April 2015 by McMahon Group

CONVENTION ISSUE:

Society of American Gastrointestinal and Endoscopic Surgeons

GENERALSURGERYNEWS.COM

April 2015 • Volume 42 • Number 4

The Independent Monthly Newspaper for the General Surgeon

Opinion

Physicians Express Concern Over Sunshine Act Rollout

Superbugs B Y F REDERICK L. G REENE , MD

he history of medicine is replete with documentation of infections caused by previously unknown organisms that have challenged patients, surgeons, infectious disease experts and antibiotic manufacturers. The discovery and purification of penicillin was spurred on by the untold number of deaths from pneumococcal pneumonia and the soft tissue infections created during wartime conflicts. The first person treated with penicillin in 1941 was a police officer from London who had multiple facial abscesses. The officer initially responded to treatment, but eventually succumbed to overwhelming infection when the small supply of penicillin was exhausted. In more modern times, and as a consequence of treatment, resistant strains of bacteria have led to a repeated cycle of developing more potent antibacterial drugs. In recent decades, we have become challenged with multidrug-resistant Mycobacterium tuberculosiss (MDR-TB), methicillin-resistant Staphylococcus aureuss (MRSA) and Clostridium difficile. A study by the Centers for Disease Control

Many Support Transparency Goal, But Website Leaves Chore Of Correcting ting Data and Guarding Reputations to Doctors B Y V ICTORIA S TERN

octors and d pharmaceutical and device companies have worked hand-- in-hand to advance medicin ne throughout history. Withoutt such teamwork, essential innovations may have lived in obscurity or not have been n developed at all. Yet, research and experience havv e also revealed th hat such financial tiees can lead to bias in a doctor’s decision making,, for instance influencing the drug he or she prescribes or the device used. In some cases, this influence may be detrimental to patients, scien ntific research or our health care system.

Robotics for General Surgical Procedures

Hepatopancreatobiliary Surgery

see SUPERBUGS page 3

Experienced Robotic Surgeon Offers Thoughts B Y C HRISTINA F RANGOU

Managing Venous Thromboembolism Risk in Hereditary Antithrombin Deficiency See insert after page 32

SAN FRANCISCO—Amer H. Zureikat, MD, and his colleagues at the University of Pittsburgh have accumulated

the largest series of robotic hepatopancreatobiliary (HPB) procedures in the world, having performed almost 500 robotic HPB surgeries since 2010. At the 2014 Clinical Congress of

INSIDE In the News

Surgeons’ Lounge

On the Spot

Controversy Swirls Around Rising Rates of Contralateral Prophylactic Mastectomy

see SUNSHINE page 28

A Patient with a Complex Bile Duct Injury

Colleen Hutchinson Poses Questions on Controversial Issues in Colorectal Cancer Treatment to Several World Experts

see ROBOTICS page 21

Gastric Bypass Tied To Alcohol Use Disorder B Y K ATE O'R OURKE BOSTON— —About 17% of patients who und dergo Roux-en-Y gastric bypasss (RYGB) have an alcohol usee disorder three years after their su urgery, according to a study presented at Obesity Week 2014. This raate is approximately 10% higher than n what is seen in the general population n, as found in dataa from the National Insttitutes of Health ealth (NIH). James Miitchell, MD MD, chairman off the DepartDe ment of Psyychiatr try and Behavioral Scieence, University of o North N Dakota School of Medicine and Health Sciences, Graand Forks, who presented the study (abstract 20 01), said the h fi findings di suggest that alll patients ti t undergoing RYGB need to be cautioned regarding alcohol use, and routinely asked about such problems during follow-up visits. see ALCOHOL DISORDER page 4

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SUPERBUGS

jcontinued from page 1 and Prevention (CDC), published in The New England Journal of Medicine, reported that in 2011, C. difficilee infection in the United States sickened an estimated 453,000 individuals and was associated with 29,000 deaths. As byproducts of more aggressive hand-washing and other preventive measures, some good news has been recently reported regarding MRSA. The CDC reported that invasive MRSA infections that began in hospitals declined 54% between 2005 and 2011, with 30,800 fewer severe MRSA infections. Additionally, there were 9,000 fewer deaths caused by MRSA in hospital patients in 2011 than in 2005. During the 1980s, as HIV and AIDS were being recognized, many physicians who performed endoscopy, including myself, became concerned about viral transfer through endoscopes from HIV patients to uninfected individuals. Timely and well-documented guidelines for cleaning and disinfecting equipment were generated by the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) as well as other organizations. We quickly learned that HIV was labile in the presence of routine disinfection maneuvers for both upper and

lower gastrointestinal (GI) endoscopes. In more recent times, we have dealt with outbreaks of vancomycin-resistant enterococci (VRE) that have been controlled by aggressive hand-washing recommendations. Now we have become aware of carbapenem-resistant Enterobacteriaceae (CRE), but with a twist: CRE has been transmitted through endoscopes during endoscopic retrograde cholangiopancreatography (ERCP) procedures! On Feb. 19, the Los Angeles Times reported that “179 patients at UCLA’s Ronald Reagan Medical Center may have been exposed to potentially deadly bacteria from contaminated medical scopes, and two deaths have already been linked to the outbreak.” According to the Times, the two people who died were among seven patients who UCLA found were infected by the drug-resistant superbug known as CRE after having undergone ERCP between October 2014 and January 2015. A spokesperson at the hospital announced that two scopes were implicated and that both scopes had been ”sterilized according to the manufacturer’s specifications.” CDC officials announced “they were assisting the LA County Department of Public Health in its investigation of the UCLA infections.” Other endoscope-related

outbreaks have been identified at CedarsSinai Medical Center as well as at hospitals in Seattle, Pittsburgh and Chicago. CRE outbreaks are difficult to treat because some varieties are resistant to most known antibiotics. The CDC also estimates that CRE can contribute to death in up to half of seriously infected patients. Further investigation has uncovered that the CRE microbes were hiding in the interstices of the lever mechanism at the end of the duodenoscopes used for ERCP. Consequences of this type of infection and its transmission are obviously far-reaching as the mechanics of flexible endoscopes become more complex and create greater challenges for cleaning these instruments. Obviously, many entities must band together to find appropriate answers for the current CRE crisis as well as those unsuspected, but anticipated, antibioticresistant organisms that we have yet to face. Patients in many other institutions where GI endoscopy is performed are at risk. This scenario is another example of the importance of having physician input into the design and maintenance of complex instrumentation. Appropriate and updated guidelines issued by SAGES as well as other organizations having an interest in endoscopic procedures are mandatory. The

Michael Goldfarb, MD

Frederick L. Greene, MD

Long Branch, NJ

Charlotte, NC

Leo A. Gordon, MD

Editorial Advisory Board Maurice E. Arregui, MD Indianapolis, IN

Kay Ball, RN, CNOR, FAAN Lewis Center, OH

Philip S. Barie, MD, MBA New York, NY

L.D. Britt, MD, MPH Norfolk, VA

David Earle, MD Springfield, MA

James Forrest Calland, MD Philadelphia, PA

Edward Felix, MD Fresno, CA

Los Angeles, CA

Gary Hoffman, MD Los Angeles, CA

Namir Katkhouda, MD Los Angeles, CA

Jarrod Kaufman, MD Freehold, NJ

Michael Kavic, MD

Sales

Marietta, GA

Michael Enright Group Publication Director (212) 957-5300, ext. 272 menright@mcmahonmed.com

Omaha, NE

Richard Peterson, MD San Antonio, TX

Joseph J. Pietrafitta, MD Minneapolis, MN

David M. Reed, MD New Canaan, CT

Barry A. Salky, MD New York, NY

Paul Alan Wetter, MD Miami, FL

Peter K. Kim, MD

Editorial Staff

Bronx, NY

Kevin Horty Group Publication Editor khorty@mcmahonmed.com

Milwaukee, WI

Raymond J. Lanzafame, MD, MBA Rochester, NY

Timothy Lepore, MD

Robert J. Fitzgibbons Jr., MD

Shawnee Mission, KS

Youngstown, OH

Lauren A. Kosinski, MD

Nantucket, MA

John Maa, MD

David R. Flum, MD, MPH

San Francisco, CA

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mcmahonmed.com © 2015 by McMahon Publishing, New York, NY 10036. All rights reserved. General Surgery Newss (ISSN 1099-4122) is published monthly by McMahon Publishing, Sales, Production, Finance and Editorial Offices: 545 W. 45th St., 8th Floor,

—Dr. Greenee is clinical professor of sur— gery, University of North Carolina School of Medicine, Chapel Hill, N.C.

J. Barry McKernan, MD Joseph B. Petelin, MD

Senior Medical Adviser

CRE story is another example of infectious organisms finding ways to mutate as we in the medical community continue to employ aggressive newer antibiotics in the management of GI and other diseases. At least in the realm of surgical technology, the interaction between physicians and instrument makers is vital to ensure that superbugs don’t get the upper hand. Finally, the ongoing CRE story also raises a concern regarding the possibility of transmitting these organisms unwittingly to other populations as we, acting as Good Samaritans, send previously used endoscopes and other instrumentation to remote locations around the world. Many individuals, hospitals and organizations have created mechanisms to export used instrumentation. It would certainly be a global tragedy if we unwittingly transmitted resistant organisms such as CRE through this type of technical support. We must protect our own patients and also those who might benefit from previously used instrumentation in order to keep superbugs that have mutated on our shores away from unsuspecting, vulnerable, at-risk populations.

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In the News ALCOHOL DISORDER jcontinued from page 1

The study included 201 RYGB patients in the Longitudinal Assessment of Bariatric Surgery (LABS), an NIH-funded consortium of six clinical centers and a data-coordinating center that works with NIH staff to conduct research involving bariatric surgery. Patients were interviewed three years after surgery, using the Structured Clinical Interview for DSM Disorders (SCID-DSM)-IV, and accessory impulse control disorders criteria. SCID criteria for alcohol use disorder require a positive response to ingestion of five or more drinks on one occasion as a screening question, which based on pharmacokinetic research in RYGB patients, is excessive. The researchers also evaluated patients with the Alcohol Use Disorders Identification Test (AUDIT), which assigns a score based on answers to a series of questions, such as how often during the past year the respondent failed to do what was normally expected because of drinking. Alcohol use disorder symptoms were defined as an AUDIT score greater than 8, or a positive response to symptoms of alcohol dependence or alcohol-related harm. The median age of patients in the study was 48 years, and 81% were women. The investigators found that 16.9% of patients had an alcohol use disorder three years after RYGB, with 41.2% of them being a de novo problem (Table 1). Patients with a history of alcohol abuse were at highest risk, but some reported that cases were new. Conversely, 26.9% had a history of alcohol use disorder before surgery by SCID and/or AUDIT definition, but did not report symptoms of an alcohol use problem within the three years after surgery. The investigators also identified fluctuations in other addictive disorders, such as impulsive-compulsive buying and Internet use (Table 2). The study adds to the growing body of evidence showing an association between weight loss surgery and alcohol abuse. “There is definitely enough convincing evidence that some patients are at risk for problems with alcohol after [weight loss] surgery,” said Stephanie Sogg, PhD, staff psychologist at Massachusetts General Hospital, and assistant professor at Harvard Medical School, both in Boston.

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Table 1. Characterization of Patients With an Alcohol Use Disorder After Bariatric Surgery Alcohol Use Category Patients, %

Definition

Continued alcohol use 20.6 disorder

Positive on the AUDIT the year before surgery, and continues to meet SCID-IV and/or AUDIT criteria after surgery

Recurrent alcohol use 38.2 disorder

Negative on the AUDIT in the year before surgery, but positive for lifetime presurgery (SCID) and postsurgery (SCID and/or AUDIT)

New alcohol use disorder

No history of alcohol use disorder before surgery (SCID or AUDIT) but positive for the disorder after surgery (SCID and/or AUDIT)

41.2

AUDIT, Alcohol Use Disorders Identification Test; SCID, Structured Clinical Interview for DSM Disorders-IV

Table 2. Prevalence of Non–Drug-Related Compulsive Disorders Pre-Op, %

Pre- and Post-Op, %

Post-Op, %

Overall non–drug-related addictive behavior disorders

6.5

Impulsive-compulsive buying

5.5

1.5

Impulsive-compulsive Internet use

0.5

Dr. Sogg, who gave an overview of the evidence at Obesity Week, pointed out that numerous studies have been published about alcohol use after bariatric surgery, but many have small sample sizes and/or low response rates, and almost all are retrospective. The studies also use a wide range of assessment methods (i.e., questionnaires and interviews) and different definitions of alcohol use, misuse and abuse, which makes comparison across studies difficult. “Some studies merely look at alcohol use. Others look at high-risk, hazardous or problem drinking, and some studies look at whether patients have symptoms of or meet the criteria for alcohol abuse or dependence,” Dr. Sogg said. Many studies also don't make a distinction between three different subgroups: individuals who have alcohol problems at the time of surgery and continue to have problems afterward, recovered substance abusers who relapse after surgery and individuals who develop newonset alcohol problems after surgery. “These are three very clinically distinct subgroups and many studies lump them all together,” she said. Dr. Sogg pointed out that overall, studies have shown that after weight loss surgery, there is an increase in alcohol use, with a higher percentage of patients reporting any alcohol use as well as increased quantities and/or frequencies of alcohol consumption among those who use it. A previous study using data from LABS showed that the risk for developing an alcohol use disorder was greater in the second year after surgery than the first ( (JAMA A 2012;307:2516-2525). The Swedish Obese Subjects Study found that the rate of self-reported alcohol problems continued to increase for 10 years (Obesity 2013;21:2444-2451). “Across all of the studies, the prevalence of alcohol problems after surgery ranges from 4% to 28%, with about 10% meeting criteria for abuse/dependence; this includes patients who previously had these problems,” Dr. Sogg said. “What is strikingly consistent is that across all studies, if you look at all of the people who develop problems with alcohol after surgery, about 60% of those cases are new-onset cases.” In contrast, some individuals reduce alcohol intake after weight loss surgery. “Anywhere between 17% and 59% of patients who had problem drinking before surgery reported being free of such problems when they were

assessed at some point after surgery,” Dr. Sogg noted. Weight loss surgery may have opposite effects on drinking patterns, depending on an individual's genotype or phenotype. Studies in rats have revealed that RYGB increases alcohol consumption in wild-type rats (who ordinarily do not like alcohol) and decreases consumption in genetically “alcohol-preferring” rats (Obes Surg 2013;23:920-930; Biol Psychiatryy 2012;72:354-360). RYGB in particular can change the sensitivity to or the pharmacodynamics of alcohol after weight loss surgery. After RYGB, patients who drink alcohol reach a higher peak blood alcohol level more quickly, and a longer time is required for alcohol to clear out of their system (Surg Obes Relat Diss 2007;3:543-548; Obes Surgg 2010;20:744748). “These changes become more pronounced as time goes on after surgery, not less pronounced,” Dr. Sogg said. These pharmacodynamic changes may be linked to the onset of alcohol problems after RYGB. “People who have alcohol problems after surgery are much more likely to have undergone a bypass, and that makes us suspect that there is some anatomic and metabolic basis for this.” Research findings on whether similar pharmacodynamic changes occur in patients who had a sleeve gastrectomy are mixed; such changes were found in one study but not in others, and no studies have yet examined the prevalence of alcohol problems among patients who have had a sleeve gastrectomy, a procedure that only recently has been performed in large numbers. Factors common to both the gastric bypass and sleeve gastrectomy that could lead to higher and more rapid blood alcohol concentrations include less alcohol dehydrogenase in the stomach, faster gastric emptying, shorter transit time in the intestines to break down the alcohol, lower body weight and less food in the stomach when alcohol is consumed. “We tell our bariatric surgery patients not to eat and drink at the same time. If you drink on an empty stomach, you are definitely going to feel more intoxicated,” Dr. Sogg said. She said it is important for clinicians to ensure that all patients undergoing weight loss surgery be screened for alcohol use problems before surgery and be educated about the risk for postoperative problems. Dr. Sogg counsels patients to be watchful for early warning signs of increased alcohol consumption, and not to drink at all after surgery if they are going to drive.

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In the News

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

Severely Obese Subgroup Fares Worse After Bariatric Surgery, Study Shows Upper BMI Threshold Found; Experts Urge Caution in Interpreting Data B Y C HRISTINA F RANGOU

ike several other studies before, a study published recently in Annals of Surgery reported that bariatric surgery significantly increases life expectancy in obese individuals.

However, this analysis also showed that a small subgroup of patients will have a shorter life expectancy after undergoing a bariatric procedure for weight loss. Adults with a body mass index (BMI) greater than 60 kg/m2 who also have diabetes experience a reduction in life expectancy after bariatric surgery, according to the study. “For most severely obese patients with diabetes, bariatric surgery seems to improve life expectancy; however,

surgery may reduce life expectancy for the super obese with BMIs over 62 kg/ m2,” wrote the authors, led by Daniel P. Schauer, MD, MSc, assistant professor of internal medicine, University of Cincinnati College of Medicine, in the report published online in February (Ann ( Surg 2015; doi: 10.1097/ SLA.0000000000000907). The team of surgeons, internal medicine physicians and clinical researchers created a decision-analytic model

to estimate the balance between treatment risks and benefits for severely obese patients with diabetes. They used data from three large cohorts: 159,000 severely obese diabetic patients, including 4,185 who underwent bariatric surgery, from three HMO Research Network sites; 23,000 patients from the Nationwide Inpatient Sample; and 18,000 patients from the National Health Interview Survey linked to the National Death Index.

Experts in bariatric surery and bariatric medicine say the study raises questions about bariatric surgery in these severely obese patients, but does not show conclusively that there is no survival benefit.

