May 2014

CONVENTION ISSUE:

American Society of Colon and Rectal Surgeons

GENERALSURGERYNEWS.COM

May 2014 • Volume 41 • Number 5

The Independent Monthly Newspaper for the General Surgeon

Opinion

Omaha! Omaha!

Surgeon Proposes Fellowship Requirement After Residency

B Y D AVID V. C OSSMAN , MD

see OMAHA page 30

REPORT Clinical Advancements Using the ENSEAL® G2 Articulating Tissue Sealer See insert at page 8

SAVANNAH, GA.—Speaking at the 2014 Scientific Meeting of the Southeastern Surgical Congress, Frank R. Lewis, MD, executive director of the American Board of Surgery, suggested that fellowship training should be incorporated as a requirement for all surgeons after residency.

“Long-term changes in ethical, legal and financial factors have reduced resident autonomy and left residents less prepared for practice,” Dr. Lewis said.

“These factors within residency are not changeable. Therefore, we need to focus on the potential for fellowship as an opportunity for getting greater autonomy and

B Y C HRISTINA F RANGOU SAVANNAH, GA.—The number of young people undergoing laparoscopic cholecystectomy nearly quadrupled over a 12-year period, a shift due largely to the growing prevalence of obesity, according to a study presented at the 2014 Scientific Meeting of the Southeastern Surgical Congress.

Between 1998 and 2010, laparoscopic cholecystectomy rates rose from 3.4% to 13% for individuals aged 15 to 24 years. The increase far outpaced that seen for any other age group, and was almost entirely limited to obese individuals.

“Gallstone disease in childhood was see FELLOWSHIP page 8

The Elephant in the OR B Y M ICHAEL A. G OLDFARB , MD, FACS

see LAP CHOLE page 4

REPORT Improving Precision and Accuracy in Laparoscopy Using the ENDOEYE FLEX 3D Articulating Videoscope See insert at page 12

I

had been in the operating room as a medical student at New York University School of Medicine in 1963.

I was in the “Old Bellevue.” But I never realized that there was room for an elephant in the operating room until a few months ago.

INSIDE Stitches

Surgeons’ Lounge

Opinion

12

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26

The History of Laparoscopic Colectomy: An Approach Still Awaiting Widespread Use

Lap Chole Rates Surge in Younger Patients Correlates With Rise in Obesity

B Y C HRISTINA F RANGOU “Omaha! Omaha!”

For the two weeks leading up to Super Bowl XLVIII, Peyton Manning coyly explained the meaning of his mysterious audible: “I read the defense and react. Omaha! Omaha! It means run. Or pass. I hope that clarifies.”

On the first play from scrimmage somewhere between the “a” and the “h” of the second “Omaha,” the center snapped the ball over Manning’s head into his own end zone for a safety. In 15 seconds, Omaha! Omaha! went from the symbol of guile to the sorry face of confusion and defeat.

“It’s just two points, it could have been worse,” I said to TSVBMC [the still very beautiful Mrs. Cossman].

“What are you smoking? The rout is on. It’s going to get ugly.”

Wishful thinking on my part. I had 2 large on Denver. I knew I should have talked to her before I called my bookie, but who talks to his wife before betting football, even if she can see the future?

Two interceptions, five sacks, two fumbles, and two long, special-team scores for

®

Highlights From the International Colorectal Disease Symposium

Examining the NASBP B32: What the Breast Cancer Trial Should Have Asked

Since completing my general surgery training, I have performed many operations to remove various cancers from the neck down. Like all surgeons, I hated any postoperative infectious complication. I only recently see ELEPHANT page 34

CORPORATE SPOTLIGHT Streamlined Preadmission Testing Reduces Surgery Delays and Same-day Case Cancellations

See page 7

A turning point in vessel sealing Introducing ENSEAL® G2 Articulating The first articulating tissue sealer compatible with a 5mm port • Facilitates a perpendicular approach to vessels through 110° of articulation with full 360° shaft rotation • Vessels sealed with a perpendicular approach are more than 28% stronger than vessels sealed at a 45° angle1 • Seals and cuts vessels up to 7mm consistently through high uniform compression

ENSEAL® seals like no other To experience ENSEAL® G2 Articulating Contact your Ethicon Sales Professional Call 1-877-ETHICON Connect at http://www.ethicon.com/enseal-g2-articulating 1. ENSEAL® devices tested in a benchtop study on 5-7mm porcine carotid arteries.

