En a C . Z h u , BS ; Yu e s h an Hu , P hD ; a n d Timo t h y J . S o und y, MD

IntroductionCraving, loss of control, physical dependence, and toleranceare symptoms of alcoholism, with the latter symptomresulting in a higher consumption of excess alcohol.Different genetic and environmental factors contribute tothe level of alcohol consumption. Human twin studieshave also provided support that certain responses to alcoholare due to genetic influence.1,2 While there are severalgenes known to contribute to the risk of alcoholism, it isimportant to consider environmental stressors and gene-environment interactions as well. It is beneficial to consider this gene-environment interaction along withthe genes currently known to affect metabolic processesand neurotransmitters which in turn can lead to bettertreatment and prevention tactics.

Alcohol Metabolism Alcohol metabolism consists of several oxidative pathways.3

Figure 1 depicts several main enzymes involved in alcoholmetabolism. Alcohol dehydrogenase (ADH) metabolizesethanol to produce acetaldehyde.4 Cytochrome P450 andcatalase have the same function as ADH although theseenzymes primarily play a role in metabolizing ethanolwhen there is a higher ethanol concentration or if there ishydrogen peroxide present, respectively. Acetaldehyde,

the byproduct of above enzymes, is highly reactive andtoxic and potentially contributes to the addictive processand tissue damage. Acetaldehyde can also form adductswith dopamine to make salsolinol, a possible contributionto alcoholism. Therefore, aldehyde dehydrogenase(ALDH) rapidly metabolizes acetaldehyde to produceacetate and NADH. ALDH2 is mainly involved in thisprocess. The produced acetate then gets oxidized to carbondioxide.5

Figure 1. Primary enzymes involved in the oxidative pathwaysof alcohol metabolism. Alcohol dehydrogenase in the cytosolconverts ethanol to acetaldehyde. Catalase in peroxisomes also oxidizealcohol in the presence of hydrogen peroxide.Cytochrome P450 mostly in microsomes are helpful at higher ethanol concentrations in metabolizing ethanol toacetaldehyde. Aldehyde dehydrogenase in the mitochondria

metabolizes acetaldehyde into acetate.5

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Alcohol dehydrogenase and aldehyde dehydrogenase havebeen found to be associated with a higher risk of alcoholism. Looking specifically at alcohol dehydrogenase1B (ADH1B), a specific coding variant rs1229984 is common in Asian populations. This variant replacesArg48 with His48 and has been found to lower the risk ofalcoholism in East Asian populations.6 In recent years, thisvariant was analyzed in European and African populationsin regards to alcohol dependence and alcohol intake.6,7

Analyzing a population defined to be alcohol dependent,the His48 variant was found to have a significant association with a reduced risk for alcohol dependencewith a similar magnitude of effect for both European andAfrican populations.6 Another study involving a specificEuropean population obtained blood samples and had participants complete a questionnaire which includeddrinking frequency and average alcohol intake. This population was randomly selected in contrast to the otherstudy. An association between the ADH1B variant andthe frequency and intake of drinking was found.7

There are multiple studies that also support the trend ofthe ADH1B variant having an association with risktowards alcoholism. However, not much is known aboutthe mechanism behind this association. A study in whichmale subjects having different ADH1B variants wereadministered different amount of doses of ETOH or aplacebo was conducted. An association between the variant, blood ETOH, and acetaldehyde levels was found.8

This study provides the groundwork for further examiningthe protective mechanism of ADH1B variants.

Aldehyde dehydrogenase 2 (ALDH2) is a known proteinencoding gene that is a part of the oxidative pathway foralcohol metabolism. As stated previously, ALDH2 plays arole in the essential step of oxidation of acetaldehyde toacetate. A variation of this gene has been found to beprevalent in Asian populations and thought to decreasethe risk of alcohol dependence. The specific alleleALDH2*2 disrupts normal alcohol metabolism but fewstudies have looked at whether this effect is related toenvironmental context or the developmental stages.

Especially among East Asian populations, the ALDH2variant has a lower oxidative efficiency. Due to this lowerefficiency, acetaldehyde builds up in the tissues leading tosuch symptoms as a flushed face, headache, and nausea. Incomparison to those without the variant, individuals withALDH2*2 are less likely to become alcohol dependent.Oftentimes alcohol consumption will increase through

the course of adolescence to adulthood. To determine therelationship between allele variants and environmentalfactors, a sampling of 356 adopted participants of Koreandescent who carried the ALDH2*2 allele was done. Asage increased, the protective effect of ALDH2*2increased, as well. There was no correlation between thegenotype and the initiation of alcohol use. Although inthe adopted participants, parental drinking habits eitherstrengthened or weakened the protective effect ofALDH2*2 suggesting that there is a gene-environmentcorrelation for ALDH2 as the parents did not carry theALDH2*2 allele.9 More recent studies have further supported that the ALDH2*2 allele in East Asians causephysical symptoms and that there may be a more complexgene-environment correlation involved.10,11