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Analysis showed that the vast majority of severely obese diabetic patients live longer after bariatric surgery than otherwise expected. According to the model, a 45-year-old woman with diabetes and a BMI of 45 kg/m2 gained an additional 6.7 years of life expectancy with bariatric surgery (38.4 years versus 31.7 years without surgery). However, as BMI increased, the gain in life expectancy decreased. When BMI levels reached 60 and greater, bariatric surgery was associated with a net loss in life expectancy. “At [that] point, no surgery is the preferred strategy,” wrote the researchers. Similar results were seen for men and women in all age groups. The study did not examine race. Experts in bariatric surgery and bariatric medicine say the study raises questions about bariatric surgery in these severely obese patients, but does not show conclusively that there is no survival benefit. “This statistical decision-making model raises some questions about the mortality benefit of bariatric surgery in this high-BMI group of patients, but should not deter patients in this group from seeking bariatric surgery. Similarly, [these] data should not be used by bariatric surgeons to make individual clinical decisions with patients in this high-BMI group,” said Stacy Brethauer, MD, staff surgeon at the Bariatric and Metabolic Institute at the Cleveland Clinic, in Ohio. “The best we can say at this point is that it is uncertain what the survival benefit will be for this group of patients,

In the News

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

since it hasn’t been adequately studied in a prospective clinical trial.” Dr. Brethauer, who performs bariatric surgery in patients with BMI greater than 60, said the benefits of surgery “far exceed” the risks, even in severely obese patients. “There are benefits to patients in terms of diabetes control and other comorbidities that weren’t examined in this study.” Oliver Varban, MD, director of the Adult Bariatric Surgery Program at the University of Michigan Health System in Ann Arbor, said the study findings are contrary to what he expected. “One would expect that patients with a higher BMI would have the most benefit from successful weight loss after bariatric surgery.” The results of the study may be different if the analysis were repeated today, he noted. Bariatric surgery changed during the study’s timeline. Most bariatric procedures are now performed laparoscopically, resulting in fewer complications and deaths, and shorter hospitals stays. Sleeve gastrectomy is performed more often, and gastric banding has fallen out of favor. Instead of deterring patients from bariatric surgery, the study results should encourage patients to undergo surgery earlier in the disease process and before their BMI reaches 60, Dr. Varban said. “Patients with a BMI over 60 may lose a substantial amount of weight [more than 100 lb] after bariatric surgery but still be considered morbidly obese, in which case they may not achieve all of the benefits from surgery because their comorbidities remain. In this respect, I think it is important to offer bariatric surgery as a weight loss intervention for patients at an earlier stage [BMI 35-45], before their BMI increases to an unmanageable level.” In an interview, Dr. Schauer said it is unclear why diabetic patients with a BMI greater than 60, who represent less than 3% of the bariatric surgery patients in national databases sampled, may experience a decrease in life expectancy after surgery. “There are several theories but until more research is done, the reason remains unknown. It may be that the super obese, while losing a large proportion of their excess weight, are less likely to lose enough to be classified as overweight or obese. They may have a longer duration of diabetes and are less likely to have remission after surgery.” The investigators noted that diabetic patients with a BMI greater than 60 kg/m2 may still reap benefits from surgery, such as improved quality of life and reduced burden of obesity-associated diseases. These measures were not included in the model.

AT A GLANCE Researchers used data from three large cohorts of patients. The vast majority of patients live longer after bariatric surgery. As body mass index increased, gain in life expectancy decreased.

A body mass index greater than 60 kg/m2 was associated with a loss in life expectancy. Results may be different if analysis were reported today due to increased use of laparoscopy and changes in surgical approaches.

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In the News

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

Controversy Swirls Around Rising Rates of Prophylactic Mastectomy B Y K ATE O’R OURKE SAN ANTONIO—For more than a decade, the rate of contralateral prophylactic mastectomy (CPM) has been rising in patients with unilateral breast cancer. At the San Antonio Breast Cancer Symposium (SABCS), clinicians discussed the controversy and some of the drivers behind this trend. CPM rates have skyrocketed in the

United States, from an estimated 1.9% in 1998, to 4.5% in 2003 and 11.2% in 2011 ((J Clin Oncoll 2007;25:5203-5209; JAMA Surgg 2015;150:9-16). Numerous studies, however, have shown that CPM does not improve survival over unilateral mastectomy or breast-conserving surgery plus radiation. “There is really very little to support the widespread use of CPM, and the increasing trend toward greater use of CPM is perplexing,” said Ismail Jatoi,

MD, PhD, from the Division of Surgical Oncology and Endocrine Surgery at the University of Texas Health Science Center, in San Antonio. “Contralateral prophylactic mastectomy is not justified, except in a few instances. For example, it would be justified in patients who harbor the BRCA1/BRCA2 gene [mutation], where the risk of contralateral breast cancer is very high.” In a study of BRCA1/2 mutation carriers, the 10-year survival rate was 89%

in women receiving CPM and 71% in women receiving unilateral mastectomy (P<0.001) (Breast Cancer Res Treat 2013;140:135-142). But setting aside these high-risk women, most clinicians do not feel evidence supports CPM. “It seems counterintuitive that in an era of minimally invasive surgery, in a time when surgical oncologists are trying to remove only that which they have to, that the women themselves are actively choosing more aggressive surgery, despite the fact that there is no survival benefit,” said Andrea Pusic, MD, associate professor of plastic and reconstructive surgery at Memorial Sloan-Kettering Cancer Center, in New York City.

The Message Is Not Getting Through Although patients are told that numerous studies show that CPM does not improve survival, this message does not seem to be getting through, according to results of a study by Rosenberg et al surveying 123 women ((Ann Intern Medd 2013;159:373-381). “When we asked women, ‘why did you choose CPM,’ 90% told us improved survival was one of the important reasons,” said Ann Partridge, MD, MPH, a senior physician and director of the Program for Young Women with Breast Cancer at Dana-Farber Cancer Institute, in Boston, who was involved with the study. According to Dr. Jatoi, a few recent studies have identified an association between CPM and an improvement in breast cancer–specific and overall survival; however, a selection bias is the most likely reason for this finding in women who are not high risk (Breast Cancer Res Treatt 2013;142:465-476; J Natl Cancer Instt 2010;102:401-409). In a recent analysis of almost 500,000 patients, CPM was associated with a 16% reduction in breast cancer–specific mortality, a 17% reduction in allcause mortality, but an even greater reduction, 29%, in noncancer mortality (Breast Cancer Res Treatt 2014;148:389396). “Obviously CPM should not have any effect on noncancer mortality,” said Dr. Jatoi. “What this suggests is that there is a strong selection bias favoring women who undergo CPM. Women who undergo CPM are perhaps a healthier cohort of women or a cohort of women with better access to health care.” Dr. Jatoi pointed out that the risk for a woman with unilateral breast cancer to develop a cancer in the opposite breast has decreased since 1985, when hormonal therapy became standard. EXP-AP-0020-201301

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GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

emotionally, and they articulate to me on a regular basis, ‘I wish I had the other side off,’” Dr. Pusic said. The downsides of CPM include detrimental sexual and emotional effects, and an increased risk for surgical complications. Benjamin Anderson, MD, a professor of surgery at the University of Washington and the director of the Seattle Cancer Care Alliance’s Breast Health Clinic, said he believes some women have unrealistic beliefs about how their reconstructions will work, particularly in relation to nipple sensation. “I have often had patients come in

‘It seems counterintuitive that in an era of minimally invasive surgery ... that the women themselves are actively choosing more aggressive surgery, despite the fact that there is no survival benefit.’ —Andrea Pusic, MD Studies show, however, that women overestimate their risk. The survey by Rosenberg et al showed that the average-risk woman believes she has a 10% chance of developing contralateral breast cancer without CPM within five years of her surgery. This is much higher than the roughly 1% rate identified in the scientific literature (2012 SABCS, abstract 69). Dr. Partridge said that some women may be unable to comprehend their cancer risk because of innumeracy or because they are like a “deer in headlights” after a breast cancer diagnosis. Others, especially very young women, might think the risk estimates do not pertain to them. “Your risk of getting breast cancer is on the order of one in 2,000 if you are [age] 35, or one in 200 if you are 40,” noted Dr. Partridge. But, she added, women who already have had a breast cancer often say, ‘I wasn’t supposed to get breast cancer in the first place, and now you are going to tell me it is not going to happen again. Why wouldn’t it happen again!’ These women often articulate that they feel like they have a target on their back, and they want to do everything they can to get rid of it.” Other women might believe that any risk for developing additional cancer is too much risk. According to Dr. Partridge, one advantage to CPM is the diminished need for surveillance. “This has real value for some women,” she said. Dr. Pusic agreed. “I have women who are traumatized by the follow-up mammogram

and say, ‘no one told me that I would be numb,’” said Dr. Anderson.

Who Is Choosing CPM? An analysis of the National Cancer Data Base revealed that the majority of patients who opt for CPM have no major genetic or familial risk factors for contralateral disease (JAMA ( Surgg 2014 May 21. [Epub ahead of print]). Women are more likely to choose CPM if they have higher baseline levels of anxiety, have a child, are more worried about recurrence or have genetic testing, regardless of whether the see MASTECTOMY page 14

Surgeons’ Lounge

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

Dear Readers, Welcome to the April issue of The Surgeons’ Lounge. This issue features Roberto Gedaly, MD, FACS, chief, abdominal transplant program, Department of Surgery, Transplant and Hepatobiliary Division, University of Kentucky, Lexington. Dr. Gedaly discusses the case of a patient with complex bile duct injuries associated with a vascular injury. Take the Surgeon’s Challengee and look for the answer in the next issue! We welcome your questions and comments. Sincerely, Samuel Szomstein, MD, FACS Editor, the Surgeon’s Lounge Szomsts@ccf.org

Dr. Szomstein n is associate director, Bariatric Institute, Section of Minimally Invasive Surgery, Department of General and Vascular Surgery, Cleveland Clinic Florida, Weston.

Question

Dr. Gedaly’s

for Roberto Gedaly, MD Valery Vilchez, MD, Research Fellow, Department of Surgery, Transplant and Hepatobiliary Division, University of Kentucky, Lexington

25-year-old morbidly obese woman with a previous history of laparoscopic cholecystectomy five days before presented to the emergency room with generalized abdominal pain and total bilirubin of 3.7 mg/dL. Magnetic retrograde cholangiopancreatography (MRCP) was performed and findings were consistent with a biliary injury and a large fluid collection. A computed tomography (CT) scan liver protocol was performed and revealed a large fluid collection and no visualization of the right hepatic artery (Figure 1). Because the MRCP did not clearly demonstrate the proximal extent of the injury, an endoscopic retrograde cholangiopancreatography (ERCP) was performed showing occlusion of the distal common bile duct with no visualization of the proximal biliary tract (Figure 2A). A percutaneous transhepatic cholangiography (PTC) was completed to better delineate the proximal aspect of this injury (Figure 2B). Intraoperative findings included injury of right and left hepatic ducts (segments 2 and 3 branches were found isolated from segment 4 branch), segment 1 ductal injury and absence of right hepatic arterial flow. • What are the management options for complex bile duct injuries associated with vascular injury? • What operation would you perform given the extent of this injury? • Is there a difference in postoperative morbidity and outcomes in patients with bile duct injuries associated with vascular injuries?

Figure 1. Computed tomography liver protocol in the arterial phase demonstrating patency of the left hepatic artery (yellow arrow), and a hypovascular right hepatic lobe (below red arrow) when compared with left hepatic lobe (above red arrow) with no visualization of the right hepatic artery.

Figure 2. (A) Endoscopic retrograde cholangiopancreatography showing multiple clips and transection of the common bile duct. (B) Percutaneous transhepatic cholangiography through the right hepatic duct showing a bile leak and lack of communication with the left hepatic system.

This is a complex biliary injury with vascular compromise. The most frequent etiology for biliary injuries is misidentification of the biliary anatomy during a laparoscopic cholecystectomy (LC), one of the most common surgical procedures in the world. Ten years after the introduction of LC, the number of these procedures increased 25% to 30%. Despite the tremendous impact of LC on the management of biliary pathology, surgeons continue to face challenges in the application of this procedure in daily practice. Several concepts and strategies have been promoted to ensure safe LC. One is the “critical view” in which the surgeon should be able to dissect and identify structures in the triangle of Calot. Specifically, the critical view mandates that only two structures, the cystic duct and the cystic artery, remain attached to the gallbladder before clipping, tying or cutting any structure. Intraoperative cholangiogram has been proposed by several authors as an instrument to get a better definition of the anatomy and reduce the amount of biliary injuries. Mandatory cholangiography has been suggested by several groups. However, due to the possibility of difficult cannulation or injury during the procedure, its use remains selective in most centers. The morbidity rate after LC is still in the 2% range. Prompt diagnosis of iatrogenic biliary injuries (IBI) is critical because unrecognized lesions can lead to serious complications such as sepsis, biliary cirrhosis, hepatic failure or death. Factors associated with increased risk for IBI include coexisting acute and chronic inflammation around the gallbladder and hepatoduodenal ligament, obesity, fat within the hepatoduodenal ligament, poor exposure of the surgical area and anatomical variants of the biliary ducts and hepatic vasculature. This patient presented with a complex biliary injury, which usually refers to those involving the hepatic duct confluence, those associated Continued ON PAGE 12

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Surgeons’ Lounge jcontinued from page 10 with portal hypertension or secondary biliary cirrhosis and those with vascular injuries. The Strasberg’s classification of bile duct injuries is probably the most complete and easy to understand. This classification divides the ductal injuries into five groups: 1. Class A involves cystic duct or accessory duct injury. 2. Class B is a section of an accessory duct with no continuity with the common bile duct. 3. Class C is a leak from a bile duct with no continuity with the

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

common bile duct. 4. Class D is a partial section of the bile duct with no complete loss of continuity with the rest of the bile duct system. 5. Class E is a complete section of the bile duct with subtypes (E1E5) according to the length of the stump. A vascular lesion has to be suspected when a bleeding accident occurs during the laparoscopic procedure, when there is a sudden increase in aspartate transaminase (AST) and alanine transaminase (ALT) levels during the

postoperative course, or when there are multiple metallic clips on the images of the abdomen, as the ERCP showed in this case. The common clinical manifestations of bile duct injuries are jaundice, fever, chills and epigastric pain. The diagnosis of IBI includes clinical, laboratory and radiologic assessments. Imaging diagnostic tests include ultrasonography, CT, MRCP, ERCP and PTC. Ultrasonography allows imaging of intrahepatic ducts for biliary dilation and the presence of fluid collections. MRCP is a good initial test to characterize the

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© 2014 Vector Surgical, LLC ZĞĨĞƌĞŶĐĞƐ͗ ŚĂŶĚ͕ E͖͘ ĞƌƚƐƐĞŶ͕ ͖͘ ĂŶĚ ZŽǇůĞ͕ '͘ ͞ ǆŝůůĂƌǇ ͚ ǆĐůƵƐŝŽŶ͛ Ͷ ^ƵĐĐĞƐƐĨƵů dĞĐŚŶŝƋƵĞ ĨŽƌ ZĞĚƵĐŝŶŐ ^ĞƌŽŵĂ &ŽƌŵĂƟ ŽŶ Ō Ğƌ DĂƐƚĞĐƚŽŵǇ ĂŶĚ ǆŝůůĂƌǇ ŝƐƐĞĐƟ ŽŶ͘͟ Advances in Breast Cancer Research 2 ;ϮϬϭϯͿ͗ ϭͲϲ͖ ŚĂƌŵĂǁĂŶ͕ Z͖͘ EĂŐĂůŝŶŐĂŵ͕ ^͖͘ dĂǇ͕ >͖͘͘ tŽŶŐ͕ ͖͘ ĂŶĚ dĂŶ͕ ͘ ͞dŚĞ hƐĞ ŽĨ ŽŵƉƌĞƐƐŝŽŶ Ğůƚ ŝŶ ƚŚĞ WƌĞǀĞŶƟ ŽŶ ŽĨ ^ĞƌŽŵĂ &ŽƌŵĂƟ ŽŶ WŽƐƚͲ ƌĞĂƐƚ ĂŶĐĞƌ ^ƵƌŐĞƌǇ͗ ZĂŶĚŽŵŝǌĞĚ dƌŝĂů͘͟ WŽƐƚĞƌ ƐĞƐƐŝŽŶ ƉƌĞƐĞŶƚĞĚ Ăƚ͗ DŝůĂŶ ƌĞĂƐƚ ĂŶĐĞƌ ŽŶĨĞƌĞŶĐĞ͖ ϮϬϭϯ :ƵŶĞ ϮϬͲϮϭ͖ DŝůĂŶ͕ /ƚĂůǇ͖ <ŽŶƚŽƐ͕ D͖͘ WĞƚƌŽƵ͕ ͖͘ WƌĂƐƐĂƐ͕ ͖͘ dƐŝŐƌŝƐ͕ ͖͘ ZŽǇ͕ W͖͘ dƌĂĨĂůŝƐ͕ ͖͘ ĂƐƚŽƵŶŝƐ͕ ͖͘ ĂŶĚ <ĂƌĂŵĂŶĂŬŽƐ͕ W͘ ͞WƌĞƐƐƵƌĞ ƌĞƐƐŝŶŐ ŝŶ ƌĞĂƐƚ ^ƵƌŐĞƌǇ͗ /Ɛ dŚŝƐ ƚŚĞ ^ŽůƵƟ ŽŶ ĨŽƌ ^ĞƌŽŵĂ &ŽƌŵĂƟ ŽŶ͍͟ Journal of B.U.ON. 13.1 (2008): 65-67.

Overall early postoperative morbidity rate after surgical repair of iatrogenic bile duct injury is around 20% to 30%, with a mortality rate in the range of 0 to 2%. lesion and is now considered gold standard, specifically to delineate the proximal aspect of the injury, an important factor in the planning of the operative repair. ERCP is a good addition if the suspected injury may only require endoscopic treatment (cystic duct and some accessory posterior right hepatic duct injuries) or when MRCP is not able to characterize the extent of the injury. PTC may be indicated if MRCP or ERCP have failed to demonstrate the proximal extension of the injury or for treatment of minor injuries not addressed by the initial endoscopic treatment. It is our practice to perform a CT or MRI before surgery to determine if there is vascular involvement. To answer the question about the type of surgical management—before the repair, it is important to determine time of diagnosis, and type, extent and level of the bile duct injury. Most patients with biliary injuries needing surgical intervention will require a Roux-en-Y hepaticojejunostomy for reconstruction. In this case, an exploratory laparotomy was performed finding multiple surgical clips in the hepatic hilum. The right hepatic duct and artery were transected. There was injury of a segment 1 branch and segment 2, 3 and 4 ducts. We proceeded with suture ligation of the small segment 1 branch. Segment 2 and 3 ducts were anastomosed side to side to the segment 4 duct and two separate bilio-enteric anastomoses were performed with the right and the segments 2/3 and 4 ducts. Six months after surgical repair, the patient presented to the emergency room with right upper quadrant pain and elevated liver function test levels. An MRCP was performed demonstrating biliary dilatation of the right and left hepatic ducts more prominent in the left system. At that time, a left percutaneous transhepatic biliary drainage (PTBD) was placed followed by a right duct PTC and PTBD. This patient has been treated with balloon dilation and drainage of the right and left systems for several months. She is currently without drainage and completely asymptomatic four years after the initial

Surgeons’ Lounge

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

The Surgeon’s Challenge Submitted by David Nguyen, MD, Surgical Resident (PGY-1), Cleveland Clinic Florida, Weston A 69-year-old man presented with a long-standing history of nausea, vomiting, abdominal pain and weight loss. Based on the CT images, what is your diagnosis?

biliary reconstruction. Her liver function tests included a total bilirubin of 0.3mg/dL, AST 23 IU/L, ALT 27 IU/L, with a slight elevation of alkaline phosphatase, at 276 IU/L. Overall early postoperative morbidity rate after surgical repair of IBI is around 20% to 30%, with a mortality rate in the range of 0 to 2%. The most frequent complication is wound infection followed by biliary fistula, biloma, intraabdominal abscess, strictures and cholangitis. The exact incidence of right hepatic artery injuries during cholecystectomy is unknown. It has been reported by Strasberg et al that approximately 10% of patients with right hepatic artery injuries will develop severe ischemia that could result in intrahepatic bilomas and strictures. It has been previously published that hepatic artery injury is a predictor of poor long-term patency of the biliary reconstruction. In summary, IBI after LC is a surgical catastrophe associated with significant overall morbidity and mortality. The optimal management depends on timing, extent of bile duct injury, the patient´s condition and the availability of an experienced hepatobiliary surgeon.