With NSLG2C35A devices, median burst pressures were 51% higher for vessels sealed at a 90° angle compared to vessels sealed at a 45° angle (P=0.0007).

With NSLG2S35A devices, mean burst pressures were 29% higher for vessels sealed at a 90° angle compared to vessels sealed at a 45° angle (P=0.001).

Better surgery for a better world © 2013 Ethicon Endo-Surgery, Inc. All Rights Reserved. DSL 13-0840

GSN Editorial

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

The Surgeons’ Gyre Frederick L. Greene, MD, FACS Clinical Professor of Surgery UNC School of Medicine Chapel Hill, North Carolina

T

he term blogg is a contraction of “Web log” in which one or more individuals record their thoughts, ideas or concepts in an Internet-based format and solicit interaction with others of like mind who have an interest in the ideas espoused by the “blogger.” Blogs run the gamut of subject matter: professions, religions, ideologies, politics and most any subject that has been deemed important by at least one interested chronicler.

Although I admit to only being tempted by a few medically related blogs, the advent of a blog especially for surgeons has truly caught my interest.

The blog, Surgeons’ Gyre (surgeonsgyre.com) has recently appeared, and rather than just being a repository for recent surgical research, surgical organization topics or other mundane information, it delves into the heart, spirit and emotions of all of us who have chosen surgical careers. The concepts presented emulate and resonate with the daily conflicts that we experience in and out of the hospital setting. Given the modern pressures that affect all surgeons, this blog and its subject matter allows for reflection on issues that may not even be explored in surgeons’ lounge banter.

A blog name should reflect and anticipate the overall

concept created. In this case, the Surgeons’ Gyre is well named. The term gyre in the oceanographic lexicon relates to a large system of rotating ocean currents associated with undulating and ever-changing wind patterns.

Additionally, gyree may refer to a vortex in the air or sea, even one that is man-made.

Many of you, as I, tend to eschew these outlets as further intruding on our valuable time. I assure you the Surgeons’ Gyre does not fit into this genre.

For us as surgeons, we continue to face economic, political, ethical and emotional forces that continuously change direction and are unrelenting and uncontrolled even by our collective surgical force. These “winds of change” have occurred without our individual or collective influence and create additional stresses unknown to our surgical brethren of the past who had a better opportunity for autonomy and individual decision making.

Concepts of hospital-based employment, involvement in federally mandated health initiatives, public reporting of payments and outcomes, mandatory hospital-based

electronic health charting and stultifying multilayered administrative health care institutions have caused us to seek occasional respite in nontraditional sites.

As the Surgeons’ Gyre states, “these times beg for reflection and for creative responses to the challenges of providing surgical care in changing circumstances.” This surgical interface offers “a place of restoration of self, of ideals, of professional identity.” The opportunities to find such respite and to have meaningful dialogue are few and far between. An additional goal of the Surgeons’ Gyre is “to facilitate deriving solutions that enhance the integrity of the guild and bring us into closer alignment with the core values that inspired our arduous journey to the practice of surgery.”

The advent of social media and Internet-based communication opportunities has been a double-edged sword. Many of you, as I, tend to eschew these outlets as further intruding on our valuable time. I assure you the Surgeons’ Gyre does not fit into this genre. It is a medium that you will enjoy and find stimulating and refreshing as you experience the exigencies of contemporary surgical practice. Open the Surgeons’ Gyre and be engulfed by its vortex.

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In the News

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

Type 1 Diabetes Patients Benefit From Bariatric Surgery in Small Study More Complications Seen in Type 1 Patients Than Other Bariatric Patients B Y C HRISTINA F RANGOU

O

verweight patients with poorly controlled type 1 diabetes can experience significant improvements in glycemic status and comorbid conditions after bariatric surgery, a small study suggests.

“These patients will enjoy the metabolic benefits of bariatric surgery even if we can’t put their diabetes in remission,” said lead author Stacy A. Brethauer, MD, a bariatric surgeon at the Cleveland Clinic in Ohio.