Further examining these genes and their respective variants not only could provide more information on therisk of alcoholism, but also the risk for other health issues.Alcohol is one of the risk factors for colon cancer.13 Inrecent years, an observed study population of 3,545 individuals observed an association between the ADH1Bpolymorphism and colorectal cancer risk.14 Anotherrecent study conducted in Japan suggested an influencefrom polymorphisms in both ADH1B and ALDH2 on thedevelopment of colorectal tumors.15

GABA ReceptorsAnimal models have shown evidence of the γ-aminobutyricacid (GABA) receptor A(GABRA) regulating alcoholself-administration.16 Genome-wide scans for humanshave also provided additional evidence linking alcoholismto genes encoding GABRA subunits. An analysis usingStudy of Addiction: Genetics and Environment (SAGE)data and genome-wide association studies (GWAS) datasets found that some single-nucleotide polymorphisms(SNPs) of GABRA are associated with alcoholism. FiveGABA receptor genes were analyzed with alcoholdependence and the meta-analysis suggested that theGABA receptor gene, GABRA2 (γ-aminobutyric acid Areceptor α2 subunit gene), is involved in the developmentof alcoholism. GABRG2 and GABRA6 were also foundto have an association with alcohol dependence.GABRA2 was additionally found to be associated withalcohol dependence through SAGE and GWAS datasets.17

Using the in vivo method known as the alcohol clamp,alcohol was distributed to the study population throughintravenous infusion. The findings showed that GABRA2

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alleles play a role in alcohol usage risk. More specifically,seven SNPs were included in the analysis and three(rs279869, rs279858, and rs279837) that are located inthe middle of the GABRA2 gene were shown to have sig-nificant associations with subjective responses to alcohol.1

Although the molecular mechanism for GABRA2 and itsassociation with alcoholism is not fully understood, theusage of induced pluripotent stem cells (iPSCs) as a modelsystem provides insight on the correlation in human neural cells. The mRNA expressions on chromosome4p12 GABAA subunit genes (which includes GABRA2)in iPSC differentiated human neural cell lines suggestedthat genotype effects on GABAA expression associatedwith alcoholism has an effect on regulation of the clusterof subunit genes on the chromosome of interest duringneural development.18

Corticotropin-Releasing Hormone Receptor 1 (CRHR1)The CRHR1 gene has been found to interact with stressand modulating excessive alcohol consumption.19 A particular CRHR1 gene variant was found to influenceresponse to negative emotional stimuli. The gene variant,rs110402, was observed through fMRI to influence negative emotional words in the right ventrolateral prefrontal cortex. This variant also was found to beinvolved in the internalizing negative affect pathway,therefore modulating the risk of problem drinking.20

Previously, the ALDH2*2 allele was introduced as beingpresent in primarily East Asian populations. Keeping thatin mind, a study included participants of exclusivelyKorean descent. Similarly, the results suggested that theCRHR1 gene is an important genetic factor in thecause/risk of alcoholism. However, the CRHR1 gene variants observed in this study were different from the previous study.21 This suggests the possibility of severalCRHR1 gene variants to be involved in the interactionbetween stress and alcoholism.

Gene-Environment InteractionHeritability of alcoholism has been estimated in approximately 50 percent of those who fulfill the criteriafor alcohol dependence. This suggests that both geneticand environmental factors are involved.19 Alcoholism, inpart due to its classification as a type of addiction, is achronic, relapsing disorder. For alcoholics, an observablecharacteristic includes a negative emotional state whichleads to a higher susceptibility to stress. Stress and alcoholcues were found to cause neural changes in the brain

through fMRI imaging.22 However, the connectionbetween stress and alcohol is complex and not quiteunderstood. Both animal and human studies have beenconducted in order to provide a better understanding ofthis relationship. Various studies found that chronic stressresulted in elevated drinking later in adulthood.23 Alcoholexposure was also observed to be a stressor itself causing anincrease in voluntary alcohol consumption.24

ConclusionAlcohol addiction has a heavy impact on our society andany advancements to reduce this burden would be welcome.There is evidence supporting genetic factors having anassociation with alcoholism. However, the subject andextent of the genetics is a topic of interest that is stillbeing researched and studied. Keeping in mind not onlythe genetic influences, but the gene-environment interactions in addition will be beneficial in futureendeavors for understanding and handling this type ofaddiction.

REFERENCES1. Roh S, Matsushita S, Hara S, Maesato H, Matsui T, Suzuki G, Miyakawa T,

Ramchandani VA, Li TK, Higuchi S. Role of GABRA2 in moderating subjectiveresponses to alcohol. Alcoholism: Clinical and Experimental Research.2011;35:400-7.

2. Verhulst B, Neale MC, Kendler KS. The heritability of alcohol use disorders: ameta-analysis of twin and adoption studies. Psychological Medicine.2015;45:1061-72.

3. Edenberg HJ. The genetics of alcohol metabolism: role of alcohol dehydrogenaseand aldehyde dehydrogenase variants. Alcohol Research & Health. 2007;30:5-13.

4. Cederbaum AI. Alcohol metabolism. Clinics in Liver Disease 2012;16:667-85.5. Zakhari S. Overview: how is alcohol metabolized by the body? Alcohol Research &

Health. 2006;29:245-54.6. Bierut LJ, Goate AM, Breslau N, Johnson EO, Bertelsen S, Fox L, Agrawal A, et al.