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Suggested reading Jablonska B, Lampe P. Iatrogenic bile duct injuries: etiology, diagnosis and management. World J Gastroenterol. 2009;15:4097-4104. Stewart L, Way LW. Bile duct injuries during laparoscopic cholecystectomy: factors that influence the results of treatment. Arch Surg. 1995;130:1123-1128. Ahrendt S, Pitt H. Surgical therapy of iatrogenic lesions of biliary tract. World J Surg. 2001;25:1360-1365. de Santibanes V, Pekolj A. Complex bile duct injuries: management. HPB 2008;10:4-12. Strasberg SM, Helton WS. An analytical review of vasculobiliary injury in laparoscopic and open cholecystectomy. HPB B 2011;13:1-14.

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Ξ ϮϬϭϰ sĞĐƚŽƌ ^ƵƌŐŝĐĂů͕ >> ZĞĨĞƌĞŶĐĞƐ͗ ;ϭͿ ŽŽůĞǇ͕ t͘ ͘ ĂŶĚ WĂƌŬĞƌ͕ :͘ ͞hŶĚĞƌƐƚĂŶĚŝŶŐ ƚŚĞ DĞĐŚĂŶŝƐŵƐ ƌĞĂƟ ŶŐ &ĂůƐĞ WŽƐŝƟ ǀĞ >ƵŵƉĞĐƚŽŵǇ DĂƌŐŝŶƐ͘͟ American Journal of Surgery ϭϵϬ ;ϮϬϬϱͿ͗ ϲϬϲͲϲϬϴ͘ ;ϮͿ ƌŝƩ ŽŶ͕ W͘ ͖͘ ^ŽŶŽĚĂ͕ >͘/͖͘ zĂŵĂŵŽƚŽ͕ ͘<͖͘ <ŽŽ͕ ͖͘ ^ŽŚ͕ ͖͘ ĂŶĚ 'ŽƵĚ͕ ͘ ͞ ƌĞĂƐƚ ^ƵƌŐŝĐĂů ^ƉĞĐŝŵĞŶ ZĂĚŝŽŐƌĂƉŚƐ͗ ,Žǁ ZĞůŝĂďůĞ ƌĞ dŚĞǇ͍͟ European Journal of Radiology ϳϵ ;ϮϬϭϭͿ͗ ϮϰϱͲϮϰϵ͘ ;ϯͿ DŽůŝŶĂ͕ D͘ ͖͘ ^ŶĞůů͕ ^͖͘ &ƌĂŶĐĞƐĐŚŝ͕ ͖͘ :ŽƌĚĂ͕ D͖͘ 'ŽŵĞǌ͕ ͖͘ DŽī Ăƚ͕ &͘>͖͘ WŽǁĞůů͕ :͖͘ ĂŶĚ ǀŝƐĂƌ͕ ͘ ͞ ƌĞĂƐƚ ^ƉĞĐŝŵĞŶ KƌŝĞŶƚĂƟ ŽŶ͘͟ Annals of Surgical Oncology ϭϲ ;ϮϬϬϵͿ͗ ϮϴϱͲϮϴϴ͘ ;ϰͿ DĐ ĂŚŝůů͕ >͘ ͖͘ ^ŝŶŐůĞ͕ Z͘D͖͘ ŝĞůůŽ ŽǁůĞƐ͕ ͘:͖͘ &ĞŝŐĞůƐŽŶ͕ ,͘^͖͘ :ĂŵĞƐ͕ d͘ ͖͘ ĂƌŶĞǇ͕ d͖͘ ŶŐĞů͕ :͘D͖͘ ĂŶĚ KŶŝƟ ůŽ͕ ͘ ͘ ͞sĂƌŝĂďŝůŝƚǇ ŝŶ ZĞĞǆĐŝƐŝŽŶ &ŽůůŽǁŝŶŐ ƌĞĂƐƚ ŽŶƐĞƌǀĂƟ ŽŶ ^ƵƌŐĞƌǇ͘͟ :ŽƵƌŶĂů ŽĨ ƚŚĞ ŵĞƌŝĐĂŶ DĞĚŝĐĂů ƐƐŽĐŝĂƟ ŽŶ ϯϬϳ͘ϱ ;ϮϬϭϮͿ͗ ϰϲϳͲϰϳϱ͘

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GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

Primary Tumor Resection in Colorectal Cancer May Be Overused B Y C HRISTINA F RANGOU

rimary tumor resection may be performed too frequently for patients with advanced colorectal cancer (CRC) in the United States, according to a new study. According to a report published online in JAMA Surgery, patients with stage IV CRC are undergoing primary tumor resection (PTR) less often since 1998, with a marked drop-off after 2001 as new chemotherapeutic and biologic agents became available ((JAMA Surgg 2015 [Epub ahead of print]). By 2010, the last year of data analyzed, 57.4% of patients underwent PTR, down from 74.5% in 1988, the study found. However, the investigators said that despite the decrease, those figures indicate many patients may be undergoing surgery for CRC needlessly. “It appears that current treatment practice may still lag behind evidence-based treatment guidelines and that there is still work needed to translate evidence on the effectiveness of health care decisions into clinical practice,” reported Chung-Yuan Hu, MPH, PhD, and colleagues at the University of Texas MD Anderson Cancer Center, Houston. Current National Comprehensive Cancer Network guidelines recommend systemic chemotherapy without PTR in patients presenting with non-obstructive unresectable stage IV disease. However, questions persist about the potential benefits and harms of PTR in the absence of symptoms. Many physicians and patients are concerned that patients whose primary tumors are asymptomatic may develop symptoms such as obstruction and bleeding on chemotherapy, said senior author George Chang, MD,

MASTECTOMY jContinued from page 9 result is positive or negative, said Dr. Partridge. White race, family history of breast cancer, the use of breast reconstruction and the use of magnetic resonance imaging (MRI) also are associated with CPM ((Ann Plast Surgg 2014;72:s153-s157). “Women who undergo preoperative MRI have more than a twofold increase in the risk of undergoing removal of the opposite breast,” said Dr. Jatoi. “The reason is that MRI is associated with a higher false-positive rate in the opposite breast, which oftentimes prompts CPM.” CPM has increased dramatically in younger women. In an analysis of 2011 data from a population-based California Cancer Registry, 12.3% of women undergoing treatment for unilateral breast cancer underwent a bilateral mastectomy compared with 2% in 1998; but the rate rose to 33% from the 1998 rate of 3.6% in women younger than age 40 years ((JAMA 2014;312:902-914). Dr. Jatoi said there was an inextricable link between CPM and breast reconstruction, and that perhaps women prefer the better symmetry associated with bilateral

associate professor, Surgical Oncology and Health Services Research, at MD Anderson, in a statement. “We know from a previous Phase II, cooperative group study that it’s safe to give chemotherapy even with biologics to patients with metastatic disease. Yet, there’s still controversy about the role of primary tumor resection because some believe there’s a survival association.” The study was designed to evaluate use of PTR in patients with metastatic CRC in everyday practice and nationally by examining trends in the proportion of metastatic-disease patients undergoing PTR. For the retrospective, population-based study, Dr. Chang and his colleagues used the National Cancer Institute’s (NCI) Surveillance, Epidemiology, and End Results (SEER) program database to identify 64,157 patients, all of whom were diagnosed with metastatic colon or rectal cancer between Jan. 1, 1988 and Dec. 31, 2013. Overall, 67.4% of patients underwent PTR, with those receiving the surgery more likely to be female, younger than 50 years old, married, and to have colon cancer and a high-grade tumor. Independent of receiving PTR, the researchers also found that the median relative survival rate of metastatic colon cancer patients improved from 8.6% in 1988 to 17.8% in 2009. Dr. Chang said he hopes the findings might help patients and physicians make decisions about the need for PTR in the metastatic setting. Experts who were not involved with the study agreed that PTR “may” be overused in the United States, but highlighted the need for more research. “I agree with the conclusion that we probably do overuse primary tumor resection in someone who is nonsymptomatic from their cancer and has really truly unresectable disease,” said Christopher Mantyh, MD, chief of colorectal

mastectomy and reconstruction. Roughly 85% of women undergoing CPM opt for breast reconstruction ((Ann Plast Surg 2014;72:s153-s157). In the United States, said Dr. Pusic, women are more likely to undergo an implant reconstruction rather than a flap reconstruction, and longterm aesthetic outcomes from an implant reconstruction are better if the surgery is done bilaterally rather than unilaterally. The significant rise in immediate reconstruction rates in the United States correlates closely with a 203% expansion in implant use (Plast Reconstr Surg 2013;131:15-23). “Unilateral implant reconstruction can be disappointing in the long term,” said Dr. Pusic, noting that as the remaining natural breast falls as a woman ages, the implant rises. “It’s very important that women understand expected outcomes with unilateral implant over time. However, excellent aesthetic long-term results can be obtained with unilateral mastectomy and autologous reconstruction, and we are just not seeing women choosing that option.” Although clinicians have believed that an autologous reconstruction has a more difficult recovery, unpublished data, from a 2,000-patient study

surgery at Duke University Medical Center, Durham, N.C., who was not involved with the study. He said the study’s strength and its weakness is that the conclusions are based on analysis of the SEER database. “Obviously, it’s a huge database, but it only represents 20% of patients in the country, so clearly there can be a selection bias.” Moreover, SEER does not include important details on issues such as individual patient factors and institutional factors that can affect the decision to use or not to use PTR, Dr. Mantyh noted. “The issue is more complicated than just knowing how many patients undergo PTR,” said Steve Sentovich, MD, MBA, clinical professor and chief of colon and rectal surgery at City of Hope Hospital in Duarte, Calif. “As the authors admit in their discussion, they don’t know if the PTR was done for palliation (as indicated by current guidelines) or with a resection of a metastasis (also indicated by current guidelines).” The study did not directly compare survival between patients who received and did not receive PTR, as SEER data make such evaluation impossible without significant risk for bias. The researchers also lacked information about systemic chemotherapy. A large randomized trial is currently underway in Europe that will examine the issue of PTR and survival. It is not known when results from this trial will be available. Beyond the current primary indication for PTR, Dr. Chang said there may be a group of patients for whom PTR may be beneficial because it may allow them to continue to receive chemotherapy. In the general population of metastatic CRC patients for whom resection cannot be performed, PTR can result in unanticipated delays or inability to receive systemic therapies.

Dr. Pusic is leading, show that at three months postsurgery, women who undergo autologous reconstruction have less discomfort and morbidity than women who have implant surgery. Lindi Vanderwalde, MD, a general surgeon at Baptist Medical Group, in Memphis, Tenn., pointed out that in a community setting, patients are only offered implant reconstruction. “Microvascular surgery has become limited to academic centers,” she said.

Peace of Mind Is Major Factor According to Dr. Partridge, although aesthetic outcome is a factor in the rising CPM rates, it is not the principal driver. In the survey by Rosenberg et al, 60% of women ranked cosmetic symmetry as extremely important or very important in their decision to have CPM, but the most important reason, noted by 95%, was peace of mind. In another study, 36% of patients cited wanting their breasts to match as a reason for undergoing CPM, but worry about getting another breast cancer was listed by 80% ((Am J Surg 2011;201:615-618). Whatever their reasons for choosing CPM, women appear to be satisfied with

their decision. In a survey of women younger than 40 years of age who underwent CPM, 80% said they were extremely confident in their decision, and 90% said they would definitely choose CPM if deciding again ((Ann Intern Medd 2013;159:373-381). Only one-fourth of these women were BRCA1/2 mutation carriers. Regardless of whether patients feel satisfied, however, clinicians need to do more to ensure that CPM risks and benefits are effectively communicated, Dr. Partridge said. Although 80% of women are speaking to physicians about their reasons for choosing CPM, only 50% say physicians are discussing the reasons not to have the surgery with them, according to the survey by Rosenberg et al. “Recent findings suggest that women are making decisions about surgery based on inaccurate risk perceptions and understanding. Decisions are potentially being made without adequate information or psychosocial support,” said Dr. Partridge. “Clearly there is work to be done.” Dr. Pusic receives royalties from the Breast-Q (a patient-reported outcome questionnaire) when it is used in industrysponsored clinical trials.

Thin is in. The uncommonly slender chassis and front bezel first catch your attention. Then you notice the exceptional brightness of the display. Corner-to-corner uniformity is superb. You see how the robust OptiContrast Panel™ protects the screen while reducing glare and reflection. Finally you realize Sony’s 27-inch* screen provides a larger viewing area and fits onto the same carts and boom arms that currently take 26-inch models. Design meets technology. And you meet a brand new standard in visualization for today’s OR. Arrange a demo at sony.com/lmd27. © 2014 Sony Electronics Inc. All rights reserved. Reproduction in whole or in part without written permission is prohibited. Features and specifications are subject to change without notice. Sony and OptiContrast Panel are trademarks of Sony. * Viewable area, measured diagonally. CAUTION: Federal (USA) law restricts this device to sale by or on the order of a physician or other appropriately licensed medical professional. CAUTION: See product labeling for indications, contraindications, warnings, cautions, and directions for use.

On the

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

{Spot}With Colleen Hutchinson Colorectal 2015:

Dueling Debates in Colorectal Surgery A Participants Conor Delaney, MD, PhD, is chief of colorectal surgery and surgical director of the Digestive Health Institute at University Hospitals Case Medical Center, Cleveland.

s I have done for my past On the Spott columns that focus on colorectal surgery, this year I enlisted the help of Steven Wexner, MD, to identify the most legitimately debatable topics in this arena and the best-qualified voices to weigh in on them. This On the Spott is also once again a dueling debates in colorectal surgery, where each contributor weighs in on only one topic rather than

Statement: Transanal total mesorectal Jonathan Efron, MD, is interim director, Department of Surgery, associate professor of surgery and urology, and Mark M. Ravitch MD endowed professorship of surgery, Johns Hopkins University, Baltimore. Abe Fingerhut, MD, FACS, FRCPS (g), FRCS (Ed), (Hon c.), is professor of surgery, University of Graz, Graz, Austria.

Stephen R. Gorfine, MD, FACS, FASCRS, FACP, is clinical professor of surgery at the Icahn School of Medicine at Mount Sinai, and attending surgeon, Division of Colon and Rectal Surgery, Mount Sinai Hospital, New York City. Antonio Lacy, MD, is chief, Gastrointestinal Surgery Department, Hospital Clinic, and professor of surgery, University of Barcelona School of Medicine, Barcelona, Spain.

Jorge Lagares-Garcia, MD, is chair, Division of Colon and Rectal Surgery, Roper Hospital, Charleston, South Carolina. Disclosure: Dr. Lagares-Garcia is instructor and consultant for Intuitive Surgical, Sunnyvale, Calif.

Feza H. Remzi, MD, is chairman, Department of Colorectal Surgery at Cleveland Clinic, in Ohio.

Steven Wexner, MD, is director of the Digestive Disease Center and chairman of the Department of Colorectal Surgery, Cleveland Clinic Florida, Weston. Disclosure: Dr. Wexner reported stock options from past consulting with Intuitive Surgical, Sunnyvale, Calif.; and consulting fees, laparoscopy; inventor’s income, transanal endosurgery from Karl Storz.

Oded Zmora, MD, is associate professor of surgery; director, Colon and Rectal Surgery; vice chair, Department of Surgery, Sheba Medical Center, Tel Aviv, Israel.

excision (TaTME) for rectal cancer offers superior oncologic outcomes as compared to standard transabdominal TME.

Conor Delaney, MD: Disagree. TaTME is an interesting new extension of an old technique, but there are as yet no data supporting superior oncologic outcomes. Remember, intersphincteric resection has been around for a long time for the tumors within 1 cm of the dentate line, and many surgeons do a transanal mobilization of the distal rectum for lower-third rectal tumors, especially when approached laparoscopically. These appear to be equivalent to a standard transabdominal approach (whether open or laparoscopic). In fact, in a systematic review we recently published in Surgical Endoscopy, 11.8% of TaTME circumferential margins were positive, and pneumo-retroperitoneum, air embolism and urethral injury had been reported, despite TaTME generally being done to date by very experienced surgeons. Although TaTME may help reduce the conversion rate for laparoscopic surgery for low rectal tumors in obese males, we must be careful that we do not trade this for worse oncologic outcomes and higher complication and injury rates. TaTME is likely to be oncologically equivalent, and must be evaluated to make sure it is so, but we need more data before saying it is better.

Antonio Lacy, MD: Agree. Recently, some studies have shown the feasibility of TaTME, and some comparative studies have been published showing that it is not inferior to standard transabdominal TME in terms of short-term outcomes. These outcomes also stand for surgical-related aspects that may have future impact on disease recurrence, such as better measure of distance from the anal verge or circumferential resection margin (CRM). And last year, a randomized study concluded that, for low rectal cancer, TaTME reduced the risk for positivity of that margin. And what to say about differences in distal margin! Nowadays, everybody looks forward to oncologic long-term outcomes. We all know that randomized controlled trials are warranted; however, existing data seem to be promising, suggesting a tendency to improve disease-free survival after TaTME. These questions will be answered in the near future, but as an experienced rectal surgeon,

all contributors weighing in on all statements. With a special thanks to Dr. Wexner for lending his expertise and thoughts on each topic, I present some of the most current debates in colorectal surgery. Read on, take a side, access On the Spot online and share your view with a comment. Thanks for reading! —Colleen Hutchinson

I strongly believe that a quality surgery may offer superior long-term oncologic outcomes.

Dr. Wexnerr weighs in: TaTME is a very promising new technology that seems to result in equivalent—and may, in fact, ultimately be proven to offer superior—oncologic outcomes to transabdominal TME. Moreover, part of the tremendous appeal of TaTME is the ability to avoid the expense of the robotic platform to “facilitate” the distal pelvic dissection. Virtually every study during the past nearly 25 years has shown numerous significant shortterm benefits comparing laparoscopic to open TME relative to pain, length of hospitalization, length of cosmetic outcomes, length of ileus and other variables. Additionally, a myriad of authors have demonstrated oncologic superiority relative to lymph node harvest and/or tumor-free margins. Although robotic TME has failed to confer any proven advantage as compared with laparoscopic TME, many individuals market this approach as a way to flatten, shorten or eliminate the learning curve to transition from open to minimally invasive transabdominal TME. TaTME is appealing in that it offers the possibility to eliminate the costly cumbersome robotic platform while conveying equivalent or perhaps even superior oncologic outcomes. Therefore, although TaTME has not yet been proven to offer superior oncologic outcomes compared with standard transabdominal TME, it does certainly offer promise in this direction.

Statement: Bowel preparation is mandatory for elective colorectal surgery.