In a letter published in the journal Diabetes Care, Dr. Brethauer and colleagues describe 10 morbidly obese patients with poorly controlled type 1 diabetes who underwent laparoscopic bariatric surgery between 2005 and 2012.

Patients included one man and nine women with a mean age of 45.6 years and a mean baseline body mass index of 41.6 kg/m2. Most had been diagnosed with diabetes more than two decades earlier. They were considered higher-risk patients as each had approximately 10 obesity- or diabetes-related comorbidities.

Following surgery, nine of 10 patients achieved an excess weight loss greater than 60%, a rate similar to that expected for a general bariatric surgery population.

Patients who lost weight experienced improvements in key diabetic measures, including reductions in glycated hemoglobin (10%±1.6% vs. 89%±1.1%; P P=0.039) and daily insulin requirements (0.74±0.32 vs. 0.40±0.15 U/ kg per day; P P=0.004). They also improved in low-density lipoprotein (–23±19.3; P P=0.007) and triglycerides (–30.5±17.1 mg/dL; P P=0.007). Hypertension resolved or improved in five of seven patients and albuminuria resolved in one of the two patients with preoperative microalbuminuria.

Sivamainthan Vithiananthan, MD, associate professor

LAP CHOLE

jcontinued from page 1 once considered rare but clearly there has been a noticeable change in demographics. No longer is this a disease of women in their 40s who have had multiple childbirths,” said lead author James J. Tucker, MD, chief surgical resident at York Hospital, York, Pa. Dr. Tucker and colleagues examined International Classification of Diseases version 9 codes in the National Inpatient Sample to identify patients who underwent laparoscopic cholecystectomy or laparoscopic partial cholecystectomy between 1998 and 2010. They then classified the 4.5 million patients into age groups: 15 to 24, 25 to 34, 35 to 54, and 55 years and older.

The 15- to 24-age group experienced the largest surge in rates of laparoscopic cholecystectomy at 3.2%, compared with 2.2% for patients aged 24 to 35, 1.3% for patients aged 35 to 54, and 0.7% for the

of surgery (clinical) and chief of barriatric surgery at Brown University, said d the findings could have significant im mplications for the 15% to 20% of individu uals with type 1 diabetes who are obese.

“These patients, who are often young or adolescents, don’t have just tyype 1 diabetes when they are obese bu ut may have some degree of type 2 diab betes as well, meaning they have insulin resistance on account of their weight. It becoomes a vicious cycle.

“What bariatric surgery can do is help stop that process by addressing thee obesity and adiposity that’s driving their insulin resistance. Therefore, they can be at a much lower dosage of insulin, have better control of theiir sugar and experience better long-term outcomes.”

Dr. Vithiananthan, who was noot involved with the study, has performed bariatric surggery on people with type 1 diabetes. Generally, these patieents are referred after an event like a heart attack or failing kidneys. “Hopefully, this study will encourage people to send people for surgery earlier rather than after an even nt,” he said.

Patients with type 1 diabetes who underwent bariatric surgery do have a higher risk forr postoperative complications compared with other bariatric atric patients, a trend expected with a sicker patient population, said Dr. Brethauer. Five postoperative complications occurred including diabetic ketoacidosis, one deep vein thrombosis, an ulcer at the gastrojejunal anastomosis, esophageal dysmotility and persistent nausea.

Physicians should monitor these patients carefully after surgery to watch for ketoacidosis as they adapt to a new diet, said Dr. Brethauer.

No intraoperative complications were reported and no patient was converted to laparotomy.

Before this study, fewer than 12 cases of bariatric surgery in type 1 diabetes were reported in the literature.

oldest patients (P<0.001).

Similarly, this youngest age group also underwent the largest increase in obesity, with prevalence rising 10.8% over 12 years. Among other groups, obesity climbed between 8.9% and 10.2%.

Among young patients, factors associated with obesity included being female, being white, residing in an urban location or the southern region of the United States, undergoing treatment at a nonteaching hospital or a large hospital and having a Charlson comorbidity index score of 3 or higher.

Analysis showed that obesity was the most significant independent driver for the escalating laparoscopic cholecystectomy rates among younger patients.

Laparoscopic cholecystectomy rates rose 10.8% in obese individuals. In comparison, there was only a 2.3% increase among nonobese 15- to 24-yearold patients.