ADH1B is associated with alcohol dependence and alcohol consumption in popu-lations of European and African ancestry. Molecular Psychiatry. 2012;17:445-50.

7. Hubacek JA, Pikhart H, Peasey A, Kubinova R, Bobak M. ADH1B polymorphism,alcohol consumption, and binge drinking in Slavic Caucasians: results from theCzech HAPIEE study. Alcoholism: Clinical and Experimental Research.2012;36:900-5.

8. Kang G, Bae KY, Kim SW, Kim J, Shin HY, Kim JM, Shin IS, et al. Effect of the allelic variant of alcohol dehydrogenase ADH1B*2 on ethanol metabolism.Alcoholism: Clinical and Experimental Research. 2014;38:1502-9.

9. Irons DE, Iacono WG, Oetting WS, McGue M. Developmental trajectory and environmental moderation of the effect of ALDH2 polymorphism on alcohol use.Alcoholism: Clinical and Experimental Research. 2012;36:1882-91.

10. Peng GS, Chen YC, Wang MF, Lai CL, Yin SJ. ALDH2*2 but not ADH1B*2 is acausative variant gene allele for Asian alcohol flushing after a low-dose challenge:correlation of the pharmacokinetic and pharmacodynamics findings.Pharmacogenetics and Genomics. 2014;24:607-17.

About the Authors:Ena C. Zhu, BS, Department of Genetics, Cell Biology, and Development, College ofBiological Sciences, University of Minnesota, Twin Cities. Timothy J. Soundy, MD, Department of Psychiatry, University of South DakotaSanford School of Medicine.Yueshan Hu, PhD, Department of Psychiatry, University of South Dakota SanfordSchool of Medicine; Avera Institute for Human Genetics, Avera McKennan Hospital &University Health Center, Sioux Falls, South Dakota; Department of PharmaceuticalSciences, College of Pharmacy, South Dakota State University.

Please note: Due to limited space, we are unable to list all references. You may contact South Dakota Medicine at 605.336.1965 for a complete listing.

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229May 2017

Antimicrobial resistance is threatening availabletreatment options and accounts for 23,000deaths annually.1 The top offending organisms

include multiple-drug resistant (MDR) Acinetobacter andPseudomonas aeruginosa, extended-spectrum β-lactamase(ESBL) and carbapenem-resistant Enterobacteriaceae.Nearly 900 unique�β-lactamases provide the mechanismof resistance for MDR gram-negative infections.2 The established cephalosporin, ceftazidime, has extendedgram-negative coverage when combined with the new β-lactamase inhibitor avibactam therefore providing a treatment option for MDR organisms.3 Ceftazidime-avibactam (Avycaz) received marketing approval from theFood and Drug Administration (FDA) in February 2015for treatment of complicated intra-abdominal infections(cIAI) with concomitant metronidazole and complicatedurinary tract infections (cUTI) caused by resistant gram-negative organisms.4

Chemical Structure and Mechanism of ActionCeftazidime is a semisynthetic, β-lactam, third-generationcephalosporin exhibiting affinity for penicillin bindingproteins (PBP).5 The overall activity is bactericidal by disruption of cell wall synthesis. Much of ceftazidime’sactivity is isolated to PBP3 of P. aeruginosa and Escherichiacoli. Several bacteria develop β-lactamases to hydrolyzeand disrupt the classic 4-membered rings of the β-lactamantimicrobials, making these agents less effective.3 Addingβ-lactamase inhibitors allows various β-lactam antibioticsto retain antimicrobial activity. In combination, avibactamprotects ceftazidime from degradation by serine β-lactamasesto preserve activity against clinically significant gram-negative organisms. Avibactam is a diazabicyclooctanone,non-β-lactam β-lactamase inhibitor with no directantimicrobial activity. The extended spectrum to variousMDR organisms is likely due to the activity at the serinesite, avibactam forms a highly stable carbamoyl link disabling the catalytic activity of the serine residue.5

Spectrum of ActivityCeftazidime-avibactam demonstrates time-dependentbacterial killing at greater than two-times the minimum

inhibitory concentration (MIC).5 Avibactam is capable ofinhibiting Class A, C, and variable D β-lactamases.Coverage includes extended spectrum β-lactamases(ESBL), AmpC-mediated resistant P. aeruginosa, and carbapenemases (Table 1).