Abe Fingerhut, MD and Hester Cheung, MD: Agree. Mechanical bowel preparation (MBP) before elective colorectal surgery—a time-honored dogma—is thought to decrease the intraluminal fecal mass and, presumably, also the bacterial load in the bowel, in turn reducing the postoperative infectious complication rate (including anastomotic leakage and surgical site infection). Challenged by trauma surgeons when primary repair of colonic injury provided good results (Br J Surg 2007;94:689-695) several studies have since contested this idea; one of the most recent systemic reviews and meta-analysis does not support

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GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

the routine use of MBP before colonic cancer surgery in terms of reduction of infectious postoperative complications (Lancett 2007;370:2112-2117). However, the impact of MBP is still unclear in rectal surgery because many studies in the literature excluded rectal surgery, and only one French multicenter randomized trial has demonstrated that rectal surgery without MBP is associated with higher risk for overall and infectious morbidity rates, suggesting continuing to perform MBP before elective rectal resection (Cochrane Database Syst Rev v 2011:CD001544). Because laparoscopy may pose specific difficulties in localization of small, nonpalpable lesions without serosal surface landmarks, bowel preparation should still be considered because of the need for intraoperative colonoscopy in this setting. In conclusion, there is no strong evidence suggesting the routine use of MBP for elective colonic resection. However, preoperative MBP may be recommended in selected patients with intraperitoneal rectal and/or small colorectal cancer in whom intraoperative colonoscopy might prove necessary for localization. This is especially important for patients undergoing laparoscopic surgery, where the surgeon’s ability to palpate the colon is limited.

Oded Zmora, MD: Strongly disagree. Numerous randomized prospective studies, including two large multicenter randomized prospective trials (one in Sweden with 1,343 patients and one from The Netherlands with 1,260 patients) and a meta-analysis, all showed no advantage

to MBP in terms of anastomotic leak, surgical site infection and postoperative complications. Scientific data are strong enough to support the omission of the routine use of MBP in elective colorectal surgery. It is time for a well-designed and well-performed North American study to convince most American surgeons, also. Special considerations that may selectively require MBP include small tumors that may need intraoperative endoscopy for tumor localization, and perhaps rectal surgery. A single French randomized trial suggested a higher complication rate without preparation specifically in rectal surgery. These results should be reassessed in further studies. An interesting study was recently published by the Swedish multicenter group, suggesting that no bowel preparation may be associated with higher rate of cancer recurrence (Br J Surg 2014;101:1594-1600). The mechanism for this possible phenomenon, however, is poorly understood, and this should be further investigated in future studies.

Dr. Wexnerr weighs in: The main reason to perform bowel preparation for elective colorectal surgery is to facilitate bowel manipulation and intraoperative endoscopy. We have clearly demonstrated a lower incidence of postoperative anastomotic problems when routine intraoperative endoscopy is performed to assess pelvic anastomoses than when it is only selectively employed. Additionally, it may be necessary to perform endoscopy to visualize lesions, ink marks and bowel mucosa. Therefore, although routine MBP does not seem to

be required for its originally stated purpose (to decrease or avoid surgical site infection), it has become a very useful adjunct to allow intraoperative endoscopic visualization, particularly during laparoscopic procedures. Also, the minimally invasive instrument manipulation of a fecally loaded colon seems less safe than is the handling of an empty colon.

Statement: Routine one-stage (as opposed to two-stage) restorative proctocolectomy is recommended.

Feza Remzi, MD: Disagree. I do believe patients who undergo restorative proctocolectomy (RPC) have the best outcome when all goes well at the initial surgery. Personally, by doing a routine one-stage RPC, we are taking an unnecessary risk on behalf of our patients, especially in patients with inflammatory bowel disease (IBD). This was a controversial topic to start with in the prebiologic era. Some did it routinely; some, like our group, did it selectively, depending on the preoperative and intraoperative stringent criteria. We are in the biologic era in which almost no patient with IBD is referred to surgery without the trial of biologics. These drugs are immunosuppressant to start with and there is a trend prolonging the treatment with biologics trying to avoid the unavoidable. These result in septic complications, which negatively affect the long-term outcomes. In my opinion, offering our patients a routine RPC in the biologic era is riskier

than before. I do believe, unless it is a familial adenomatous patient who is motivated and fits to stringent criteria we employ, doing a one-stage RPC is an absolute contraindication in the biologic era.

Stephen Gorfine, MD: Disagree. One-stage RPC can be performed safely for a group of highly selected patients only. “Routine” use of this technique is not recommended. Temporary diversion in the setting of RPC does not prevent pouch or anastomotic leaks, but rather mitigates the consequences should one occur. One-stage RPC offers suitable patients the relative benefits of elimination of the risks, discomfort and costs associated with a second surgery; reduced total hospital time; and complete avoidance of an ileostomy. These benefits must be weighed against the risk for potentially severe septic complications. Patients suitable for a one-stage RPC are generally taking less than 20 mg of prednisone daily and are not on multiple immunosuppressive medications such as infliximab in combination with cyclosporine and 6-mercaptopurine. Candidates for one-stage surgery are generally not overtly malnourished or “sick” with an acute exacerbation of colitis. Surgery is always performed in the elective setting and must proceed smoothly. The ileal pouch–anal anastomosis (IPAA) must be completely tension-free. The final decision concerning omission of ileostomy is always made after the pouch and IPAA have been constructed. Using these Continued ON page 18

Gut Reaction: Colorectal 2015 State of malpractice insurance in colorectal surgery

“Obamacare”

Best advice to the new medical student who plans to specialize in colorectal surgery

Best advice to the community surgeon who would like to become more involved in colorectal surgery association leadership and general research/publication

The dynamic between oncologist and oncologic surgeon

Dr. Efron

The same as for Making significant the rest of surgery: changes. poor.

Obtain the best training you can; it is the foundation for the future care you deliver.

Research and participation in a national A symbiotic relationship that society is dependent on the person, not their partners to improve patient type of practice; if you enjoy either, you can care. do both.

Dr. Gorfine

Abysmal

Worse than expected.

Great field; work hard and go for it!

Join the ASCRS and participate.

Often harmonious, sometimes testy.

Dr. Lacy

Not qualified to comment on the situation in the United States.

Not qualified to com- Work hard, take care of ment on the situation patients, study, then enjoy. in the United States.

Surgery is essential, but innovation is too.

We work together in the committees and have a close relationship.

Dr. LagaresGarcia

Really adequate?

“Equal access” must Best decision you ever will reflect “equal care.” make.

Join local societies and Web chats in ASCRS.

Needs improvement and a common goal.

Dr. Remzi

It is all over the place.

Let’s be part of the solution.

Best is yet to come; please join Please tell us who you are. us.

We complete each other.

Dr. Zmora

Lose–lose situation.

Thank God I live in Israel.

Go for your dreams!

Multidisciplinary team: a winwin situation

Go for your dreams!

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GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

criteria, we have successfully performed more than 400 one-stage RPCs. Longterm functional results and complication rates are similar among patients undergoing RPC with and without diversion.

Dr. Wexnerr weighs in: Although one-stage pouches can be performed, I disagree that they should be done so routinely. The vast majority of studies and meta-analyses have decided in favor of two-stage J-pouches rather than one-stage J-pouches. Nonetheless, with careful patient selection, meticulous technique and a very well-informed patient, the

procedure can, in selected cases, be undertaken. If after a lengthy informed consent, the patient still desires a one-stage procedure and is a medically appropriate candidate (without significant malnutrition, taking less than 20 mg per day of prednisone, remote from any anti–tumor necrosis factor agents, and is not anemic or obese), then the surgeon must rely on the intraoperative decision-making algorithm. Only in instances of a “quick and easy” RPC with minimal blood loss and a tension-free anastomosis should avoidance of a temporary ileostomy be contemplated.

Statement: Robotic rectal cancer surgery has multiple proven advantages as compared to the laparoscopic approach.

Jorge Lagares-Garcia, MD: Agree. Laparoscopic TME has been proven to be safe, with lower morbidity and mortality. Despite that, the operative times and conversion rate are high, especially in patients with narrow pelvis or high body mass index (BMI). The robotic platform offers the surgeon an improved dexterity and vision in the performance of complex pelvic operations like rectal cancer.

To date, the largest North American data of robotic rectal cancer recently published by Hellan et al showed comparable operative times than laparoscopic while offering an extremely low positive circumferential margin of 0.9% and 5.9% conversion rate independent of the patient’s BMI in 425 patients ((Ann Surg Oncoll 2014 Dec 9. [Epub ahead of print]). Local recurrence rate was 1.7%. Although the limitations of this study are clear in its retrospective nature, this large number of high-volume expert robotic surgeons clearly indicates the potential in rectal cancer surgery, although further randomized controlled trials, appropriately powered for each technique, are needed. In our current personal experience of more than 450 cases, in a nonteaching institution with a dedicated team, robotic proctectomy ranges from 120 to 150 minutes (unpublished data), clearly superior times to laparoscopic current series. Although the initial expense and cost is higher per case, the minimal conversion rate and the completion of the TME as a quality indicator in our current series is excellent.

Jonathan Efron, MD: Disagree.

WHY SETTLE FOR RESORPTION OR ENCAPSULATION WHEN YOU CAN HAVE

REGENERATION?* SurgiMend enables strong, long-lasting hernia repair. 1-6

Although I use the robot for rectal cancer surgery, there has yet to be any published data to support the statement: “Robotic rectal cancer surgery has multiple proven advantages as compared to the laparoscopic approach.” What I really disagree with in the statement is the word “proven.” I do feel the robot provides the added benefits of superior visualization, increased flexibility and greater ability to retract in the pelvis; those benefits have not been translated into proven advantages over the laparoscopic technique in any published trial. Multiple retrospective reviews have compared robotic to open, and robotic to laparoscopic proctectomy; the only advantage being proven to date is perhaps a lower conversion rate with the robotic technique. To the detriment of the robot, its use clearly increases the length, and the cost of minimally invasive proctectomies. To date, there is no good prospective trial demonstrating any benefit of the robotic technique over the laparoscopic technique. Hopefully, we will see some definitive data to either support or refute this statement in the near future as randomized trials comparing the two techniques are underway and near completion. For now, I am forced to disagree with the above statement.

Dr. Wexnerr weighs in: Within five years of the advent of laparoscopic colorectal surgery, a myriad of studies had demonstrated superior outcomes for pain, immunosuppression, length of ileus, ability to tolerate oral intake, resumption of bowel activity, hospital discharge, resumption of normal lifestyle, improved cosmesis, decreased

*SurgiMend does not trigger a detrimental foreign-body inﬂammatory response that would lead to rapid degradation or encapsulation. Photograph displays cellular repopulation and revascularization of 3 mm thick SurgiMend in a small animal intra-abdominal implant model. References: 1. Clemens MW, Selber JC, Liu J, et al. Bovine versus porcine acellular dermal matrix for complex abdominal wall reconstruction. Plast. Reconstr. Surg. 2013;131(1):71–9. 2. Adelman DM, Selber JC, Butler CE. Bovine versus porcine acellular dermal matrix: a comparison of mechanical properties. Plast. Reconstr. Surg. Glob. Open. 2014. 3. Deeken CR, Eliason BJ, Pichert MD, et al. Differentiation of biologic scaffold materials through physicomechanical, thermal, and enzymatic degradation techniques. Ann. Surg. 2012. 4. Adelman DM. Radiographic evaluation of biologic mesh repair in ventral abdominal herniorrhaphy. In: Proceedings of the American College of Surgeons. Washington DC; 2013. 5. Booth JH, Garvey PB, Baumann DP, et al. Primary fascial closure with mesh reinforcement is superior to bridged mesh repair for abdominal wall reconstruction. J. Am. Coll. Surg. 2013. 6. Cornwell KG, Greenburg AG, James KS. A generative tissue fabricated with SurgiMend has a mesothelial lining limiting adhesion formation in a model of large ventral hernia repair. In: American Hernia Society; 2010. © 2014 TEI Biosciences Inc. All rights reserved. SurgiMend is a registered trademark of TEI Biosciences Inc.

www.teibio.com

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GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

adhesions, decreased ventral incisional hernia, decreased morbidity and decreased mortality. Within 10 years of the advent of laparoscopic colorectal surgery for rectal carcinoma, many more studies had already demonstrated either equivalent, or, in some cases, superior oncologic outcomes to laparotomy. Perhaps the most relevant study for robotics is the recent study by Park et al concluding that robotic rectal cancer surgery failed to confer any oncologic or other benefit [over standard laparoscopy]. In the study by Park et al, 217 patients who underwent minimally invasive surgery for rectal cancer were prospectively enrolled to undergo either robotic or laparoscopic rectal cancer surgery ((Ann Surgg 2015; 261:129-137). The authors concluded that “robotic surgery for rectal cancer failed to offer any oncologic or clinical benefit compared with laparoscopy” despite a 2.34 times higher cost than laparoscopic surgery. I concur with this highly esteemed group of experienced robotic surgeoninvestigators. Moreover, the robotic

platform is touted by its proponents and enthusiastically embraced by surgeons to “flatten” or “shorten” the “learning curve.” The reduced learning curve should therefore allow surgeons who do not frequently operate on rectal cancers to do so in a minimally invasive fashion. Although the short-term recovery benefits of the minimally invasive approach to the patients seem inherently obvious, unfortunately the long-term oncologic problems of lowvolume surgeons have been well demonstrated. Numerous studies have shown that rates of permanent colostomy and local recurrence are in inverse proportion

of permanent colostomy and a higher rate of local recurrence. Thus, the results of rectal cancer surgery are probably far less dependent on the method of access than on the expertise and commitment of the surgeon and the center at which the surgeon operates.

—Colleen Hutchinson is a communications consultant who specializes in the areas of general surgery and bariatrics. She can be reached at colleen@ cmhadvisors.com.

Experience the ENTEREG EFFECT ENTEREG is indicated to accelerate the time to upper and lower gastrointestinal (GI) recovery following surgeries that include partial bowel resection with primary anastomosis.1

NEW

› In clinical trials, ENTEREG added to an accelerated care

Quick Pulse Corner

pathway (ACP) was more effective than an ACP alone1

On the use of genomic testing/genome sequencing in colorectal cancer. Dr. Lacy: Life, science, medicine, … almost everything has been developed thanks to the existence of genes. And the future of colorectal surgery is to focus again on them. Every day I have the opportunity to work with great experts in that area. Nevertheless, we must work to be able to give every patient a personalized treatment based on his or her own genetic features. Dr. Gorfine: Therapeutic application of genomic testing is currently in its infancy. Although we are regularly using molecular markers to identify patients with Lynch syndrome, for example, this application demonstrates only a fraction of the potential of this technology. “Personalized medicine,” based on an individual patient’s genome, will offer dramatic advances in colon cancer treatment and, hopefully, prevention. Dr. Remzi: It is the future. Many unnecessary operations, chemoradiation therapeutic regimens will be avoided by it. It will guide us to tailor the correct surgical and nonsurgical modalities for our patients. Dr. Lagares-Garcia: Clearly the combination of genetics and surgical treatment will standardize and personalize colorectal cancer care in the near future. Dr. Efron: Genomic testing and sequencing will eventually guide therapy for colorectal cancer and be considered standard of care. Dr. Wexner: There’s incredible value to this technology; the future of colorectal cancer care, and perhaps all of oncology, will be significantly and positively impacted. The idea of targeting therapy based on a patient’s predicted response to a treatment is tremendous, as is the ability to direct potential therapeutic benefits to patients most likely to respond and avoiding potential morbidity in patients unlikely to respond. Significant resources should be directed towards expediting development and maturation of this field.

to the volume of rectal cancer operations performed by individual surgeons and within individual institutions. Therefore, when robotic rectal cancer surgery is offered to patients by high-volume rectal cancer surgeons in high-volume rectal cancer centers, the oncologic outcomes are probably similar to the oncologic outcomes of either laparoscopy or open TME when performed by those same surgeons. However, sadly, the widespread advent of “easier” minimally invasive access may potentially allow lower-volume surgeons to operate on rectal cancer, which could possibly result in a higher incidence of use

– ENTEREG improved mean time to GI recovery by 11-32 hours vs. placebo1* – ENTEREG also reduced time to discharge order written by 13-22 hours1,2*

ENTEREG improved mean time to GI recovery by up to 20% compared to placebo1* *Data are from 5 multicenter, randomized, double-blind, placebo-controlled studies in patients undergoing bowel resection and 1 study in patients undergoing radical cystectomy. Patients were administered ENTEREG 12 mg or placebo 30 minutes to 5 hours prior to surgery and twice daily after surgery until discharge or a maximum of 7 days. Patients who received more than 3 doses of an opioid (regardless of route) during the 7 days prior to surgery and patients with complete bowel obstruction or who were scheduled for a total colectomy, colostomy, or ileostomy were excluded.1

Important Safety Information for ENTEREG

› ›

WARNING: POTENTIAL RISK OF MYOCARDIAL INFARCTION WITH LONG-TERM USE: FOR SHORT-TERM HOSPITAL USE ONLY Increased incidence of myocardial infarction was seen in a clinical trial of patients taking alvimopan for long-term use. No increased risk was observed in short-term trials Because of the potential risk of Myocardial Infarction, ENTEREG is available only through a restricted program for short-term use (15 doses) called the ENTEREG Access Support and Education (E.A.S.E.®) ENTEREG REMS Program

Contraindications

› ENTEREG Capsules are contraindicated in patients who have

taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG

Warnings and Precautions

› There were more reports of myocardial infarctions in patients

treated with alvimopan 0.5 mg twice daily compared with placebo-treated patients in a 12-month study of patients treated with opioids for chronic pain. In this study, the majority of myocardial infarctions occurred between 1 and 4 months after initiation of treatment. This imbalance has not been observed in other studies of alvimopan, including studies of patients undergoing bowel resection surgery who received alvimopan 12 mg twice daily for up to 7 days. A causal relationship with alvimopan has not been established

› ENTEREG should be administered with caution to patients receiving more than 3 doses of an opioid within the week prior to surgery. These patients may be more sensitive

to ENTEREG and may experience GI side effects (eg, abdominal pain, nausea and vomiting, diarrhea)

› ENTEREG is not recommended for use in patients with severe hepatic impairment, end-stage renal disease, complete gastrointestinal obstruction, or pancreatic or gastric anastomosis, or in patients who have had surgery for correction of complete bowel obstruction

Adverse Reactions

› The most common adverse reaction (incidence ≥1.5%) occurring with a higher frequency than placebo among ENTEREG-treated patients undergoing surgeries that included a bowel resection was dyspepsia (ENTEREG, 1.5%; placebo, 0.8%)

E.A.S.E.® Program for ENTEREG

› ENTEREG is available only to hospitals that enroll in the

E.A.S.E. Program. To enroll in the E.A.S.E. Program, the hospital must acknowledge that: – Hospital staff who prescribe, dispense, or administer ENTEREG have been provided the educational materials on the need to limit use of ENTEREG to short-term, inpatient use – Patients will not receive more than 15 doses of ENTEREG – ENTEREG will not be dispensed to patients after they have been discharged from the hospital Please see following brief summary of Prescribing Information for ENTEREG.