This equates to substantial costs and health care burden, said Dr. Tucker.

The reports generally showed significant weight reduction and glycemic control, although the reports were not consistent.

Dr. Brethauer said the favorable metabolic effects of bariatric surgery may facilitate medical management of type 1 diabetes in the setting of morbid obesity. But the true role of bariatric surgery in these patients requires longer follow-up studies, he said.

“The take-home point is that type 1 diabetics may be candidates for surgery. You can have good metabolic outcomes in these patients even though they may be higher risk from a medical standpoint.”

Total charges per procedure rose more than $3,000 to $22,802 for obese patients aged 15 to 24 years.

Hospital ength of stay increased from two to three days.

Total charges per procedure rose more than $3,000 to $22,802 for obese patients aged 15 to 24 years (P<0.001).

Hospital length of stay increased from two to three days (P<0.001).

“This study clarifies and quantifies the challenges that surgeons see every day as a result of the growing number of surgical patients presenting with obesity as a comorbidity,” said Michael S.

Nussbaum, MD, professor of surgery and chief of general surgery at the University of Florida College of Medicine in Jacksonville.

“Gallbladder disease is such a common problem that the changing demographics demonstrated in this study may get overlooked. However, with the increased incidence of gallstones and the need for cholecystectomy in the younger obese population, this will add further to the overall health care costs related to obesity.”

Dr. Tucker identified several other factors likely contributing to the rise in laparoscopic cholecystectomy, including an increased use of ultrasound, the lithogenic effects of estrogen and a reduced threshold for surgery.

The investigators note that the correlation between obesity and laparoscopic cholecystectomy does not address causality. They used electronic medical records, which likely resulted in significant underreporting of body mass index.

In the News

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

Board of Surgery Sets Endoscopy Requirement for Surgical Trainees B Y C HRISTINA F RANGOU

B

eginning in 2017, all general surgery residents who apply for certification by the American Board of Surgery (ABS) will need to complete a standardized national curriculum in the use of endoscopic techniques.

“The new requirement will give the public greater assurance that ABS-certified general surgeons have obtained sufficient training in the use of endoscopy to treat gastrointestinal diseases,” according to statement released by the ABS. Endoscopy is one of the top five procedures performed by ABS-certified general surgeons and in many areas general surgeons are the only available providers of endoscopic services, the ABS said in the announcement.

The new program was developed partly in response to earlier criticisms from gastroenterology societies that surgery residents fail to receive adequate training in endoscopy. In 2011, four gastroenterology societies issued a statement calling the ABS requirement of 50 colonoscopies and 35 upper endoscopies “inadequate to achieve training and/or competency, and should not be considered as part of training criteria for surgery.”

The new ABS curriculum does not specify numbers on how many procedures a resident should perform. The ABS and other surgical societies feel that case numbers fail to reflect a surgeon’s skill or proficiency, said Gerald Fried, MD, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) president and chair of the Department of Surgery at Montreal’s McGill University, in Canada.

“It may take one person 100 cases to get really good at something, it may take

someone 200 cases and it may take a third person 50 cases. It’s highly variable,” said Dr. Fried.

“Although case numbers are still an important aspect of tracking a resident’s experience, whether that is the best measure of the type of proficiency we’re trying to ensure our trainees get, I personally question,” he said.

Instead of focusing on numbers, the new curriculum requires residents to pass national tests of knowledge and endoscopic skills.

The program was developed in collaboration with SAGES, the American Society of Colon and Rectal Surgeons, the American Society for Metabolic and Bariatric Surgery and the Society for Surgery of the Alimentary Tract. It is expected to cost approximately $250 per resident to implement.

One of the final milestones in the curriculum is the Fundamentals of Endoscopic Surgery program (FES), created

by SAGES several years ago. The FES program provides an objective, validated assessment of a surgeon’s competency in flexible endoscopy and includes didactic materials, a multiple-choice examination and a hands-on skills test that must be performed on a virtual reality simulator at a certified testing site. Preparation for the skills test can be achieved using resources already available at all residency programs and do not require purchase of a simulator.

FES is modeled on SAGES’ Fundamentals of Laparoscopic Surgery (FLS) program, which the ABS made a requirement for board certification five years ago.