The combination remains inactive against class B metallo-β-lactamase organisms, demonstrates minimal activityagainst most Acinetobacter species, and variable susceptibilityto anaerobes with the most notable being Prevotella spp.3

Organisms with overexpressed efflux pumps or porinmutations may not be susceptible to ceftazidime-avibactam.4

The addition of avibactam provides no additional gram-positive coverage compared to ceftazidime alone.3

Literature ReviewTwo identical, randomized, double-blind phase 3 studiesevaluated safety and efficacy of ceftazidime-avibactamplus metronidazole (n = 520) compared to meropenem (n= 523) in the treatment of cIAI. Baseline characteristicswere similarly matched according to age, race, gender,body mass index (BMI), Acute Physiology and ChronicHealth Evaluation (APACHE) score, primary diagnosis,renal function, and infection type. A majority of thepatients with a ceftazidime-resistant, gram-negativepathogen (ceftazidime-avibactam plus metronidazole,

Pharmacotherapy Review of Ceftazidime-Avibactam By Ambe r Ya e g e r, P h a rmD ; a n d J o hn K a p p e s , P h a rmD , BCCCP

Table 1. Ceftazidime-Avibactam Spectrum of Activity4,5

High Susceptibility

Citrobacter freundii K. oxytoca (ESBL)

Citrobacter koseri K. pneumoniae(ESBL)

Enterobacter aerogenes K. pneumoniae carbapenemase

Enterobacter cloacea Proteus spp (ESBL)

E.coli (ESBL) P. aeruginosa (MDR)

H. influenza

Minimal Susceptibility

Acinetobacter spp Prevotella spp

Clinical Significance Unknown

Morganella morganii Providencia stuartii

Providencia rettgeri Serratia marcescens

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n=47; meropenem, n=64) grew E. coli and K. pneumoniae.The primary endpoint evaluated clinical cure at day 28-35and ceftazidime-avibactam was considered noninferior tomeropenem if achieving a between-group difference withthe lower limit of a 95 percent confidence interval (CI)greater than -12.5 percent. Clinical response was similarin the treatment of ceftazidime-resistant organisms (ceftazidime-avibactam plus metronidazole, 83 percent;meropenem, 85.9 percent). Patients with moderate renalfunction (CrCl 31-50 mL/min) experienced decreasedclinical cure rates with ceftazidime-avibactam plusmetronidazole treatment compared to meropenem 72 per-cent and 88 percent, respectively. Ceftazidime-avibactamplus metronidazole was noninferior to meropenem anddisplayed similar efficacy compared to ceftazidime againstceftazidime-susceptible cIAI. No new safety considerationswere identified in these studies.7

Two identical, randomized, multicenter, double-blind,double-dummy, parallel-group phase 3 studies evaluatedthe safety and efficacy of ceftazidime-avibactam (n = 393)compared to doripenem (n = 417) in the treatment ofcUTI. Baseline characteristics were similarly matchedaccording to age, race, gender, BMI, diagnosis, renal function, and pathogen. Patients were randomized 1:1 toeither ceftazidime-avibactam 2.5 grams every eight hoursor doripenem 500 mg every eight hours. Primary endpoints evaluated the proportion of patients with resolution of symptoms, excluding flank pain, at the five-day follow-up and the proportion of patients with infectioneradication and symptom resolution at 21-25 days.Noninferiority was determined by a treatment differencewith the lower limit of a 95 percent CI greater than -12.5percent. Ceftazidime-resistant organisms consisted mostlyof E. coli and K. pneumoniae (ceftazidime-avibactam,n=75; doripenem n=84). Resolution at five-day follow-upoccurred in 70.2 percent of ceftazidime-avibactam and66.2 percent of doripenem while infection eradication at21-25 days occurred in 77.4 percent and 71 percent,respectively. Favorable microbiological response rateswere similar between ceftazidime-avibactam (64 percent)and doripenem (60 percent) in the treatment of cef-tazidime-resistant organisms. Overall, the study suggestsceftazidime-avibactam is an alternative therapy option forpatients with cUTI, particularly caused by ceftazidime-resistant and carbapenemase organisms.8

The REPRISE trial, a randomized, pathogen-directed,international, phase 3 study evaluated ceftazidime-avibac-tam compared to the best available therapy for the treat-

ment of cIAI or cUTI caused by ceftazidime-resistant E.coli, K. pneumoniae, Enterobacter cloacae and P. aeruginosa.The 333 recruited patients were randomized 1:1 to ceftazidime-avibactam 2.5 grams intravenously (IV) everyeight hours or the best available therapy (97 percent beinga carbapenem). Patients were similarly matched accordingto age, race, gender, BMI, renal function, pathogen, andinfection type. The cIAI group was composed of relativelysmall numbers (ceftazidime-avibactam, n=10 and bestavailable treatment, n=11) and a substantially largergroup observed for cUTI (ceftazidime-avibactam, n=144and best available treatment, n=137). The Jeffery methodwas used to calculate a two-sided 95 percent confidenceinterval with no formal set power. The primary endpointevaluated clinical response (cure, intermediate, or failure)at seven to 10 days following the last day of treatment. Ahigh proportion of clinical cure (91 percent) resulted inboth treatment groups, supporting the use of ceftazidime-avibactam as an alternative to carbapenems in resistantgram-negative infections. This study provided safety andefficacy results consistent with previous evaluations of ceftazidime-avibactam.9

Dosage and AdministrationCeftazidime-avibactam FDA approved dosing is 2.5 gramsIV every eight hours with a two-hour infusion time.Treatment of cIAI, with concurrent metronidazole, is recommended for five to 14 days, while treatment of cUTIis recommended for seven to 14 days. The Cockcroft-Gault formulation is used to estimate renal function fordose adjustments (Table 2).4