References: 1. ENTEREG [package insert]. Lexington, MA: Cubist Pharmaceuticals U.S.; 2014. 2. Lee CT, Chang SS, Kamat AM, et al. Eur Urol. 2014; 66(2):265-272. ©2014 Cubist Pharmaceuticals ENTEREG and E.A.S.E. are registered trademarks of Cubist Pharmaceuticals. www.ENTEREG.com ENT-0229 November 2014

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GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

Intraoperative Local Anesthetic Shows No Benefit for Postoperative Hernia Pain B Y V ICTORIA S TERN

hronic pain is one of the most common complaints after inguinal hernia repair, but the incidence of chronic pain can vary significantly from study to study. Estimates of chronic pain after open mesh and laparoscopic repairs tend to fall between 4% and 30% (Surg Endosc 2010;24:1707-1711; Ann Surg

2006;244:212-219), but some trials report values of greater than 50% (Br J Anaesth 2005;95:69-76). Studies evaluating chronic pain after pure tissue repair report ranges from about 4% to 14% for various techniques (Anesthesiology ( 2000;93:1123-1133). “Such huge variations, caused by different definitions of pain or pain severity, make it almost impossible to identify specific causes or treatments,” said Uwe Klinge, MD, a surgeon in the Department

of General, Visceral and Transplant Surgery, University Hospital of the RWTH Aachen, in Germany. A new study published in Surgery attempted to better understand one facet of pain after inguinal hernia repair: the effect of intraoperative infiltration of local anesthetic on the development of chronic postoperative pain (Surgery 2015;157:144-154). The main hypothesis, according to study author Anita Kurmann, MD, a surgeon in the Department

BRIEF SUMMARY OF PRESCRIBING INFORMATION

ENTEREG® (alvimopan) capsules, for oral use The following is a brief summary only; see full prescribing information for complete product information. WARNING: POTENTIAL RISK OF MYOCARDIAL INFARCTION WITH LONG-TERM USE: FOR SHORT-TERM HOSPITAL USE ONLY There was a greater incidence of myocardial infarction in alvimopan-treated patients compared to placebo-treated patients in a 12-month clinical trial, although a causal relationship has not been established. In short-term trials with ENTEREG®, no increased risk of myocardial infarction was observed. Because of the potential risk of myocardial infarction with long-term use, ENTEREG is available only through a restricted program for short-term use (15 doses) under a Risk Evaluation and Mitigation Strategy (REMS) called the ENTEREG Access Support and Education (E.A.S.E.®) Program. INDICATIONS AND USAGE ENTEREG is indicated to accelerate the time to upper and lower gastrointestinal recovery following surgeries that include partial bowel resection with primary anastomosis. CONTRAINDICATIONS ENTEREG is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG. WARNINGS AND PRECAUTIONS Potential Risk of Myocardial Infarction with Long-term Use There were more reports of myocardial infarctions in patients treated with alvimopan 0.5 mg twice daily compared with placebo-treated patients in a 12-month study of patients treated with opioids for chronic non-cancer pain (alvimopan 0.5 mg, n = 538; placebo, n = 267). In this study, the majority of myocardial infarctions occurred between 1 and 4 months after initiation of treatment. This imbalance has not been observed in other studies of ENTEREG in patients treated with opioids for chronic pain, nor in patients treated within the surgical setting, including patients undergoing surgeries that included bowel resection who received ENTEREG 12 mg twice daily for up to 7 days (the indicated dose and patient population; ENTEREG 12 mg, n = 1,142; placebo, n = 1,120). A causal relationship with alvimopan with long-term use has not been established. ENTEREG is available only through a program under a REMS that restricts use to enrolled hospitals. E.A.S.E. ENTEREG REMS Program ENTEREG is available only through a program called the ENTEREG Access Support and Education (E.A.S.E.) ENTEREG REMS Program that restricts use to enrolled hospitals because of the potential risk of myocardial infarction with long-term use of ENTEREG. Notable requirements of the E.A.S.E. Program include the following: ENTEREG is available only for short-term (15 doses) use in hospitalized patients. Only hospitals that have enrolled in and met all of the requirements for the E.A.S.E. program may use ENTEREG. To enroll in the E.A.S.E. Program, an authorized hospital representative must acknowledge that: hospital staff who prescribe, dispense, or administer ENTEREG have been provided the educational materials on the need to limit use of ENTEREG to short-term, inpatient use; patients will not receive more than 15 doses of ENTEREG; and ENTEREG will not be dispensed to patients after they have been discharged from the hospital. Further information is available at www.ENTEREGREMS.com or 1-877-282-4786. Gastrointestinal-Related Adverse Reactions in Opioid-Tolerant Patients Patients recently exposed to opioids are expected to be more sensitive to the effects of μ-opioid receptor antagonists, such as ENTEREG. Since ENTEREG acts peripherally, clinical signs and symptoms of increased sensitivity would be related to the gastrointestinal tract (e.g., abdominal pain, nausea and vomiting, diarrhea). Patients receiving more than 3 doses of an opioid within the week prior to surgery were not studied in the postoperative ileus clinical trials. Therefore, if ENTEREG is administered to these patients, they should be monitored for gastrointestinal adverse reactions. ENTEREG is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG. Risk of Serious Adverse Reactions in Patients with Severe Hepatic Impairment Patients with severe hepatic impairment may be at higher risk of serious adverse reactions (including dose-related serious adverse reactions) because up to 10-fold higher plasma levels of drug have been observed in such patients compared with patients with normal hepatic function. Therefore, the use of ENTEREG is not recommended in this population. End-Stage Renal Disease No studies have been conducted in patients with end-stage renal disease. ENTEREG is not recommended for use in these patients. Risk of Serious Adverse Reactions in Patients with Complete Gastrointestinal Obstruction No studies have been conducted in patients with complete gastrointestinal obstruction or in patients who have surgery for correction of complete bowel obstruction. ENTEREG is not recommended for use in these patients. Risk of Serious Adverse Reactions in Pancreatic and Gastric Anastomoses ENTEREG has not been studied in patients having pancreatic or gastric anastomosis. Therefore, ENTEREG is not recommended for use in these patients. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The adverse event information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. The data described below reflect exposure to ENTEREG 12 mg in 1,793 patients in 10 placebo-controlled studies. The population was 19 to 97 years old, 64% were female, and 84% were Caucasian; 64% were undergoing a surgery that included bowel resection. The first dose of ENTEREG was administered 30 minutes to 5 hours before the scheduled start of surgery and then twice daily until hospital discharge (or for a maximum of 7 days of postoperative treatment).

Among ENTEREG-treated patients undergoing surgeries that included a bowel resection, the most common adverse reaction (incidence ≥1.5%) occurring with a higher frequency than placebo was dyspepsia (ENTEREG, 1.5%; placebo, 0.8%). Adverse reactions are events that occurred after the first dose of study medication treatment and within 7 days of the last dose of study medication or events present at baseline that increased in severity after the start of study medication treatment. DRUG INTERACTIONS Potential for Drugs to Affect Alvimopan Pharmacokinetics An in vitroo study indicates that alvimopan is not a substrate of CYP enzymes. Therefore, concomitant administration of ENTEREG with inducers or inhibitors of CYP enzymes is unlikely to alter the metabolism of alvimopan. Potential for Alvimopan to Affect the Pharmacokinetics of Other Drugs Based on in vitroo data, ENTEREG is unlikely to alter the pharmacokinetics of coadministered drugs through inhibition of CYP isoforms such as 1A2, 2C9, 2C19, 3A4, 2D6, and 2E1 or induction of CYP isoforms such as 1A2, 2B6, 2C9, 2C19, and 3A4. In vitro, ENTEREG did not inhibit p-glycoprotein. Effects of Alvimopan on Intravenous Morphine Coadministration of alvimopan does not appear to alter the pharmacokinetics of morphine and its metabolite, morphine-6-glucuronide, to a clinically significant degree when morphine is administered intravenously. Dosage adjustment for intravenously administered morphine is not necessary when it is coadministered with alvimopan. Effects of Concomitant Acid Blockers or Antibiotics A population pharmacokinetic analysis suggests that the pharmacokinetics of alvimopan were not affected by concomitant administration of acid blockers or antibiotics. No dosage adjustments are necessary in patients taking acid blockers or antibiotics. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B Risk Summary: y There are no adequate and/or well-controlled studies with ENTEREG in pregnant women. No fetal harm was observed in animal reproduction studies with oral administration of alvimopan to rats at doses 68 to 136 times the recommended human oral dose, or with intravenous administration to rats and rabbits at doses 3.4 to 6.8 times, and 5 to 10 times, respectively, the recommended human oral dose. Because animal reproduction studies are not always predictive of human response, ENTEREG should be used during pregnancy only if clearly needed. Animal Data: Reproduction studies were performed in pregnant rats at oral doses up to 200 mg/kg/day (about 68 to 136 times the recommended human oral dose based on body surface area) and at intravenous doses up to 10 mg/kg/day (about 3.4 to 6.8 times the recommended human oral dose based on body surface area) and in pregnant rabbits at intravenous doses up to 15 mg/kg/day (about 5 to 10 times the recommended human oral dose based on body surface area), and revealed no evidence of impaired fertility or harm to the fetus due to alvimopan. Nursing Mothers It is not known whether ENTEREG is present in human milk. Alvimopan and its ‘metabolite’ are detected in the milk of lactating rats. Exercise caution when administering ENTEREG to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of patients in 6 clinical efficacy studies treated with ENTEREG 12 mg or placebo, 46% were 65 years of age and over, while 18% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment based on increased age is required. Hepatic Impairment ENTEREG is not recommended for use in patients with severe hepatic impairment. Dosage adjustment is not required for patients with mild-to-moderate hepatic impairment. Patients with mild-to-moderate hepatic impairment should be closely monitored for possible adverse effects (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high drug or ‘metabolite’ levels, and ENTEREG should be discontinued if adverse events occur. Renal Impairment ENTEREG is not recommended for use in patients with end-stage renal disease. Dosage adjustment is not required for patients with mild-to-severe renal impairment, but they should be monitored for adverse effects. Patients with severe renal impairment should be closely monitored for possible adverse effects (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high drug or ‘metabolite’ levels, and ENTEREG should be discontinued if adverse events occur. Race No dosage adjustment is necessary in Black, Hispanic, and Japanese patients. However, the exposure to ENTEREG in Japanese healthy male volunteers was approximately 2-fold greater than in Caucasian subjects. Japanese patients should be closely monitored for possible adverse effects (e.g., diarrhea, gastrointestinal pain, cramping) that could indicate high drug or ‘metabolite’ levels, and ENTEREG should be discontinued if adverse events occur. ENTEREG and E.A.S.E. are trademarks of Cubist Pharmaceuticals. Any other trademarks are property of their respective owners. Distributed by: Cubist Pharmaceuticals U.S. Lexington, MA 02421 USA © Cubist Pharmaceuticals. All rights reserved. October 2014 ENT-0232

of Visceral Surgery and Medicine at Bern University Hospital, in Switzerland, was that intraoperative local anesthesia may disrupt nociceptive signals and thus may decrease the incidence of chronic postoperative pain. In the study, Dr. Kurmann and her colleagues randomized 356 patients with 402 hernia repairs to three procedures: Lichtenstein (open mesh), Barwell (open autogenous similar to Bassini or Shouldice) and total extraperitoneal (TEP) inguinal hernia repair (laparoscopic), with or without a local anesthetic. The authors defined chronic pain as any pain lasting more than three months, as described by the International Association for the Study of Pain (Pain Suppl 1986;3:S1-S226).

‘Pain is incredibly complex, and there are many reasons patients can experience chronic pain after inguinal hernia repair.’ —Uwe Klinge, MD A total of 322 inguinal hernia repairs were performed using the Lichtenstein technique, with 168 receiving local infiltration of bupivacaine 0.25% 20 mL (intervention group) and 154 receiving a saline solution (placebo group); 13 underwent the Barwell technique, with six in the intervention group and seven in the placebo group; and 51 underwent TEP, with 26 in the intervention group and 25 in the placebo group. About half of the patients in the intervention (44%) and placebo (48%) groups had a nerve resection of the ilioinguinal, iliohypogastric or genitofemoral nerves. Chronic pain was evaluated three months postoperatively using the visual analog scale (VAS), with chronic pain defined as a score of 30 or greater. After accounting for patients lost to follow-up, the analysis included 347 hernia repairs in 307 patients. Three months postoperatively, the authors reported an incidence of chronic pain of 5.8% (10 of 173 hernias) in the intervention group and 2.3% (4 of 174) in the placebo group (P=0.114). P The study also analyzed several outcomes one year postoperatively and found that the incidence of surgical complications—including recurrent hernia, and superficial and deep surgical site infections—bodily pain and physical functioning were similar in the intervention and placebo groups. The authors could not confirm a difference in the development of chronic pain see HERNIA page 31

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GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

ROBOTICS

jContinued from page 1 the American College of Surgeons, Dr. Zureikat presented his experience with robotic surgery, outlining the pros and cons of using the robot in HPB surgery. After his presentation, he spoke with General Surgery News to offer his thoughts on the role of robotic technology in one of the most complex areas of general surgery. GSN:: Youâ&#x20AC;&#x2122;ve been using the robot now for more than five years. Can you tell us about your experience? Dr. Zureikat: I started using the robot in 2010, after training in both laparoscopic and robotic surgical oncology. Although I use standard laparoscopy for many operations, I found the robot to have an edge over laparoscopy for complex abdominal operations, particularly operations requiring suturing and reconstruction and ones that may involve significant bleeding, which may be difficult to control laparoscopically. Some of these complex oncologic procedures include the pancreaticoduodenectomy (Whipple). This can be done laparoscopically, but the conversion rate to laparotomy may be lower with the robotic approach. Iâ&#x20AC;&#x2122;ve also utilized the robotic approach for gastric cancers, since I believe the visualization and ability to perform a comprehensive lymphadenectomy is superior. Similarly, I have used it for liver resections, particularly for lesions located in the challenging posterior segments of the liver, since these are areas that are hard to resect using standard non-wristed laparoscopic instruments, or may require a substantial laparotomy in order to remove a relatively small specimen. The robotic platform may be particularly applicable to patients with higher BMI [body mass index], since these operations may be challenging with greater complication rates. The ability to complete these complex resections in minimally invasive fashion may prove to be particularly advantageous in this subgroup of patients. Of the 500 robotic pancreas cases done at the University of Pittsburgh, almost 250 were Whipples, 125 were distal pancreatectomies and the remaining cases were a combination of central pancreatectomies, total pancreatectomies, total pancreatectomies with auto islet transplantations, enucleations, Puestow-type procedures, and cystgastrostomies for pancreatic pseuodocysts or walled-off necromas. This variety of cases is a testament to the versatility of this platform. GSN: You just published an important study in the Journal of the American Medical Association. Can you tell us about that study? Dr. Zureikat: Itâ&#x20AC;&#x2122;s a paper that addresses the learning curve of the robotic

Whipple. It allows us to recognize how many cases a surgeon needs [to do] in order to optimize his or her outcomes. We looked at our first 200 [cases of ] robotic pancreatoduodenectomy. For metrics like conversion and blood loss, the learning curve was short, at about 40 cases. For operative times, we found the learning curve to be approximately 80 cases, due to the continuous modifications we made to the technique throughout the experience. We believe this learning curve will be shorter for new adopters of this platform if a robust training curriculum and adequate mentorship are available. In

terms of outcomes, the pancreatic fistula rate decreased significantly after 40 cases. Length of stay and complications also decreased, but this drop was not significant. This may be due to an underpowered sample size, and we hope these numbers become more clinically meaningful with larger series. Importantly, more than 80% of the cases were performed for malignant indications, with 41% of cases being done for pancreatic adenocarcinoma. This is a large number of pancreatic cancers and implies that if the robotic Whipple is implemented in a safe and thoughtful

way by surgeons experienced in pancreatic surgery, the outcomes are just as good as the open operation. Additionally, it was quite interesting to find that our robotic Whipple learning curve of 80 cases was roughly similar to the open learning curve reported by others from MD Anderson [Cancer Center] and Indiana University, implying that there is some inherent similarity between the open and robotic approaches since they both rely on stereotactic vision, wristed instruments and relatively straightforward ergonomics. see ROBOTICS page 22

In the News ROBOTICS

jContinued from page 21 It’s important to note that we employed a two-attending approach in performing these early Whipples and the majority of our early distal pancreatectomies. We thought this was essential for safety early on. I think this is why our safety data are comparable and maybe even slightly better than other centers trying to implement new technology to complex procedures. This learning curve is also dependent on a high volume of cases. It will be difficult for a program to implement robotic Whipples if they are doing one case every few months. The learning curve is predicated on continuous improvement of robotic skills. GSN:: Mortality is a major concern with complex HPB surgery. What does the data show with regard to mortality after robotic Whipple? Dr. Zureikat: Mortality for robotic Whipple in our series is within the national average. The mortality rate for an open Whipple performed by high-volume surgeons should be under 2%. Our 30-day mortality rate for robotic Whipple was 1.5%. So in the hands of experienced pancreatic surgeons at high-volume institutions, the robotic Whipple mortality

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

‘A surgeon who is not experienced in open HPB or minimally invasive surgery should not be venturing into robotic HPB procedures without adequate training and mentorship.’ —Amer H. Zureikat, MD and morbidity is on par with the national average. Even early in our experience, the mortality rate was consistently low. This was a direct result of the careful and thoughtful approach with which we implemented our robotic pancreas [surgery] program. We had two attendings doing these robotic Whipples together to ensure that the case proceeds safely. Some reports of increased morbidity and mortality following robotic Whipples are concerning, but they are a direct consequence of lack of careful planning and experience. A surgeon who is not experienced in open HPB or minimally invasive surgery should not be venturing into robotic HPB procedures without adequate training and mentorship. GSN:: We see a great deal of marketing from hospitals advertising that they offer the robot, including in HPB surgery. There are ads online that claim the robot offers advantages in HPB, including an

ability to start chemotherapy earlier. What does the published data show? Dr. Zureikat: Our experience and that of others would say that that’s true: You can start chemotherapy earlier. But a recently published article in the Journal of Clinical Oncologyy that examined nearly 1,000 patients previously enrolled in the prospective ESPC-3 trial stipulated that it’s not the time to chemotherapy that

matters, but the ability to complete all doses of the chemotherapy (J ( Clin Oncol 2014;32:504-512) 2 . A recent retrospective report from Mayo Clinic showed that patients who underwent a laparoscopic Whipple started adjuvant chemotherapy earlier than their open counterparts; however, overall survival was the same for both groups ((J Gastrointest Surgg 2015;19:189194). Certainly, in our data—and this is

In the News

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

purely retrospective and likely subject to selection bias—more patients get adjuvant chemotherapy after a robotic Whipple. We are currently examining the differences in completion of all scheduled adjuvant chemotherapy for both open and robotic Whipples to determine if there is a survival advantage. GSN:: Are there any advantages to using the robot in HPB? Dr. Zureikat: At the moment, with the data that we have on the learning curve, the one obvious benefit is the reduced blood loss compared with open surgery. This finding has been confirmed by other groups. Blood loss (and consequently blood transfusion requirements) in cancer surgery is very important, since it is an independent predictor of poor survival. Other advantages have not been well documented, and this is mainly because most surgeons (including our group) were still within their learning curve. Robotic HPB surgery may not show any advantages currently, but these comparisons are premature and uninformative at this stage. Outcomes of length of stay, morbidity, readmissions, completion of chemotherapy and, ultimately, survival can be formally assessed after the learning curve is achieved. At the University of Pittsburgh, we are in a unique situation to start looking at these outcomes carefully, since we believe the learning curve has been identified and surmounted. GSN:: What about disadvantages? There were some concerns about potential to increase fistula rates with robotic surgery. Dr. Zureikat: We classify our fistulas by International Study Group for Pancreatic Fistula (ISGPF) criteria. The rate of fistula for open Whipples is anywhere between 10% to 25%. After our initial 40 cases, our fistula rate is within the national reported average at 14%. Importantly, only half of those are clinically significant, ISGPF Class B and C fistulas. These are numbers on par with other major institutions. I think the only real disadvantage at the moment is cost. All the other metrics are similar to what we see with open surgery: fistula, mortality, morbidity, length of stay. All these are within the national average, but the cost is certainly higher. We’re currently performing a cost analysis model based on deviations from expected outcomes for open versus robotic Whipples beyond the learning curve. Again, the central issue is completing the learning curve; looking at outcomes for a technology that’s only been available for a decade and comparing that with an operation that’s been around for 80 or 90 years is not appropriate. Now that we’ve identified the learning curve, we are looking to see if cost is reduced with the outcomes

we are seeing beyond the learning curve. GSN: Are there any last things to point out about robotic HPB? Dr. Zureikat: Robotic surgery is heavily advertised and marketed by hospitals and surgeons alike. That may be applicable for urologic and gynecologic procedures, but we have to be careful about marketing this for HPB surgery. A surgeon must be well experienced in both minimally invasive and open HPB surgery and must have prior experience with less complex robotic procedures, like cholecystectomies, splenectomies and partial

gastrectomies before attempting HPB procedures. Additionally, we are in need of specific training modules and curricula for the few surgeons who wish to incorporate complex HPB procedures into their practice. As mentioned earlier, our learning curve was pretty long, but the methodology and results were sound. In this outcomes-driven era, we advocate that programs interested in implementing this platform seek the advice and guidance of well-established robotic programs. In an effort to reduce the learning curve and avoid unnecessary poor outcomes, we and others have developed a framework to

guide new adopters and offer them pearls and pitfalls for these complex operations. If I were to summarize the role of robotics in HPB, I’d say incorporation of robotics in HPB can be performed at high-volume centers by experienced HPB surgeons in carefully selected patients. The learning curve for the complex robotic resections resembles the open learning curve, but a team approach is very important in the implementation phase. As surgeons overcome the learning curve, comparisons with open surgery may reveal potential advantages to this new platform.