Multiple studies have confirmed FLS is a reliable and valid tool for teaching and evaluating laparoscopic surgery.

O. Joe Hines, MD, chief of general surgery and program director for general

Instead of focusing on numbers, the new curriculum requires residents to pass national tests of knowledge and endoscopic skills.

surgery at UCLA’s David Geffen School of Medicine, Los Angeles, said he expects the new endoscopic curriculum will raise the level of endoscopic training for surgery residents across the country.

Today, residents at various institutions receive vastly different exposure to endoscopy, he said. At UCLA, for instance, gastroenterologists perform most endoscopy procedures. “So it’s been a challenge for our residents to get a quality experience and learn how to do endoscopy,” said Dr. Hines.

“For us, this new curriculum is going to be a very good thing because it provides a framework for education and refocuses our efforts for residents in this area.”

He added that the new program sends a strong message to the public that new surgeons have achieved uniform standards for competency in endoscopy.

“They’ll know that surgeons who go into the community across the country can do endoscopy.”

A decade-long debate has gone on among surgeons, gastroenterologists and family medicine physicians regarding who should perform endoscopic procedures and how these practitioners should be trained.

Dr. Fried said flexible endoscopy now represents a “very big part” of a general surgeon’s practice and he expects it will grow further as endoscopy becomes more interventional.

“We’re now treating diseases endoscopically that were traditionally treated by surgeons with traditional surgical techniques. Just as we’ve evolved from open techniques to laparoscopy for surgical care, we’re evolving to use endoscopy as another important tool for surgical treatments.”

Transfusions Linked to Increased Infection Risk B Y P AUL B UFANO About one in every 20 hospitalized patients develops an infection as a result of their care, but limiting blood transfusions to patients with low hemoglobin levels may decrease their risk for acquiring one, researchers have found.

Although donated blood is carefully screened for infectious agents and the likelihood of developing an infection from a transfusion is slim, some patients may react poorly to substances found in stored blood, increasing their risk for infection from other sources.

In the new study, Mary Rogers, PhD, from the Department of Internal Medicine at the University of Michigan, in Ann Arbor, and her colleagues conducted a systematic review and meta-analysis of 18 randomized clinical

trials that included more than 7,500 patients. The experiments compared liberal transfusion strategies to restrictive approaches—generally when patients’ hemoglobin levels dropped below 7 g/dL or they had symptoms of anemia—and the associated risks for infections, such as pneumonia, mediastinitis and sepsis.

The researchers found that the chance for serious hospital-related infections was about 17% for patients in whom liberal transfusion strategies were used but only 12% for those treated with more restrictive triggers.

They calculated that for every 1,000 patients in whom a transfusion is potentially warranted, 26 could potentially be spared an infection if transfusions were reserved for emergency situations.

The clinical setting had a substantial effect on the risk for infection. In patients who underwent hip or knee surgery, for example, or who already had sepsis, a restrictive

strategy reduced the risk for infection by at least 30%.

However, transfusion strategy did not appear to affect infection risk in patients with cardiac diseases, who were critically ill, had acute upper gastrointestinal bleeding and for infants with low birth weight.

“There’s been a huge shift in what we now know compared to what the prevailing medical knowledge has been,” said Dr. Rogers. “Many physicians don’t yet know about this problem and not too long ago many of them were giving two red blood cell units at a time thinking that it couldn’t hurt. But with some simple steps we now have the potential to limit serious infections, so I really hope that more doctors will adapt these restrictive strategies.”

The researchers published their findings in the Journal of the American Medical Association (2014;311:1317-1326).

The study was funded by the National Heart, Lung, and Blood Institute.

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NO ONE LIKES TO BE KEPT WAITING When a surgical procedure gets held up, it can affect your schedule and the efficiency of your entire surgical practice. That's why more and more surgeons and hospitals are relying on Sheridan for their anesthesiology program management. Reliable anesthesiologists. More efficient ORs. Satisfied surgeons.

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Streamlined Preadmission Testing

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Corporate Spotlight

Reduces Surgery Delays and Same-day Case Cancellations Sheridan’s ClearPATh protocol is designed to ensure surgical readiness of patients

S

ame-day case cancellations cost hospitals millions each year. These cancellations have a ripple effect down to all constituents in the hospital: surgeons’ schedules must be adjusted, anesthesiologists are left idle, and patients are inconvenienced and left waiting after a night of fasting. Surgeries delayed by even a few minutes can have a negative effect in nearly the same way.