The original package labeling identified the componentsof the individual agents, ceftazidime 2 grams and avibactam0.5 grams. However, due to confusion with dose adjustmentsrecommendations are based on total grams.6 Due to concerns regarding potential dosing errors, the packagelabeling now identifies the strength as a combination of

Table 2. Ceftazidime-Avibactam Renal Dose Adjustment4,

Estimated Creatinine Clearance (CrCl) Dose Modification

> 50 mL/min No adjustment necessary

31-50 mL/min 1.25 grams every 8 hours

16-30 mL/min 0.94 grams every 12 hours

6-15 mL/min 0.94 grams every 24 hours

≤ 5 mL/min 0.94 grams every 48 hours

End stage renal disease on Dose based on estimatedintermittent hemodialysis CrCl, given after dialysis on

hemodialysis days

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the products with 2.5 grams on the vial. There is lack ofsafety and efficacy data to guide dosing in pregnancy, lactation and children less than 18 years old.4

Adverse Effects, Warnings and PrecautionsCeftazidime-avibactam is generally well tolerated with lessthan 10 percent occurrence of diarrhea, nausea, vomiting,headache, dizziness and abdominal pain in trials.4

Patients with renal function of CrCl 30-50 mL/min, experienced decreased efficacy in the treatment of cIAI.Patients in this subgroup were potentially under treatedwith doses 33 percent lower than recommended doses.

Hypersensitivity reactions may occur in those with previous penicillin allergies.

Clostridium difficile-associated diarrhea has occurred inpatients treated with ceftazidime-avibactam.

Seizure and other neurologic effects may occur. Patientswith renal impairment and inappropriate dosing adjustments are at increased risk.

Drug InteractionsWhen ceftazidime-avibactam is administered at clinicallyrelevant concentrations, in vitro studies show neitherinduction nor inhibition of cytochrome P450 isoforms,hepatic, or renal transporters. Avibactam is a substrate ofthe OAT1 and OAT3 hepatic transporters and exhibited56-70 percent reduction in uptake with concomitantprobenecid. Therefore, probenecid increases levels ofavibactam and co-administration is not recommended.4

Laboratory Test InteractionsAdministration of ceftazidime-avibactam may interferewith laboratory results including Coombs test and urineglucose. In clinical trials, ceftazidime-avibactam caused agreater number of seroconversion from negative to positive direct Coombs test compared to carbapenems.Enzymatic glucose oxidase reaction is the preferred testingmethod to assess urine glucose to avoid false-positiveresults common to ceftazidime.4

ConclusionsThe combination of the third generation cephalosporinceftazidime with the non-β-lactam β-lactamase inhibitoravibactam provides an effective option for treatment ofcIAI and cUTI. Ceftazidime-avibactam is a treatmentoption for select MDR gram-negative infections, particularly in situations of carbapenem resistantEnterobacteriaceae when alternative treatments are limited.

Ceftazidime-avibactam is not active against all β-lactamasesthus initial susceptibility testing can identify candidatesfor ceftazidime-avibactam treatment. Appropriate antimicrobial stewardship should reserve the use of ceftazidime-avibactam to patients with few or no alternativetreatment options and promptly modify treatment whenculture and sensitivities become available.

REFERENCES1. Centers for Disease Control and Prevention (CDC). Antibiotic resistance treats in

the United States, 2013. Retrieved from www.cdc.gov/drugresistance/threat-report-2013/pdf/ ar-threats-2013-508.pdf.

2. Bush K. Bench-to-bedside review: The role of beta-lactamases in antibiotic-resistant Gram-negative infections. Crit Care. 2010;14(3):224.

3. Sharma R, Park TE, Moy S. Ceftazidime-Avibactam: A novel cephalosporin/β-lactamase inhibitor combination for the treatment of resistant gram-negativeorganisms. Clin Ther. 2016;38(3):431-44.

4. Avycaz (ceftazidime-avibactam) package insert. Forest Pharmaceuticals;Cincinnati, OH: 2015.

5. Mello RJ. Product quality microbiology review. Food and Drug Administration.Retrieved from www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206494Orig1s000MicroR.pdf

6. FDA Drug Safety Communication: FDA cautions about dose confusion and medication error with antibacterial drug Avycaz (ceftazidime and avibactam). U.S. Food & Drug Administration. Retrieved fromwww.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm463595.htm.

7. Mazuski JE, Gasink LB, Armstrong J, Broadhurst H, Stone GG, Llorens L, et al.Efficacy and safety of ceftazidime-avibactam plus metronidazole versus meropenem in the treatment of complicated intra-abdominal infection: resultsfrom a randomized, controlled, double-blind, phase 3 program. Clin Infect Dis.2016;62(11):1380-9.

8. Wagenlehner FM, Sobel JD, Newell P, Armstrong J, Huang X, Stone GG, et al.Ceftazidime-avibactam versus doripenem for the treatment of complicated urinarytract infections, including acute pyelonephritis: RECAPTURE, a phase 3 randomized trial program. Clin Infect Dis. 2016;63(6):754-62.