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McMahon Group Acknowledges Exemplary Staff Every year the entire McMahon Group staff takes a moment to review the past year and celebrate the achievements of its various departments and the company overall. McMahon Group’s print and digital properties enjoyed signiﬁcant successes during 2014, often advancing in both readership and revenues.

2014

The following employees were singled out as exemplary at this year’s annual celebration. We thank them, and we thank our readers for their continued enthusiasm for our medical journalism, which has made many of our publications the best read in their specialty.

SUPPORT/ART/PRODUCTION/IT/FINANCE

This award is for a commingled group of several vital departments within the company, without any one of which the company would not thrive, and as such there are two recipients of this award. MARTIN BARBIERI is the production manager for several of the company’s newsmagazines—a complicated task, which he accomplishes seamlessly month after month.

KWANGHEE CHUNG is senior lead developer in the IT Department, having input in all things digital, including our various websites, internal content management systems, and apps, to name a few.

EDITOR OF THE YEAR

SALES ACHIEVEMENT AWARD

This award is for the outstanding editor among the publication, copy and projects editorial staffs. KEVIN HORTY Y won for his editorial direction of General Surgery News, the best-read publication in general surgery. His contributions have included an important effort to enhance our Web-based video offerings.

MATTHEW SPOTO is senior account manager for Gastroenterology & Endoscopy News, the best-read publication in gastroenterology. This award celebrates creative thinking to enhance sales and customer service.

SALESPERSON OF THE YEAR

THE MCMAHON GROUP PARTNERS’ AWARD

RICHARD TUORTO, the senior group publication director for Anesthesiology News and Pain Medicine News, both of which are the best-read publications in their fields, earned this award for the ninth year in a row for generating the most revenue in the calendar year.

ROSANNE MCMAHON is a partner and co-founder of the company and the wife of CEO Ray McMahon. For many years she was personally involved in financial oversight, but nowadays she continues to do what she has done expertly from the very beginning: supporting the CEO and family members working at the company!

THE MCMAHON GROUP PERSON OF THE YEAR RICHARD TUORTO, this year’s Salesperson of the Year, was voted Person of the Year by McMahon Group employees for his longstanding excellence in both sales and publication management.

Question the norm. Do the tools you need exist today?

According to us, the answer is no. But each new device takes us closer. Zenapro, for instance, is the first hybrid hernia-repair device. A sheet of ultra-lightweight polypropylene mesh surrounded by extracellular matrix, Zenapro gives patients a permanent repair while leaving behind minimal foreign material in the body. Learn more: visit zenapro.cookmedical.com. Zenapro Hybrid Hernia Repair Device â&#x201E;˘

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GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

Rectal Cancer: What Is Optimal Timing for Surgery After Radiation? B Y C HASE D OYLE SAN FRANCISCO—Although an interval up to 75 days between radiation and surgery may achieve higher rates of pathologic complete response (pCR), a delay of more than 60 days from radiation to surgical resection decreases overall survival (OS) in patients with rectal cancer, according to data presented at the 2015 Gastrointestinal Cancers Symposium (abstract 510).

“In patients with locally advanced rectal cancer, there was a significant difference in complete pathologic response, positive margin status and survival before and after 60 days’ interval between radiation and surgery,” said Jonathan C. Salo, MD, a surgical oncologist at the Levine Cancer Institute at Carolinas Medical Center, in Charlotte, N.C. “A radiation–surgery [R-S] interval of less than 60 days was associated with greater OS than an interval of greater than 60 days.”

The optimal timing of surgery relative to the conclusion of neoadjuvant therapy has been ambiguous, according to Dr. Salo, who presented the results of the retrospective study that was led by Ciara R. Huntington, MD, a general surgeon at Carolinas Medical Center. “Other studies have shown that in treatment of locally advanced rectal adenocarcinoma, an increased time interval of six to 12 weeks from the end of radiation therapy to surgery may increase the rate of

Interested in conducting your own research? Consider the Merck Investigator Studies Program. What is MISP? The mission statement of the Merck Investigator Studies Program (MISP) is to advance science and improve patient care by supporting, through the provision of drug/vaccine and total/partial funding, high-quality research that is initiated, designed, implemented and sponsored by external investigators. Who Can Participate? The Merck Investigator Studies Program is open to all academic and community-based physicians, anesthesiologists, surgeons, and researchers worldwide who are interested in conducting their own research. How Does the Program Work? This program consists of committees of medical and scientiﬁc staff from different therapeutic areas who meet regularly to review Merck investigator study proposals. Support and funding are provided based on the scientiﬁc merit of the proposal as well as whether it is in alignment with the published areas of interest.

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pCR,” said Dr. Salo, “but the optimal time interval with respect to survival has not been established. This study evaluated the impact of time delay on overall mortality.” The National Cancer Data Base was queried for patients with adenocarcinoma of the rectum and no evidence of metastasis at diagnosis, who underwent preoperative chemoradiation followed by radical surgical resection from January 2004 through December 2006. The cohort consisted of 6,805 patients, who generally were treated with low anterior resection (57.3%), colon-anal reanastomosis (8.4%) or abdominoperineal resection (28.4%). They had a median survival of 66.6 months. Dr. Salo outlined the findings: • OS was equivalent in groups with R-S interval less than 60 days. • OS was shorter for a R-S interval of more than 60 days compared with less than 60 days (hazard ratio, 1.25). • The pCR rate increased up to 75 days after radiation, and did not increase further thereafter (P=0.0003). P • Positive surgical margins occurred at equivalent rates for all groups of R-S interval less than 60 days. • Positive surgical margin rate increased after 60 days following radiation (P=0.0067). P “There was a significant relationship between radiation–surgery interval and complete pathologic response (P=0.0002),” P he said. “Additionally, a radiation–surgery interval of more than 60 days was associated with 20% greater risk for mortality. This effect became more pronounced with increasing intervals; an interval of greater than 75 days was associated with 28% increased risk of mortality, while patients with an interval of less than 60 days saw a survival benefit.” Other significant predictors of survival were age, surgical margins, cormorbidity index, time to discharge after surgery, TMN pathologic staging, surgical volume and patient income (P<0.05 for all values). Nancy Kemeny, MD, attending physician at Memorial Sloan-Kettering Cancer Center and professor of medicine at Weill Cornell Medical College, both in New York City, noted several limitations of the study: The data could be outdated due to improvements in chemotherapy and surgery; some patient- and treatment-related specifics were lacking or not reported; and the overall pCR rate of 6.8% is lower than most current reports (12%-28%). However, Dr. Kemeny added that this large retrospective study “has given support to the concept that a longer interval … from the end of chemoradiation to surgery is necessary to increase the chance of complete response, but waiting more than 60 days decreases overall survival.”

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GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

Study Finds Wide Variation Among Rectal Cancer Guidelines B Y A SHLEY W ELCH

ide variation exists in clinical practice guidelines for rectal cancer, according to a recent study from the University of Michigan Comprehensive Cancer Center, in Ann Arbor. The report, published in Cancer, r looked at the clinical practice guidelines for rectal cancer from five top institutions in the United States, Canada and Europe. Researchers evaluated the guidelines— all published in the past six years—with respect to overall quality using a tool that rated them on a percentage scale on six quality domains. The scores ranged from 27% to 90%, suggesting wide variation. The Michigan investigators said the study highlights some important information for physicians who are following such guidelines and underscores the importance of not following guidelines blindly. “The guidelines are of varying quality and they have varying recommendations,” said lead investigator Sandra L. Wong, MD, MS, an associate professor of surgery at the University of Michigan Medical School. “It’s not as easy as just viewing a guideline and following it.” The guidelines from the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom had the overall highest score, whereas those from the European Society for Medical Oncology (ESMO) ranked lowest. All five organizations, which also included the American Society of Colon and Rectal Surgeons (ASCRS), Cancer Care Ontario (CCO) and the National Comprehensive Cancer Network (NCCN), scored highest on the “clarity of presentation” domain. Overall, the lowest scores were in the “applicability” domain. The greatest disparity existed in the “rigor of development” domain, with NICE scoring 96% and ESMO 17%. Additionally, NICE, ASCRS and CCO included systematic reviews in developing their guidelines, whereas ESMO and NCCN did not. Dr. Wong and her colleagues also assessed 21 common points of care among the guidelines and found that all five guidelines agreed on only eight recommendations for care. Six processes of care

Although it may take time to develop a complete response, in the absence of a tumor response, these longer intervals may actually be harmful, she said. “An increased time delay could facilitate local tumor growth and metastasis, enhance fibrosis, and delay the resumption of postoperative chemotherapy,” Dr. Kemeny said, suggesting that the optimal strategy might be “measuring response more frequently.”

were in direct conflict with one another. These included differences in diagnosing and staging, the role of laparoscopic surgery and the duration and methods of aftercare surveillance. Furthermore, the study found that even when guideline panels used the same randomized clinical trials as evidence, they sometimes make different recommendations. For example, when it came to postoperative chemotherapy in patients who received preoperative chemoradiation,

recommendations among the guidelines were highly variable, although they cited the same trial. “We found that to be pretty striking,” Dr. Wong said. “If you’re somebody who’s looking at the guidelines trying to figure out what’s the best thing to do for your patient, you can see how that can get very confusing very quickly.” Several factors may account for the discrepancies in recommendations. First, there are no global guidelines for creating

clinical practice guidelines. Geography also should be taken into account. The study authors point to the differences in practice between North America and Europe in the use of short-course radiation therapy for moderate-risk rectal cancer patients. The makeup of the panel at each organization also can affect the outcome. Some of the guidelines panels included experts in a single specialty, whereas others encompassed multidisciplinary specialties and patient advocates.

IMPORTANT CORRECTION OF DRUG INFORMATION ABOUT EXPAREL® (BUPIVACAINE LIPOSOME INJECTABLE SUSPENSION) Pacira Pharmaceuticals, Inc., received a warning letter from the US Food and Drug Administration (FDA) Office of Prescription Drug Promotion (OPDP) on September 22, 2014 concerning an advertisement for EXPAREL, which you may have seen published in several professional journals. This publication provides important corrective information about the false and misleading claim. The FDA stated that the advertisement was false or misleading because it overstates the efficacy of EXPAREL. The FDA objected to the claims that EXPAREL provides pain control that lasts for up to 72 hours because the claims suggest that EXPAREL has been shown to provide pain control beyond 24 hours. According to the Prescribing Information, “The primary outcome measure was the AUC [area under the curve] of the NRS [numeric rating scale] pain score (cumulative pain scores) collected over the first 72 hour period.…In this clinical study, EXPAREL demonstrated a significant reduction in pain intensity compared to placebo for up to 24 hours. The difference in mean pain intensity between treatment groups occurred only during the first 24 hours following study drug administration. Between 24 and 72 hours after study drug administration, there was minimal to no difference between EXPAREL and placebo treatments on mean pain intensity.” Excerpts from the applicable sections of the FDAapproved package insert for EXPAREL follow. The FDA has reviewed and approved this communication. Indication for EXPAREL EXPAREL is a liposome injection of bupivacaine, an amide-type local anesthetic, indicated for administration into the surgical site to produce postsurgical analgesia. EXPAREL has not been studied for use in patients younger than 18 years of age. Clinical Studies Hemorrhoidectomy The primary outcome measure was the AUC of the NRS pain intensity scores (cumulative pain scores) collected over the first 72 hour period. There was a significant treatment effect for EXPAREL compared to placebo. ©2015 Pacira Pharmaceuticals, Inc. Parsippany, NJ 07054 PP-EX-US-0623

2/15

In this clinical study, EXPAREL demonstrated a significant reduction in pain intensity compared to placebo for up to 24 hours. The difference in mean pain intensity between treatment groups occurred only during the first 24 hours following study drug administration. Between 24 and 72 hours after study drug administration, there was minimal to no difference between EXPAREL and placebo treatments on mean pain intensity; however, there was an attendant decrease in opioid consumption, the clinical benefit of which was not demonstrated. Important Safety Information EXPAREL is contraindicated in obstetrical paracervical block anesthesia. EXPAREL has not been studied for use in patients younger than 18 years of age. Non-bupivacaine-based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more. Other formulations of bupivacaine should not be administered within 96 hours following administration of EXPAREL. Monitoring of cardiovascular and neurological status, as well as vital signs should be performed during and after injection of EXPAREL as with other local anesthetic products. Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, EXPAREL should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations. In clinical trials, the most common adverse reactions (incidence ≥10%) following EXPAREL administration were nausea, constipation, and vomiting. Reporting Adverse Events Heath care providers and patients are encouraged to report adverse events in patients taking EXPAREL to Pacira at 1-855-793-9727. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. Please see accompanying brief summary of Prescribing Information.

In the News SUNSHINE

jcontinued from page 1 The ubiquity of these physician– industry relationships, along with concerns about conflicts of interest, has spurred a national effort by the federal government to make such financial ties more transparent. On Sept. 30, 2014, the Centers for Medicare & Medicaid Services (CMS) unveiled the Open Payments website, publishing data on 4.4 million financial transactions between industry and doctors in the five months from Aug. 1 to

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

Dec. 31, 2013. These transactions represented industry financial relationships with an estimated 546,000 doctors and other health care professionals, as well as 1,360 teaching hospitals, totaling almost $3.7 billion. Going forward, Open Payments will report financial transactions spanning 12 months, from Jan. 1 to Dec. 31 of each year, and will be published by June 30 of the following year. “The main goal of Open Payments is to present the most comprehensive data on financial relationships between industry and doctors,” Shantanu Agrawal, MD, director and deputy administrator

of CMS’ Center for Program Integrity, told General Surgery News. “There have been attempts to bring this information together in the past, but nothing that has provided a national picture like Open Payments does.” The Open Payments program, otherwise known as the Physician Payment Sunshine Act, requires that pharmaceutical and device companies report payments made to physicians and teaching hospitals—meals, honoraria, travel expenses, gifts and grants—that are more than $10. Manufacturers and group purchasing organizations also must report

EXP-AP-0020-201301

whether a physician or his or her immediate family member has ownership or investment interests in a company. Physicians have largely been supportive of this effort to track information on physician–industry relationships nationwide. “I’m in complete agreement with the Open Payments program,” said Robert J. Fitzgibbons, MD, Harry E. Stuckenhoff professor of surgery at Creighton University School of Medicine, in Omaha, Neb. “We have seen tremendous biases stemming from these financial relationships. Physicians don’t always publicly report their conflicts of interest, and having a system like Open Payments will be a great way to help sort out potential biases.” Benjamin K. Poulose, MD, MPH, associate professor of general surgery and director of the Vanderbilt Hernia Center, in Nashville, Tenn., thinks Open Payments is a good idea, and John Maa, MD, immediate past president of the Northern California Chapter of the American College of Surgeons, believes that Open Payments will be a great way to promote transparency and highlight conflicts of interest. But Drs. Fitzgibbons, Poulose and Maa all noted that the key to its success will be obtaining reliable and accurate information. “If the data is not accurate, like anything else, it can be harmful,” Dr. Fitzgibbons said. To this end, Dr. Agrawal stressed, it is essential for physicians to register for the Open Payments system and engage in the data review and dispute process to ensure that the data published are accurate. But technical issues with the Open Payments system have made this seemingly simple request difficult for many physicians. Hoping to address these concerns before the data became public, more than 100 medical societies and associations in the United States sent a letter to CMS administrator Marilyn Tavenner, expressing their concern about the implementation of the program. The letter highlighted that a difficult registration process, coupled with a short deadline, impeded physicians’ ability to register, review and dispute their data. The letter requested that CMS delay the publication of Open Payments data until March 31, 2015, so physicians could have adequate time to register, review and dispute the entries in the system. In response to these concerns, Robert Wah, MD, president of the American Medical Association, issued a statement remarking that “if the government releases incorrect information to the public, it can lead to misinterpretations, harm reputations and cause patients to question their trust in physicians.” In early August, CMS was alerted to a specific glitch in the system and took the Open Payments system offline between Aug. 3 and Aug. 14 to resolve