Sheridan Healthcare, Inc. understood that coordinated preadmission testing procedures were key to reducing surgery delays and same-day cancellations, so a team of Sheridan anesthesiology leaders collaborated in a year-long process to develop ClearPATh as a solution to this pervasive problem.

Vetted by the Perioperative Directors at Brigham & Women’s Hospital, a teaching affiliate of Harvard Medical School, ClearPATh is a proprietary preadmission testing program that streamlines the preadmission testing process. It is based on American Society of Anesthesiologists guidelines as well as extensive research and evidence-based medicine.

“When the ClearPATh system is implemented within a hospital’s perioperative process, surgeon satisfaction significantly improves,” explained Dr. Adam Blomberg, vice chief of anesthesiology for Memorial Regional Hospital in Hollywood, Fla. “More of a surgeon’s procedures actually take place when they are scheduled and they start on time, all due to careful planning and preparation before the patient even enters the operating room.”

order specific tests for each patient, instead of the same battery of tests for every patient receiving a particular surgery. This patient-centric approach to testing significantly decreases false positives that could delay or cancel surgery.

ClearPATh also stresses the need for preadmission testing well before the day of the procedure. This allows the surgeon and anesthesiologist to review and coordinate care prior to the procedure so that resources can be allocated properly. These open lines of communication not only improve OR efficiency and ensure that the OR is booked accordingly but also provide patients with care better tailored to their situation.

Surgeries can account for 60 percent of a hosIn the past, surgeons would order as pital’s revenue, and these case cancellations and many tests as possible prior to surgery: delays significantly eat into the bottom line as Dr. Adam Blomberg, Vice full blood work panels, EKGs and x-rays, unused operating rooms cost hospitals upwards Chief of Anesthesiology at with the idea that if the anesthesiologist of $80 per minute. ClearPATh has already Memorial Regional Hospital, had all that information, the case would decreased same-day cancellations, increased National Director for the not be cancelled. What evidence shows, on-time starts and maximized operating room Anesthesiology Division at however, is that unnecessary testing efficiency for many hospitals since its rollout in Sheridan increases costs, particularly for insurance late 2013. In particular, one hospital has already companies, and increases patient dissatisdecreased cancellation rates from 8.7 percent to faction. Patients not only have to travel to 3.3 percent since ClearPATh’s introduction. several locations for tests but can be denied surgery due to false positives, which happen in otherwise healthy patients. In this In each of these cases, ClearPATh turns a fragmented sysmanner, ClearPATh helps to verify surgical readiness, sched- tem into a coordinated system to save money and provide ule only necessary preoperative visits, communicate proper better care. patient instructions for same-day surgery and ensure that all proper, relevant tests are completed.

The methodology is being rolled out nationally to each of Sheridan’s anesthesiology programs.

The patient-centric approach takes each patient’s medical history into account to eliminate these unnecessary tests.

ClearPATh includes guidelines and algorithms for high-, medium- and low-risk procedures cross-referenced with high-, medium- and low-risk patients based on the patient’s own medical history. This guidance enables the surgeon to

Sheridan Robert Bauman, Vice President of Business Development 855-252-2970

8

In the News FELLOWSHIP

jcontinued from page 1 independence.”

He stressed that his comments reflect his personal views and not those of the American Board of Surgery (ABS).

It is a time of ongoing debate in the surgical community about the current five-year system of training: Does it provide sufficient time to train a skilled general surgeon?

A number of recent studies indicate that it does not (J ( Am Coll Surg 2014 Feb 6. [Epub ahead of print]). One year ago this spring, at the American Surgical Association meeting, surgeons presented results from a survey of fellowship program directors who said residents were inadequately prepared for fellowship and independent practice. One-fifth of the respondents said new fellows arrived unready for the operating room and 38% demonstrated a lack of patient ownership. The respondents said that 30% of the new fellows could not independently perform a laparoscopic cholecystectomy and 66% were deemed unable to operate unsupervised for 30 minutes during a major procedure ((Ann Surg 2013;258:440-449).