9. Carmeli Y, Armstrong J, Laud PJ, Newell P, Stone G, Wardman A, et al.Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinarytract infections or complicated intra-abdominal infections (REPRISE): a ran-domised, pathogen-directed, phase 3 study. Lancet Infect Dis. 2016;16(6):661-73.

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Special Features

“Quality Focus “ is a monthly feature sponsored by SDFMC, South Dakota’s Quality Improvement Organization. For more information about the SDFMC, visit their website at www.sdfmc.org.

Q u a l i t y F o c u s :

Antimicrobial Stewardship: Cultural ChangeContinuing ChallengeBy S t e ph an D . S c h r o e d e r, MDMed i c a l D i r e c t o r, S o u t h D a k o t a F o und a t i o n f o r Med i c a l C a r e

Antimicrobial resistance is one of the most significant public health threats in the U.S. withan estimated 2 million infections and 23,000

deaths yearly due to resistant organisms. As much as 30percent of antibiotic use may be unnecessary, perhapseven higher in the outpatient setting. Antibiotic resistance infections are costly in terms of morbidity, mortality and financial burden.

Simply defined, antimicrobial stewardship is the process ofencouraging the timely administration of antimicrobialagents. This has been made a priority for the Center forDisease Control and Prevention (CDC). With supportfrom the White House to multiple state and local healthagencies, the CDC is leading efforts to curb resistance andfoster the timely administration of antimicrobials. Thechoice of drug, dosing and length of treatment are coreelements of appropriate use. Overuse is obviously a majorconcern, but certain situations such as sepsis or bacterialpneumonia require rapid assessment and initiation ofthese agents.

Usage is easier to monitor in an inpatient environmentthrough medical records, culture results and continuousevaluation of patient status. The outpatient environmentis more difficult to track and assess. Clinics, including primary care and specialty along with acute and retailurgent care facilities, administer and prescribe antibiotics.Emergency departments and surgery centers are capable ofdelivering parenteral antimicrobial agents and would alsobenefit from a stewardship perspective.

In addition to physicians; nurse practitioners, physicianassistants, dentists and veterinarians prescribe these agentsand need to play a role in antibiotic stewardship.Pharmacists provide a valuable resource for prescribers inthe complicated process of multiple medications, interac-tions and dosing variability. Their assistance is necessaryfor the process to improve usage and promote patient safety.

Antimicrobial stewardship, though present for some time,will likely require a continuous culture change in manyprescribers due to their historical perspective and experi-ence in treating suspected bacterial infections. When theywere a developed, antimicrobial agents became a tool ofsignificant improvement in health care. Today, however,knowledge gaps exist regarding medication resistance andinterventions to prevent transmission of resistant organ-

isms. Determining the appropriate diagnoses of whenantibiotics are truly needed and for how long remains achallenge. It is beneficial to keep families apprised of thepatient status if the condition is one of “wait and watch”before blindly beginning antibiotic therapy for uncertainconditions. It is important to document that the provideris monitoring the condition of the patient.

The random use of broad spectrum antimicrobials forextended periods of time leads to overuse and misuse. Theconsequence of such activity has led to significant health-care associated infections (HAI), c. difficile infections andmulti resistant organisms. Providers can benefit fromknowledge gleaned from local antibiograms and frequentreassessment of culture sensitivities to help guide theirchoice of antibiotics. The South Dakota Department ofHealth is deeply involved in this area and their websiteoffers stewardship resources for healthcare facilities at alllevels, especially in long-term care. They have fostered anAntimicrobial Stewardship Workgroup that allows multiple organizations an opportunity to coordinateefforts in this ongoing struggle: https://doh.sd.gov/dis-eases/hai/stewardship.aspx.

The Great Plains Quality Innovation Network (QIN) hasa quality improvement initiative for CombatingAntibiotic Resistance through Antibiotic Stewardship inCommunities. We hope to recruit providers and spreadthe principles of antimicrobial stewardship in the clinicand outpatient setting. This would include activity in theFour Core Elements: 1) commitment, 2) action for practice and policy, 3) tracking and reporting and 4) education and expertise. The Great Plains QIN Learningand Action Network (LAN) will provide access to tools,resources, education and subject matter experts. This is anopportunity to network and learn from the experience ofothers with similar interests and goals. This project ismainly educational and not structured to burden providerswith excessive time or mandatory reporting. The aim is toprovide a platform for outpatient antibiotic prescribingthat will, hopefully, reduce unnecessary use. Please contact Cheri Fast at Cheri.Fast@area-A.hcqis.org if youhave interest in this activity. Ongoing efforts at appropri-ate use will need to disseminate into the outpatient andlong-term care settings in order to deliver appropriateantibiotic stewardship. Feel free to contact me in reference to the above mentioned activities atstephan.schroeder@area-A.hcqis.org.

This material was prepared the Great Plains Quality Innovation Network, the Medicare Quality Improvement Organization for Kansas, Nebraska, North Dakotaand South Dakota, under contract with the Centers for Medicare & Medicaid Services (CMS), an agency of the U.S. Department of Health and Human Services.The contents presented do not necessarily reflect CMS policy. 11S0W-GPQIN-SD-C.3.10-211/0517.