In the News

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / APRIL 2015

technical issues relating to data accuracy. Dr. Agrawal explained, “We share the desire to make sure the data is as accurate as possible, and once we realized there was an issue, we suspended activity to the site and decided to take down the records we weren’t confident enough in.” Still, when the data were published on Sept. 30, many entries were de-identified. CMS reported that the names of physicians and hospitals were withheld from about 40% of the 4.4 million records— amounting to $2.3 billion in transactions—due to concerns about accuracy. In most cases, these records were de-identified because companies had submitted national provider identifiers that failed to match the name or medical license, and thus CMS could not be certain of the actual recipient or payments. “The launch of Open Payments felt slapdash,” said Guy Voeller, MD, professor of surgery at the University of Tennessee Health Science Center, in Memphis. “The system was not finetuned before it went public.” Dr. Agrawal and his team are continuing to work out the kinks, focusing on implementing mechanisms to make sure the data are accurate and that physicians are actively engaged in the review and dispute process. For example, to correct the issue with national provider identifiers, CMS is upgrading the system to automatically exclude any data that are inconsistent. To encourage involvement, CMS has introduced a mobile app that allows information to be exchanged between physicians and companies before it is submitted to CMS to minimize data inaccuracy. Additionally, to expedite the review process, Dr. Agrawal noted that CMS can communicate with doctors when their data are available, but he noted that physicians do need to register first for security and privacy reasons. Jarrod P. Kaufman, MD, FACS, a general and advanced laparoscopic surgeon at Advanced Surgical Associates of Central Jersey, in Brick, N.J., contests the way the review process is set up. “If the data reported by industry is accurate, I don’t think anyone has a problem with Open Payments, but I take issue with the fact that the onus is placed on busy doctors to dispute and correct the data. The onus should be on CMS to set up meetings for doctors to review their information.” Dr. Poulose agreed: “I think it is somewhat unreasonable to put responsibility on busy surgeons to police the data or go through a laborious correction mechanism.” Physicians have also expressed anxiety over the possibility that the data published through Open Payments may be misconstrued. Although companies are required to specify the nature of a payment, “some doctors are apprehensive that the public will view any existence of

a physician and industry relationship to be bad,” Dr. Agrawal said. A 2014 study that evaluated the perception of physician–industry relationships uncovered a complex picture ((J Law Med Ethicss 2014;42:475-491). The researchers found that people’s perceptions were often swayed by payment type more than by amount. For example, respondents were more judgmental of doctors who owned drug company stock or received payments for meals and lodging than those who received free drug samples, which could potentially benefit patients, or consulting fees, which

implied expertise. Notably, although doctors who did not receive payments were viewed as honest, some respondents felt they were less experienced or informed about new treatments. But the role of Open Payments, according to Dr. Agrawal, is not to prejudge these interactions; it is simply to collect information and make it publicly available in a way that can encourage a dialogue. “Hopefully, people will see the data itself as a valuable resource,” Dr. Agrawal said. “We also hope people will start to analyze the data in order to begin to

interpret what it means.” So far, several outlets have done initial work on interpreting the first five months of data. The British Medical Journall (BMJ) J reported financial transactions by company, drug, specialty, type of interaction, investment share and specific doctor. BMJJ revealed the five U.S. companies that pay physicians the most—Genentech ($130 million), Johnson & Johnson’s DePuy ($35.5 million), Pfizer ($20.5 million), Zimmer Holding ($17.3 million) and AstraZeneca ($15.77 million)—and the medical specialties see SUNSHINE page 31

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See the evidence and full product information at www.Ethicon.com Color sticky notes represent customer insights. *In animal studies. 2 References: 1. Data on file. Ethicon, Inc. A. Holste J-L, Muench T, Shnoda P, Wohlert S, McRoy L. A preclinical evaluation of the tissue separation and abdominal wall integration properties of ETHICON PHYSIOMESH™ Flexible Composite Mesh. PHYSM 336-10-8/12. Ethicon, Inc. B. Holste J-L, Muench T, Shnoda P, Wohlert S, McRoy L. An evaluation of ETHICON PHYSIOMESH™ Flexible Composite Mesh in the prevention of adhesions in a rabbit model of abdominal hernia repair: a comparative study. PHYSM 335-10-8/12. Ethicon, Inc. C. Ethicon Hernia Dashboard 2014. D. Final Report, PSE Accession No. 13-0058, Project No. 12736. May 19, 2014. E. Final Report, PSE Accession No. 14-0099, Project No. 12736. November 14, 2014. F. Final Report, PSE Accession No. 13-0041, Project No. 12736. July 29, 2013. G. Report for 510k Testing for ETHICON PHYSIOMESH™ Open Flexible Composite Mesh Device, Version 2. May 14, 2014. 2. ETHICON PHYSIOMESH Open Flexible Composite Mesh Device. Instructions for Use. Ethicon, Inc. 3. Klosterhalfen B, Junge K, Klinge U. The lightweight and large porous mesh concept for hernia repair. Expert Rev Med Devices. 2005;2(1):103-107. 4. Cobb WS, Kercher KW, Heniford BT. The argument for lightweight polypropylene mesh in hernia repair. Surg Innov. 2005;12(1):63-69. 5. Junge K, Klinge U, Prescher A, Giboni P, Niewiera M, Schumpelick V. Elasticity of the anterior abdominal wall and impact for reparation of incisional hernias using mesh implants. Hernia. 2001;5:113-118.

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HERNIA

jcontinued from page 20 three months postoperatively between patients who received intraoperative infiltration of local anesthesia and those who did not. “We concluded that there is not enough evidence that intraoperative infiltration of local anesthesia has an influence on the development of chronic postoperative pain and should not be practiced,” Dr. Kurmann wrote in an n email to

General Surgery News. Commenting on the study, Robert Bendavid, MD, FACS, FRCS(C), a surgeon at the Shouldice Hospital in Toronto, Ontario, Canada, remarked that once the activity of the local anesthetic agent has passed, it should not affect pain in the short or long term after surgery. Dr. Bendavid also found the definition of chronic pain too limited. “Three months is not an adequate time frame to evaluate cchronic pain,” he said. “There can stilll be healing and scarring going on n up to a year after surgery, and

chronic pain can take even longer to manifest. I’ve seen patients reporting pain six years after surgery.” Although the current study did not explore the mechanisms of pain, the investigators surmised that postoperative chronic pain may arise from a range of factors, including intraoperative nerve injury, inflammatory reactions after surgery or scar tissue from the implanted mesh. Dr. Bendavid noted that nerve entrapment could be another explanation for chronic pain in inguinal hernia repair using mesh. In a recent study, he found

that nerves can grow through the pores and interstices of mesh, as well as within scar tissue infiltrating the mesh (Int J Clin Medd 2014;5:799-810). “Pain is incredibly complex, and there are many reasons patients can experience chronic pain after inguinal hernia repair,” Dr. Klinge said. Dr. Kurmann concluded that “further studies should focus on the pathophysiological pathway of chronic pain to identify specific interventions.”

SUNSHIINE

jcontinued frrom page 29 receiving th he highest payments are orthopedic surgery ($80 million), internal medicine dicine di i ($26.6 ($26 6 million), million) illi ) iinternal t l medicine/cardiovascular disease ($24.3 million) and psychiatry ($18.7 million). The news organization ProPublicaa broke down payments by category and found that royalties encompassed the greatest source of payments ($302.5 million), followed by promotional speaking ($202.6 million), consulting fees ($158.2 million), food and beverage ($92.8 million) and travel and lodging ($74.1 million). ProPublica also highlighted issues with the data reporting that could make analyzing the information significantly more difficult. ProPublicaa noted, for instance, that companies, such as Johnson & Johnson, attributed payments to several subsidiary companies instead of one parent company, and that other companies reported payments associated with a drug in different ways or under different names. The Open Payments program, however, is still in its infancy, and the long-term effect of the data on physicians, industry, patients and the health care system remains uncertain. Dr. Maa predicted that the information will be most useful to federal and state auditors to identify patterns that could discern waste, fraud and abuse, and will also help track funding sources to doctors. Analysis of the database has already revealed several doctors who have committed fraud or have been engaged in illegal activities. Other benefits, Dr. Maa said, are that journal editors will be better able to identify if a pharmaceutical or device company is funding research. But, he noted, it will be more challenging for patients to use the data to improve their health care. “The data will need to be carefully evaluated and refined over the years,” Dr. Maa said. “This information will likely have benefits that we can’t foresee now.”

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REPORT Managing Venous Thromboembolism Risk in Hereditary Antithrombin DeďŹ ciency ďŹ Introduction

fatal complication, many may Faculty be at increased risk for longHereditary antithrombin defiMichael Cordisco, MS, CCP term sequelae, such as pulmociency (HAD) magnifies the risk nary hypertension or venous for venous thromboembolism Chief of Perfusion insufficiency. From 10% to 30% (VTE) in affected patients.1 Its Stamford Hospital may die within a month of diagdisproportionate contribution to Stamford, Connecticut nosis.4,6 Inherited thrombophilVTE, a potentially life-threaten1,2 Medical Writer ing event, supports the value ias are detected in a small but clinically significant proportion of screening in individuals with Theodore Bosworth of patients with VTE, particurisk factors. The estimated lifeMcMahon Publishing larly those with a prior histotime risk for VTE in patients with ry of thrombosis.7,8 A diagnosis HAD ranges from 50% to 85%,3 before or early within the period of risk offers an oppor opporbut many of these individuals, particularly those with mild tunity to modify risk with anticoagulant therapies. forms, may never receive a diagnosis.1 The risk for VTE In the general population, the incidence of HAD is variin patients with HAD can be readily modified with antiably estimated at up to 0.2%.9 Of inherited thrombothrombin replacement during high-risk situations along 1 with other strategies to reduce hypercoagulability. Thus, philias involving defects in endogenous suppression of coagulation factors, which includes deficiencies in proa systematic approach toward evaluating patients for teins S and C, HAD is among the least common and HAD and initiating VTE prophylaxis in patients with HAD most severe.9 Although deficiencies in proteins S and C is potentially beneficial for this population. each increase the thrombotic risk by about 10-fold, HAD Background increases the risk 20-fold (Figure 1).8,9 HAD is less common than many of the inherited thrombophilias assoVTE is defined as deep vein thrombosis (DVT), pulciated with increased levels or function of coagulation monary embolism (PE), or both.4 In the United States, factors, such as factor V Leiden, factors Leiden hyperhomocysteinemia hyperhomocysteinemia, approximately 550,000 550 000 cases of VTE are diagnosed 5 and elevated factor VIII, but its effect on VTE risk is 4- to each year. Of the patients who develop this possibly

Editorial support provided by

Supported by

REPORT 6-fold higher.9 Overall, inherited thrombophilias may play a role in the pathogenesis of approximately 40% of provoked and unprovoked VTE episodes.7 As an endogenous anticoagulant, antithrombin binds to thrombin to prevent its activation, a critical step in the coagulation cascade, while also exerting inhibitory effects on coagulating factors Xa, IXa, XIa, XIIa, and plasmin.9-11 More than 250 genetic mutations have been associated with HAD that fall under 2 major subtypes.10 Type 1 is characterized by a quantitative deficit in functionally active antithrombin. Deficiency is variably defined as 70% to 80% of normal circulating levels.10,12 Type 2, which is more common in the general population,11 is characterized by normal levels of antithrombin but impaired binding activity. Further subdivision of type 2 can be made according to specific protein-binding defects,13 but screening for HAD is based on functional assays that detect deficiency in antithrombin activity regardless of type or subtype.1 Essentially, all patients with HAD have a heterozygous form because homozygous inheritance typically leads to death in utero.11 The risk for VTE in patients with HAD is low in individuals younger than age 20, increasing progressively with older age.14 The degree of impaired antithrombin activity in patients with either type 1 or 2 HAD varies.13 Importantly, even mild deficiency in antithrombin has been shown to increase the risk for VTE.12 In the hospital setting, the risk for VTE can be substantially increased in patients with HAD; the rates of VTE among patients undergoing cardiac, gynecologic, oncologic, or other surgical procedures associated with high VTE risk climb from

Number of Times Relative to General Population

less than 5% in patients without HAD15 to approximately 20% in those with the disorder.16 In pregnant women with HAD, the incidence of VTE also has been shown to be greater than 50%.3 Although VTE can occur outside of the hospital and in the absence of other risk factors,17 the first clinical manifestations of HAD often are triggered by surgery or prolonged immobility during hospitalization.11 For this reason, idiopathic VTE in otherwise low-risk hospitalized patients may prompt evaluation for HAD or another inherited thrombophilia. Prior history of VTE provides another consideration for thrombophilia evaluation.7

Diagnosis The diagnosis of HAD involves gathering information including patient and family history and repeated screening assays.1 Kenichi Tanaka, MD, MSc, anesthesiologist and professor at the University of Maryland School of Medicine, noted that without preadmission diagnosis, it can be difficult to differentiate HAD from acquired deficiency in the acute setting. “Medical history is of prime importance here. You can talk to the patient and figure out if there’s any personal or family history of thrombophilia,” Dr. Tanaka said. “Look at recent medical history to determine if the patient had any thrombotic events particularly within 3 months of any type of surgery or if the patient had experienced any complication during or after pregnancy. You really have to know if these patients are at risk for antithrombin deficiency.” Dr. Tanaka added that clinicians should pay attention to all patient factors that may reduce antithrombin levels, particularly when an initial HAD diagnosis cannot be made in the

5 3

Prothrombin gene mutation

Hyperhomocysteinemia

0 HAD

Protein C deﬁciency

Protein S deﬁciency

Factor V Leiden

Elevated factor VIII levels

Coagulation Disorder Figure 1. HAD presents the highest risk for thrombosis among inherited thrombophilias. Patients heterozygous for factor V Leiden have approximately a 5-fold greater risk for venous thrombosis, whereas homozygotes have approximately an 80-fold greater risk. Thrombate III (antithrombin III [human]) is not indicated for the treatment of thrombophilias other than HAD. HAD, hereditary antithrombin deficiency Adapted from reference 9.

In clinical studies of Thrombate III, the most common adverse events were dizziness, chest discomfort, nausea, and dysgeusia.

REPORT acute setting. Dr. Tanaka noted that antithrombin levels might be reduced in patients with ongoing major organ infection, disseminated intravascular coagulation (DIC), or sepsis. “Then, I also pay attention to the production of antithrombin. Antithrombin is made in the liver so if the patient has cirrhosis or any end-stage liver dysfunction, that’s an important sign that antithrombin might be low.” Right-side heart failure causing liver congestion as well as heparin exposure for more than 3 to 4 days can reduce antithrombin levels. Overall, testing antithrombin levels can help explain the response to anticoagulation used during surgery, such as heparin, which depends on antithrombin as a cofactor. Thrombophilia screening often is not recommended in an unselected population due to the low prevalence of these disorders. However, thrombophilia evaluation in patients with risk factors, such as personal or family history of VTE,7 and who are facing situations associated with high thrombotic risk, including surgery, pregnancy, trauma, or extended immobilization, may offer an opportunity for significant risk reduction.18 Of the functional tests available for antithrombin activity, the factor Xa inhibition assay is generally preferred over a thrombin inhibition assay because it avoids the confounding effects of heparin cofactor II activity, which may mask HAD.11 When screening is performed, clinicians also should be mindful of other clinical variables and interpret results accordingly. For example, at the time that the blood sample is taken, if patients are receiving anticoagulants, such as heparin or the direct Xa inhibitors, results could be affected by these medications.3 When ordering an antithrombin functional assay, a hematologist consult may be appropriate for considering the result in the context of other clinical factors. Antigenic assays should be reserved for defining HAD type after the initial diagnosis as these would be expected to miss type 2 HAD, which is the more common form.11 Although a functional antithrombin level in the normal range rules out HAD, a single abnormal test does not confirm HAD.11 Once antithrombin deficiency has been confirmed by repeated tests, the opportunity arises to educate patients about its relationship to VTE and the risk it imposes for thrombosis over the lifetime. Testing of family members also may be appropriate.11 Genetic testing also may be useful as the mechanisms for specific antithrombin deficiency can be further investigated by geneticists; however, such testing usually is not performed.1,11

Management Clotting disorders require a comprehensive approach to balance prevention of VTE against risk for bleeding events.12 Anticoagulants already are broadly applied in hospitalized patients at risk for VTE.7 HAD management should be considered within this context. In HAD, replacement of antithrombin in high-risk situations offers the most direct approach to managing the underlying disorder,1 but other steps to modify risk also should be considered. Steps to correct disorders with the potential to contribute to VTE risk, such as malnutrition or anemia,4 should not be overlooked. Discontinuing or reducing exposure to procoagulant therapies, such as oral contraceptives,4 also may be appropriate. Confirming HAD patients are on optimal doses of anticoagulants as indicated is also an important step to consider independent of antithrombin replacement.

Several exogenous therapies are available to increase antithrombin activity. These are the human plasma-derived antithrombin, marketed as Thrombate III® (antithrombin III [human]) (Grifols; Research Triangle Park, NC); the non-human recombinant antithrombin derived from goat’s milk, marketed as ATryn® (antithrombin [recombinant]) (rEVO Biologics; Framingham, MA); and fresh frozen plasma (FFP; Table).19-22 FFP was once the only available source for antithrombin replacement.23 As mentioned above, concentrated antithrombin replacement options are now available. The much lower concentration of antithrombin in FFP compared with antithrombin concentrate necessitates administration of high volumes of FFP to normalize antithrombin in a patient with HAD. Thrombate III is antithrombin concentrate derived from human plasma. It has a half-life (3.8 days) consistent with endogenous antithrombin. Because it is derived from plasma, there is a theoretical risk for transmission of infectious disease including the Creutzfeldt-Jakob disease (CJD) agent, despite steps in the manufacturing process designed to reduce this risk. However, no cases of viral disease or CJD transmission have ever been reported.19 It is indicated for the treatment of HAD in connection with surgical or obstetric procedures or when HAD patients develop a thromboembolism. In clinical studies with Thrombate III, the most common side effects were dizziness, chest discomfort, nausea, and dysgeusia.19 Thrombate III is administered in a bolus intravenous infusion (not continuous infusion) and is dosed according to patient weight to achieve antithrombin function levels between 80% and 120% of normal activity. Maintenance doses equal to 60% of the loading dose are administered as infrequently as once daily, but the interval should be assessed based on the antithrombin level achieved. Thrombate III is stored at room temperature and is readily reconstituted with sterile water.19 The non-human antithrombin concentrate ATryn (antithrombin [recombinant]), which is indicated for the prevention of perioperative and peripartum VTE but not the treatment of VTE in patients with HAD, is produced from the milk of genetically modified goats.20 The most common adverse reactions reported in clinical trials were hemorrhage and infusion site reaction. ATryn has a half-life of approximately 12 to 18 hours and is administered as a loading dose based on patient weight followed by a continuous infusion.20 ATryn requires refrigerated storage and must be brought to room temperature no more than 3 hours prior to reconstitution. ATryn is contraindicated in patients with known hypersensitivity to goat proteins.20 The difference in half-life between the plasma-derived and recombinant antithrombin formulations and the resulting difference in dosing volume and administration requirements are important clinical considerations. The products should not be considered as interchangeable. Protocols for dosing and administration must be tailored to the specific antithrombin concentrate being used. Additionally, Thrombate III is stored at room temperature19 ; therefore, there is no waiting time to bring it up to room temperature if a higher dose is needed beyond what was initially anticipated for a case.

Surgery In HAD patients scheduled for surgery, different paths are defined by the use of systemic anticoagulation with heparin. Antithrombin is essential for anticoagulation with heparin

Please see Important Safety Information on page 6 and refer to accompanying full Prescribing Information for complete prescribing details.