Fellowship program directors felt new fellows lacked adequate laparoscopic skills, with 30% unable to atraumatically manipulate tissue, 26% unable to recognize anatomical planes and 56% unable to suture.

Other studies demonstrated that residents, too, feel unprepared for independent practice after residency. In a 2011 report, only 72% of residents said they believed their operative ability was “level appropriate,” whereas 26% reported concerns that they would not feel confident enough to perform procedures independently before completing their residency ((Arch Surg 2011;146:907-914).

In his presentation, Dr. Lewis identified five principal causes contributing to the current problems in residency: Reduced surgical exposure and experience in medical school The highly variable teaching effectiveness at different institutions.

A reduced breadth and complexity of surgical resident experience.

The 80-hour workweek.

Reduced opportunity for autonomy and independent decision making in the senior years of residency.

“Nostalgia is not going to solve these problems. We’re not going to go back to what we had 20 years ago.”

Dr. Lewis proposed several changes that would boost medical student and resident exposure to surgery. These changes would make residency training more efficient and lead to greater autonomy and more independent clinical decision making by senior residents and fellows.

The redesign of surgical education needs to begin in medical school, he said. The American College of Surgeons and some medical schools have created surgical boot camps held during the final weeks of medical school. These camps are targeted to medical students who have matched to a surgical program. Students spend anywhere from four to 12 weeks learning surgery-specific skills to bring their procedural training to a minimal level.

Dr. Lewis called for a fundamental paradigm change in resident training. A new system should be founded on uniform and clearly defined expectations for residents for each year of training, he said. Part of such a change would include greater use of online training and assessment tools, such as the American Board of Surgery’s SCORE® Curriculum Outline for General Surgery

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

Residency. Dr. Lewis said ‘Nostalgia is not going to solve have more independence and autonomy, that residents would be able and performed more urgent and emerthese problems. We’re not gent cases, he said. to take more responsibility for their own education going to go back to what we Resident independence has been furif expectations were better ther curtailed by legal constraints over had 20 years ago.’ defined. the past several decades; by increased He stressed the need for financial pressure on attendings to gen—Frank R. Lewis, MD more uniformity among erate relative value units for departmenresidency programs. Results tal income; and by ethical and regulatory of board exams demonstrate the broad variability of changes, he said. teaching among institutions. Of 250 surgical residency “What we conclude from all this is that increased programs in the United States, residents of only nine autonomy and independence for residents today is probachieved perfect scores on their oral and board exams. ably not possible during residency. It’s really only going About 17% of programs fall below the threshold set by to be possible during post-residency fellowships when the Residency Review Committee. they are board eligible.”

The effects of duty-hour restrictions cannot be overDr. Lewis proposed the only way to compensate for looked, he said. Reductions in resident work hours mean the lost hours of residency training is to somehow lengthtrainees spend less time in the hospital gaining exposure en the training period. Fellowship provides that opportuto urgent and emergent operative cases, he said. Pro- nity, he said, but standards and quality of fellowship are grams need to ensure that more resident time is spent in variable under the current system. the operating room, he said.

“Post-residency fellowships all need to be brought

Five Potential Reasons for Inadequate Level of Training In Surgical Residency •

Reduced surgical exposure and experience in medical school

•

Highly variable teaching effectiveness at different institutions

•

Reduced breadth and complexity of surgical resident experience

•

The 80-hour workweek

•

Reduced opportunity for autonomy and independent decision making in the senior years of residency

Residents, particularly at the junior level, lack sufficient time in the operating room, he said. Interns, on average, do less than 100 cases in their first year, a rate of about two per week. Second-year residents do about 125 cases, or two to three per week, he estimated. “That’s a relatively poor payoff for the amount of time they put in at the hospital.”

And at the upper level, senior residents are losing cases to fellows, resulting in an insufficient amount of advanced laparoscopic cases for senior residents at many programs.

The 80-hour workweek equates to a loss of somewhere between 2,400 and 4,800 hours of in-hospital experience for residents, or between six and 12 months of residency, Dr. Lewis said. Most of those lost hours are during evenings and weekends, times when residents tended to

under a single accreditation umbrella, in my opinion,” Dr. Lewis said.

Mandatory fellowship training would be possible without additional graduate medical education funding.