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March basketball tournaments werebouncing along the TV screenwhen a player fell. The replay

showed how one fellow was shoved off balance and came down trying to stop hisfall. The camera was watching as his anklegave way and the foot turned inward. Whenhe stood again, he was limping and I couldalmost feel his pain, made more obvious bythe disappointment on his face. It wasunavoidable, he was out of the game andtournament with an injured ankle.

I don’t know for sure, but I imagine thetrainer examining his foot and noting nodeformity, making it less likely to be a broken bone. As the examiner feels the outside areas ofthe ankle, I can almost hear the player admonishing thetrainer. “Stop it. That’s where it hurts.” As the player’sfoot turned in, most likely one or more of the three outside ligaments were stretched and possibly torn.

Ligaments are the very tough fibrous tissue that connectbone-to-bone, which are different than tendons, connectingmuscle-to-bone. In this player’s case, it’s likely the ligaments involved were those that tie the outer bone ofthe lower leg to the ankle bones of the foot and that aremeant to keep the ankle from turning too far inward.Ligaments between bones are strong bonds and allow forminimal movement while preserving stability. Test yourown ankle movement by repositioning the ankle side-to-side or inward and outward. Note how limited thatmotion is when compared to the up and down movementof the foot as the calf muscles and Achilles tendon pushyou off, helping you walk or run.

Without the side-to-side stability ligaments, the footwould not be capable of normal walking on irregularground, let alone the running, turning, and leapingrequired to play in a basketball game. What is almost moreincredible is how pain from such an injury forces us to restand protect the ankle so it can heal.

The treatment for this injury and for almost any ligamentor tendon injury, is directed by the mnemonic RICE. R isfor rest, I for ice, C for compression wrap, and E for elevation. Most certainly, the trainer will use those directives and over the next two weeks, the player willgradually move back to careful and easy walking onceagain. In about six weeks, 90 percent of the healing will beachieved.

Next season he will be ready to play again.

P a t i e n t E d u c a t i o n :

Dr. Rick Holm wrote this Prairie Doc Perspective for “On Call, “ a weekly program where medical professionals discuss health concerns for the general public.“On Call “ is produced by the Healing Words Foundation in association with the South Dakota State University Journalism Department. “On Call “ airs Thursdays on

South Dakota Public Broadcasting-Television at 7 p.m. Central, 6 p.m. Mountain. Visit us at OnCallTelevision.com.

The Story of a Badly Sprained Ankle By R i c h a r d P. Ho lm , MD

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Thank You

Lisa B. Brown, MD

Howard W. Burns, MD

Philip James Eckhoff, Jr., MD

Harry Ward Hamlyn, MD

Jennifer K. May, MD

Stephan J. Miller, MD

Mary J. Milroy, MD

Homer J. Stensrud, MD

Ralph J. Tullo, MD

Lonnie L. Waltner, MD

SDSMA FOUNDATION

Donations

BENEFITFor Your Benefit:

The SDSMA provides practice managementconsulting at below-market prices, hands-onhelp with payment problems and a compre-hensive array of services to help you takecare of the business side of your practice.

• The SDSMA has access to the risk management and information technology expertise and advice of the Midwest Medical Insurance Company (MMIC);

• Legal briefs are available to SDSMA members on SDSMA’s website, www.sdsma.org.

The challenges of practicing medicine havenever been greater, and the added challengesof administering a practice can be daunting.We can help. Give us a call at 605.336.1965,or visit our website today at www.sdsma.org.

We are grateful for your attention andappreciate the trust you have placed in us.Thank you for being a member of theSDSMA.

Providing Solutionsfor Your Practice

“For Your Benefit” is the Association’smonthly update on programs and services

available to physicians through their affiliation with SDSMA.

Member NewsVisit www.sdsma.org for the latest news and information.

237May 2017

Registration Deadline Approaching – 2017SDSMA Annual Leadership Conference

The 2017 SDSMA Annual Leadership is in Deadwood on Friday, June 2. The May 19 deadline to register is quickly approaching.

With presentations, discussions, networking opportunities and social events, the AnnualLeadership Conference is a great time to share ideas and learn from fellow members.

Check out the schedule and events! Do you have a policy issue you’d like to bring tothe SDSMA’s attention? Learn how to address the Council at www.sdsma.org.Members have until May 5 to submit issues for consideration.

The Annual Leadership Conference is a benefit of your membership. For the latestdetails about exciting events taking place during the 2017 SDSMA Annual LeadershipConference, visit www.sdsma.org. Buy your tickets for the banquet and SDSMA PAClunch online.

Those who need a hotel room may call SpringHill Suites at 605.559.1600 or CadillacJacks at 605.578.1500 and ask for the South Dakota State Medical Association block.