REPORT as heparin’s mechanism of action is to bind to and catalyze the effects of antithrombin by 1,000-fold.24,25 Therefore, doses of both heparin and antithrombin must be adjusted to accommodate this effect. Intraoperative monitoring of coagulation factors, such as prothrombin time and partial thromboplastin time, international normalized ratio, and activated clotting time are appropriate. Measurement of antithrombin also is advisable, recognizing that a baseline level in anticipation of surgery may differ from the level at the time of the procedure. The degree of functional antithrombin deficiency before surgery should influence the decision of how much antithrombin concentrate to have available over the period of prophylaxis, but dosing is variable and antithrombin levels may fluctuate over the duration of a case requiring antithrombin replacement. Tengborn and colleagues reported a thrombotic complication rate of 17% in patients with HAD who underwent surgery without any supplemental antithrombin and 22% in those treated with other methods (Figure 2).16 In patients not receiving systemic anticoagulation or those receiving lowdose heparin typical during percutaneous catheterizations,26 greater attention may be applied to repletion of antithrombin to restore normal functional activity. However, management of these patients must be individualized due to variables such as the use of antifibrinolytics, which preserve clots by slowing their breakdown.27

In all patients undergoing surgery, the type and duration of anesthesia is another variable associated with risk for VTE.6 This risk is increased in patients with HAD due to the higher incidence of VTE in this population.1 Steps such as positioning of the body to improve blood flow should be employed to mitigate this risk. A diagnosis of HAD also should intensify attention to blood monitoring during surgical procedures. The goal of close monitoring is not only to reduce clotting risk but also to avoid bleeding events. If a bleeding event occurs, the focus should be to reverse the activity of heparin. “We can neutralize heparin with protamine sulfate28 but adjusting the dose of protamine can be a complex process if the clinician has given a large amount of heparin during surgery,” Dr. Tanaka added.

Immobilized Patients In HAD patients with VTE risk defined by prolonged immobilization, variables that should influence the dose and duration of antithrombin therapy, or whether to initiate antithrombin therapy, include the degree of functional deficiency, the types of other therapies being employed to prevent clot formation, and the frequency and types of blood monitoring. More conservative approaches may be most appropriate for individuals at high risk for bleeding, but sustained antithrombin therapy should be considered in patients with severe forms of HAD with multiple risk factors for VTE and a prolonged period of risk.29

Table. Properties of Thrombate III® (Antithrombin III [Human]), ATryn® (Antithrombin [Recombinant]), and Fresh Frozen Plasma Thrombate III

ATryn

Fresh Frozen Plasma

Source

Human plasma

Milk from transgenic goats

Whole blood or pooled human plasma

How supplied

500 IU vials

525 IU or 1,750 IU vials

250 mL bags

Antithrombin concentration

50 IU/mL a

164 IU/mL or 175 IU/mLb

~1 IU/mLc

Antithrombin dose for example patient: 80 kg, 60% baseline antithrombin activity level, treated for 24 hd

3,429 IUd

8,921 IUd

3,429 IUd

Volume needed for example patient

69 mL administered 54 mL administered via bolus infusion over via continuous infu10-20 min sion over 24 h

3,429 mL administered via continuous infusion over 24 h to achieve equivalent dose

After reconstitution with 10 mL sterile water for injection.

After reconstitution with 3.2 mL (525 IU vial) or 10 mL (1,750 IU vial) sterile water for injection.

Fresh frozen plasma will contain approximately 1 IU/mL of antithrombin.

Total dose in 24 h based on an 80 kg surgical patient with 60% baseline antithrombin activity. See complete Prescribing Information for Thrombate III and ATryn for full dosing guidance.

Thrombate III (antithrombin III [human]) is indicated for the treatment of patients with hereditary antithrombin deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism. Adapted from references 19-22.

The anticoagulant effect of heparin is enhanced by Thrombate III. Reduced dosage of heparin is recommended during treatment with Thrombate III to avoid bleeding.

REPORT Conclusion

For VTE management in pregnant women with HAD, postpartum prophylaxis is recommended by the American College of Chest Physicians even among those without a previous VTE, but with a positive family history, because of the high rate of events.30 For all women, including those with HAD who have had a previous VTE, heparin is further recommended by the College during the postpartum period, when the risk for VTE also remains elevated. Additional strategies for VTE prophylaxis during the postpartum period, such as the use of compression stockings, may be appropriate in severe cases of HAD.30 The inclusion of antithrombin replacement therapy provides an important opportunity to act directly on the source of elevated VTE risk in patients with HAD. More than 40% of VTE in patients with HAD occurs during defined periods of high risk.17 Although it is important to individualize therapy in the context of the complex and interrelated factors that contribute to VTE risk, antithrombin concentrate can be used in community as well as tertiary health care centers when coagulation activity is appropriately monitored.

VTE is a serious but largely preventable complication of surgery or hospitalization. Individuals with HAD, which poses the greatest risk for VTE among inherited defects in control of the coagulation cascade, are overrepresented in cases of VTE.1,2 Screening for HAD in patients with a prior history of VTE offers an opportunity to identify this disorder in advance of the period of risk. Appropriate application of strategies to lower VTE risk in these patients, including antithrombin replacement, would be expected to favorably affect overall VTE rates and isolate patient groups who could benefit from lifetime risk management.

Long-Term VTE Risk Prevention In patients with HAD, the use of antithrombin replacement therapy typically is confined to periods of acute risk, such as during perioperative or peripartum periods. Longer periods of treatment may be appropriate in nonambulatory hospitalized HAD patients when VTE risk remains elevated. Other situations associated with high risk for VTE, such as the presence of an in-dwelling catheter, also may warrant extended periods of antithrombin therapy, particularly in patients with significant impairment of antithrombin function due to HAD. After the period of acute risk, it is unclear whether patients with HAD require any change in the type or duration of anticoagulants other than antithrombin, such as vitamin K antagonists or low-molecular-weight heparin, relative to those without HAD. Referral to a hematologist for extended follow-up may be appropriate not only for guidance in the post-discharge period but for counseling in regard to modifying and avoiding the lifetime risk for thrombotic events. Despite the potential for screening and risk modification to reduce the risk for VTE in patients with HAD, published guidelines regarding the acute or long-term management of this or other inherited thrombophilias remain limited. In a review of guidelines that addressed clinical strategies for reducing VTE recurrence, some guidelines advocated specifically for tests to determine the cause of VTE, whereas others did not address this question at all.31 One remaining guideline called for testing to be limited to patients who also have a strong family history of recurrent unprovoked VTE.32 One explanation is that the limited number of prospective studies conducted in patients with HAD are an obstacle to evidence-based guidelines. However, the established risk for recurrent VTE in patients with HAD, as well as other inherited thrombophilias, supports proactive efforts to identify populations suitable for prophylaxis.

Prophylaxis Before Surgery

Pregnancy

Antithrombin concentratea,b 0 n=10

No treatment n=29

17.2%

Other treatmentsc n=18

22.2%

Incidence of Thrombotic Complications, %

Figure 2. Antithrombin replacementa helps prevent thromboembolism during surgery in patients with HAD. No patient administered antithrombin concentrate alone or in combination with other methods had signs of thromboembolism. Retrospective study of 57 surgical cases.d a

Not Thrombate III (antithrombin III [human]); plasmaderived antithrombin concentrate used was studied but not marketed.

Also combined with other types of prophylaxis.

Dextran, low-dose heparin, peroral anticoagulants, and combinations.

Twenty-three patients underwent 57 operations of various types. Fourteen of the 23 patients had previous deep vein thromboses. In 29 procedures, patients were not given thromboprophylaxis. In 28 procedures, thromboprophylaxis was used.

HAD, hereditary antithrombin deficiency Adapted from reference 16.

Because Thrombate III is made from human plasma, it may carry a risk of transmitting infectious agents, eg, viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases or CJD have ever been identified for Thrombate III. Please see Important Safety Information on page 6 and refer to accompanying full Prescribing Information for complete prescribing details.

REPORT

Case Study Managing Hereditary Antithrombin Deficiency in a Patient Undergoing Cardiac Surgery With Cardiopulmonary Bypass Introduction Outside of a known familial trait for antithrombin deficiency, thrombotic events often are the first indication that a patient may have hereditary antithrombin deficiency (HAD) and can provide clinicians an opportunity to evaluate the underlying cause of thrombosis. The following case report will discuss how the cardiac surgical team evaluated periprocedural risks, anticoagulation technique, and the conduct of cardio-pulmonary bypass (CPB) of a patient after a diagnosis of HAD.

Case Presentation A 44-year-old man was diagnosed with pulmonary embolism (PE) after several days of shortness of breath that he described as more severe than usual. The patient related a family history consistent with a genetic thromboembolic disorder and was found to have HAD based on a functional antithrombin assay result of less than 45%. The acquired form of antithrombin deficiency was ruled out after a thorough history of present illness and lack of recent heparin administration, enteric protein loss, or bleeding history. Additionally, the patient was found to have atrial fibrillation and moderate to severe mitral valve insufficiency discovered during a transesophageal echocardiogram. The patient underwent thrombolytic therapy for the PE and was subsequently referred to and followed by both a hematologist and a cardiologist who recommended elective mitral valve repair (MVR). In preparation for the MVR, the cardiac surgical team identified 3 specific risks that are unique to the patient with HAD who would need to be heparinized in order to be placed on CPB: 1) the inability to adequately and safely heparinize for CPB, 2) postprocedural bleeding due to consumptive coagulopathy from inadequate anticoagulation with heparin, and 3) the risk for thrombotic complication relative to patient positioning while under general anesthesia. To address these risks, presurgical supplemental antithrombin was administered via a commercially available preparation of Thrombate III (antithrombin III [human]) (Grifols; Research Triangle Park, NC). Thrombate III is an FDA-approved, human

plasma–derived therapy for the treatment of HAD.19 In clinical studies with Thrombate III, the most common side effects were dizziness, chest discomfort, nausea, and dysgeusia. Because Thrombate III is made from human plasma, it may carry a risk for transmitting infectious agents, such as viruses or, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of virus or CJD transmission have ever been identified.1 The loading dose of Thrombate III for this patient was calculated based on the patient’s weight and baseline antithrombin level, using the equation presented in Figure 3.19 After invasive monitoring line placement, the patient received approximately 500 additional units of reconstituted Thrombate III over several minutes in the operating room. After the median sternotomy, the patient was administered 3 mg/kg of bovine heparin before cannulation for CPB, which facilitated a safe activated clotting time (ACT) for CPB of more than 450 seconds using the Medtronic Heparin Management System (Medtronic, Minneapolis, MN). The CPB circuit consisted of a Terumo (Terumo, Ann Arbor, MI) custom tubing pack and Capiox SX-18 oxygenator with “X-Coating,” a poly2-methoxyethyl acrylate (PMEA) surface modification. Normothermic CPB, surface-modified circuitry, and Thrombate III were all part of the CPB strategy and were intended to reduce the likelihood of activation of the coagulation cascade and minimize the patient’s risk for bleeding. The surgical repair of the patient’s mitral valve was uneventful and he was weaned from normothermic CPB, transferred to the ICU, and extubated. He did not require a subsequent dose of Thrombate III and was not transfused with allogeneic blood during his surgical course.

Discussion CPB necessitates the total suspension of the coagulation cascade and normal hemostatic mechanisms with systemic unfractionated heparin as the CPB circuit and cardiac surgery will activate the common pathway of the coagulation cascade. Antithrombin deficiency, whether hereditary or acquired, makes anticoagulation with heparin difficult.

Important Safety Information Thrombate III® (antithrombin III [human]) is indicated for the treatment of patients with hereditary antithrombin deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism. In clinical studies, the most common adverse events were dizziness, chest discomfort, nausea, and dysgeusia. The anticoagulant effect of heparin is enhanced by concurrent treatment with Thrombate III in patients with hereditary

AT-III deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with Thrombate III. Thrombate III is made from human plasma. Plasma products carry a risk of transmitting infectious agents, such as viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite steps designed to reduce this risk. No cases of transmission of viral disease or CJD have ever been identified for Thrombate III.

REPORT

Units required (IU) = [desired – baseline AT activity level] × weight (kg) 1.4 Figure 3. Dosing formula for Thrombate III (antithrombin III [human]). AT, antithrombin Based on reference 19.

It remains unclear whether or not the inability to achieve an “adequate” ACT for CPB in antithrombin-deficient patients represents a true inability to anticoagulate versus current point-of-care testing limitations. For this reason, it has been reported that anticoagulation in antithrombin-deficient patients often necessitates extreme and potentially unsafe doses of unfractionated heparin.33 This is potentially due to the inability to form heparin–ATIII complexes that are necessary to inhibit factors Xa and IIa.34 Thrombate III (antithrombin III [human]) allows for replacement of antithrombin and may avoid the potential overdosing of heparin. General anesthesia by its very nature and intent will increase the risk for thrombotic complication relative to patient positioning through stasis of blood and immobility for long periods of time. This increases the risk for thrombosis in a patient with HAD greater than that of the general population. Our concern for thromboembolism was during the post-anesthetic induction period of the operation: before anticoagulation with heparin and after reversal with protamine. The weight-based

replacement dose of Thrombate III was calculated for supplemental repletion of antithrombin and was given to reduce the risk for thrombosis. Activation of the coagulation cascade and the subsequent stimulation of labile coagulation factors will cause the consumption of those factors regardless of whether or not a fibrin clot is formed. The resultant effect is coagulopathic bleeding via depletion of coagulation factors through their consumption. This degree of coagulation factor depletion is particularly dangerous in the post-cardiac surgical setting.35

Conclusion A deficiency of antithrombin naturally occurring in the plasma whether hereditary or acquired can complicate a surgical procedure increasing risk to the patient and costs to the facility. A complete assessment of risks and development of a multimodal surgical and pharmacologic strategy for the treatment of patients with HAD can help to attenuate the increased risks associated with surgery in these patients.

References 1.

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10. Crowther MA, Kelton JG. Congenital thrombophilic states associated with venous thrombosis: a qualitative overview and proposed classification system. Ann Intern Med. 2003;138(2):128-134.

Yilmaz S, Gunaydin S. Inherited risk factors in low-risk venous thromboembolism in patients under 45 years. Interact Cardiovasc Thorac Surg. 2015;20(1):21-23.

11. Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia. 2008;14(6):1229-1239.

Maclean PS, Tait RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs. 2007;67(10):1429-1440.

Beckman MG, Hooper WC, Critchley SE, et al. Venous thromboembolism: a public health concern. Am J Prev Med. 2010;38 (4 suppl):S495-S501.

Centers for Disease Control and Prevention (CDC). Venous thromboembolism in adult hospitalizations - United States, 2007-2009. MMWR Morb Mortal Wkly Rep. 2012;61(22):401-404.

Heit JA, Silverstein MD, Mohr DN, et al. Predictors of survival after deep vein thrombosis and pulmonary embolism: a populationbased, cohort study. Arch Intern Med. 1999;159(5):445-453.

Coppola A, Tufano A, Cerbone AM, et al. Inherited thrombophilia: implications for prevention and treatment of venous thromboembolism. Semin Thromb Hemost. 2009;35(7):683-694.

Rosendaal FR. Risk factors for venous thrombotic disease. Thromb Haemost. 1999;82(2):610-619.

Franchini M, Veneri D, Salvagno GL, et al. Inherited thrombophilia. Crit Rev Clin Lab Sci. 2006;43(3):249-290.

12. Di Minno MN, Dentali F, Lupoli R, et al. Mild antithrombin deficiency and risk of recurrent venous thromboembolism: a prospective cohort study. Circulation. 2014;129(4):497-503. 13. Picard V, Nowak-Gottl U, Biron-Andreani C, et al. Molecular bases of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene. Hum Mutat. 2006;27(6):600. 14. Bucciarelli P, Rosendaal FR, Tripodi A, et al. Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance: a multicenter collaborative family study. Arterioscler Thromb Vasc Biol. 1999;19(4):1026-1033. 15. White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost. 2003;90(3):446-455. 16. Tengborn L, Bergqvist D. Surgery in patients with congenital antithrombin III deficiency. Acta Chir Scand. 1988;154(3):179-183. 17. Vossen CY, Conard J, Fontcuberta J, et al. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost. 2005;3(3):459-464.

Please see Important Safety Information on page 6 and refer to accompanying full Prescribing Information for complete prescribing details.

REPORT 18. Mannucci PM. Genetic hypercoagulability: prevention suggests testing family members. Blood. 2001;98(1):21-22. 19. Thrombate III antithrombin III (human) [package insert]. Research Triangle Park, NC: Grifols. 20. ATryn, antithrombin (recombinant) lyophilized powder for reconstitution [package insert]. Framingham, MA: rEVO Biologics, Inc.; 2013. 21. Food and Drug Administration. Circular of information for the use of human blood and blood components. April 2014. www.fda.gov/ downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM364593.pdf. Accessed February 20, 2015. 22. Scott E, Puca K, Heraly J, et al. Evaluation and comparison of coagulation factor activity in fresh-frozen plasma and 24-hour plasma at thaw and after 120 hours of 1 to 6Â°C storage. Transfusion. 2009;49(8):1584-1591. 23. Bharadwaj J, Jayaraman C, Shrivastava R. Heparin resistance. Lab Hematol. 2003;9(3):125-131. 24. Kottke-Marchant K, Duncan A. Antithrombin deficiency: issues in laboratory diagnosis. Arch Pathol Lab Med. 2002;126(11): 1326-1336. 25. Chuang YJ, Swanson R, Raja SM, et al. Heparin enhances the specificity of antithrombin for thrombin and factor Xa independent of the reactive center loop sequence. Evidence for an exosite determinant of factor Xa specificity in heparin-activated antithrombin. J Biol Chem. 2001;276(18):14961-14971. 26. Rao SV, Ohman EM. Anticoagulant therapy for percutaneous coronary intervention. Circ Cardiovasc Interv. 2010;3(1):80-88. 27. Ortmann E, Besser MW, Klein AA. Antifibrinolytic agents in current anaesthetic practice. Br J Anaesth. 2013;111(4):549-563.

28. Ni Ainle F, Preston RJ, Jenkins PV, et al. Protamine sulfate downregulates thrombin generation by inhibiting factor V activation. Blood. 2009;114(8):1658-1665. 29. Simioni P, Sanson BJ, Prandoni P, et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost. 1999;81(2):198-202. 30. Bates SM, Greer IA, Middeldorp S, et al; American College of Chest Physicians. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e691S-e736S. 31. De Stefano V, Rossi E. Testing for inherited thrombophilia and consequences for antithrombotic prophylaxis in patients with venous thromboembolism and their relatives. A review of the Guidelines from Scientific Societies and Working Groups. Thromb Haemost. 2013;110(4):697-705. 32. Baglin T, Gray E, Greaves M, et al; British Committee for Standards in Haematology. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol. 2010;149(2):209-220. 33. Finley A, Greenberg C. Review article: heparin sensitivity and resistance: management during cardiopulmonary bypass. Anesth Analg. 2013;116(6):1210-1222. 34. Li W, Johnson DJ, Esmon CT, et al. Structure of the antithrombin-thrombin-heparin ternary complex reveals the antithrombotic mechanism of heparin. Nat Struct Mol Biol. 2004;11(9):857-862. 35. Horvath KA, Acker MA, Chang H, et al. Blood transfusion and infection after cardiac surgery. Ann Thorac Surg. 2013;95(6): 2194-2201.

Editorial support for this piece was provided by McMahon Publishing. Disclosures: Mr. Cordisco reported no relevant financial conflicts of interest.

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Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Grifols, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.