S C H E D U L E 8 am

Membership Meeting with presentations from AMA Chair-Elect Gerald E. Harmon, MD and SSOM Dean Mary Nettleman, MD

9:15 amMembership Open Forum

10:45 amPanel Discussion: Physician Burnout

12 pmSDSMA PAC Lunch: “Clinician Health and Wellbeing – Reducing

the Cost and Impact of Physician Burnout”

1:30 pmCouncil of Physicians Meeting

4:30 pmPolicy Council Meeting

6 pmMembership Mixer

7 pmAwards Banquet & Scholarship Recognition

During the SDSMA Annual Leadership Conference, the SDSMAPAC will feature a speaker on the topic of physician burnout.

The SDSMA PAC lunch presentation, “Clinician Health andWellbeing – Reducing the Cost and Impact of Physician Burnout,”will be held from 12-1:30 pm Friday, June 2 at the SpringHill Suites& Cadillac Jacks in Deadwood. The speaker will be Laurie Drill-Mellum, MD, MPH, chief medical officer and vice president of

safety solutions at MMIC.

SDSMA PAC Lunch tickets are $40 and are available atwww.sdsma.org. Please purchase your tickets by May 19.

It’s not too late to register for all of the activities taking place dur-ing the Annual Leadership Conference – find more information atwww.sdsma.org.

Physician Burnout is Topic of SDSMA PAC Lunch

Members are invited to the SDSMA’s Membership Mixer from 6-7pm Friday, June 2 at SpringHill Suites/Cadillac Jacks during the2017 SDSMA Annual Leadership Conference.

Enjoy a unique and fun opportunity to meet SDSMA leaders andnetwork with your peers. Meet other physicians in the state toexpand your professional network and share ideas. The event is

sure to be an all-around great time! Spouses are welcome toattend. Drinks and hors d’oeuvres will be served.

The mixer is free of charge. Tickets are required for the AwardsBanquet & Scholarship Recognition following the mixer. To buybanquet tickets, please visit www.sdsma.org or call 605.336.1965.

Membership Mixer is Networking Opportunity

Enjoy a fun-filled evening of celebration Friday, June 2 at the 2017SDSMA Annual Leadership Conference at SpringHill Suites/CadillacJacks in Deadwood.

Start the evening with the Membership Mixer at 6 p.m., and continue the celebration at the Awards Banquet and ScholarshipRecognition, where Robert E. Van Demark, Jr., MD, will be swornin as SDSMA president, awards will be bestowed upon fellow

colleagues, outgoing and incoming officers will be celebrated andwelcomed, and medical student scholarship recipients will be recognized.

The mixer is free of charge; banquet tickets are $65 and must bepurchased in advance. To buy tickets and register for other annualmeeting activities, visit sdsma.org. Please purchase tickets andregister by May 19.

Join Us for Awards Banquet & Scholarship Recognition

238

Syphilis, gonorrhea, and chancroid, venereal diseases must bereported to the appropriate public health officials and treatment forthe disease may be required by state, county or municipal healthofficials. Physicians must take a blood sample from every pregnantwoman to test for syphilis. The occurrence of the test must berecorded upon the birth or stillbirth of the child. Upon receipt ofconsent from parents or guardians, minors may be treated. Minorsmay seek treatment, absent such consent, from county or state

health departments.

For more information, download the SDSMA legal brief VenerealDisease at www.sdsma.org. Through the SDSMA Center forPhysician Resources, the SDSMA has developed more than 50legal briefs that are available to members. In addition, the Centerdevelops and delivers and programs for members in the area ofpractice management, leadership and health and wellness.

Legal Brief Highlight: Venereal Disease

Member News

239May 2017

The Issue Is…

ISSUEThe Issue Is...

The American Medical Association and other organizations repre-senting insurers, hospitals, health plan purchasers, have sent letters to President Trump and Congressional leaders urging themto address an imminent threat to the stability of the individualhealth insurance market.

Cost-sharing reduction subsidies for certain low-income enrolleesin marketplace exchange plans have been financed through payments made to insurers by the U.S. Department of Health andHuman Services. These subsidies reduce out-of-pocket costs forpatients who might otherwise be unable to afford health care services despite being insured. The U.S. House of Representativessued the Obama Administration over the way these paymentswere financed – without specific appropriations by Congress. Adistrict court held that the cost sharing payments were, in fact,unconstitutional, but stayed an injunction on making the payments

to avoid a collapse of the marketplace while the administrationappealed the decision. After the elections, the House successfullypetitioned the appeals court to put the case on hold, arguing thatsignificant health care policy changes were imminent, but absentsignificant movement on health system reform legislation theappeals court will likely move forward in coming months. Since thelaw requires insurers to finance these subsidies regardless ofwhether they receive federal payments to do so, they would faceenormous financial losses and leave the market, leaving millions ofAmericans without insurance and likely causing disruptionsthroughout the system.

The letters ask policymakers to act quickly to ensure that thesecost sharing reduction payments continue while broader market-place stabilization efforts are developed.Source: AMA

AMA, Other Organizations Send Letters to Trump & Congressional Leaders

“The Issue Is” is the SDSMA’s monthly update on key policy issues of importance to physicians.

Member News

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CONTACT:Elizabeth Reiss, South Dakota Medicine

PO Box 7406, 2600 W. 49th Street, Suite 200Sioux Falls, SD 57117-7406

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