Fellows can bill for procedures and generate adequate income to cover their salaries, he said.

The Royal Colleges of Surgeons in Glasgow, Edinburgh, England, Australia and New Zealand mandate specialty fellowship training as an integral part of surgery training.

Not everyone agrees that fellowship training is the answer. William G. Cheadle, MD, professor and program director of surgery at the University of Louisville, in Kentucky, argued that residents could be trained effectively under the current five-year program if they were to have adequate exposure to operative cases. But to do so

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POISE-2 Data Disappoint on Prevention of Post-Op Heart Attacks B Y A DAM M ARCUS

T

he perioperative administration of either aspirin or clonidine does not reduce the risk for heart attacks in patients undergoing noncardiac surgery, researchers have found.

The twin findings, part of a single trial reported recently in The New England Journal of Medicine (2014;370:14941513), mean clinicians still do not have a safe and effective medication with which to prevent myocardial infarction (MI) in surgery patients.

Daniel I. Sessler, MD, Michael Cudahy Professor and chair of the Department of Outcomes Research at Cleveland Clinic, in Ohio, who helped conduct the trial, said clinician should pay attention to the POISE (PeriOperative ISchemic Evaluation) findings because 8% of adults over the age of 45 years who undergo noncardiac surgery experience a postoperative MI. What’s more, 80% of postoperative MIs are clinically “silent,” causing no increase in troponin, no chest pain, shortness of breath or other telltale indicators of a heart attack.

“You might think the subclinical ones are less important, that they’re just a biomarker. But the mortality is exactly the same” as with a symptom-causing MI. “One in 10 patients who has [a postoperative MI] is dead within 30 days, whether clinically evident or not.”

Some experts feared the data on aspirin might prompt some clinicians to advise their patients taking the drug prophylactically to stop doing so before elective surgery. C. David Mazer, MD, an anesthesiologist at the University of Toronto, in Ontario, Canada, said that would be a mistake.

“Clinicians should examine this and other data carefully when considering the risks of withdrawing aspirin against

the risks for perioperative bleeding, especially in patients at risk for perioperative thrombotic events,” Dr. Mazer said.

Three Strikes …

In the POISE-1 trial, researchers found that perioperative administration of β-blockers did prevent heart attacks but caused more strokes, leading to an increase in total mortality among surgery patients who received the medication.

The POISE-2 trial looked at a followup question: Would the administration of low-dose clonidine or aspirin do what β-blockers could not?

The aspirin arm of POISE-2 included 10,010 patients with, or at risk for, atherosclerosis, who were undergoing noncardiac surgery at hospitals in the United States and Canada. Patients were randomly assigned to receive 200 mg of aspirin or a placebo immediately before their procedures. Those who were taking aspirin preoperatively (n=4,382) took 100 mg of the drug or a placebo for seven days after surgery. Those who were not taking aspirin preoperatively (n=5,628) took 100 mg aspirin or a placebo for 30 days thereafter.

The clonidine arm included the same 10,010 patients, randomized to receive 0.2 mg per day of clonidine or placebo immediately before surgery and by patch for 72 hours after the procedure. The primary outcome was a composite measure of death or heart attack within 30 days of surgery.

Of the patients given clonidine, 367 met the primary outcome compared with 339 in the placebo group, a statistically insignificant difference, according to the researchers. The results were similar for a secondary outcome of stroke, death or heart attack, the researchers found.

Patients on clonidine were more likely to experience “clinically important” bradycardia and hypotension, the latter of

may require cutting back on fellowships at institutions where residents don’t get enough time in the operating room, he suggested.

“If you can prove that your general surgery program is capable of training general surgeons, then it’s fine to have fellowships. But you should not have them if it’s taking away from the quality of your residency program,” said Dr. Cheadle.

He said that five of the seven chief residents at the University of Louisville this year are going directly into surgical practice without a fellowship. “That’s proof that you can train great broad-based general surgeons, which are just what the public needs, in a five-year residency.

But you must find ways to ensure they have exposure to cases. To do that, we credential them at the chief level so they develop some autonomy.”

The challenge for surgical residency programs is to

which was an independent predictor of MI. The findings from the aspirin arm of POISE-2 mirrored the results with clonidine. Of the patients who received aspirin, 351 (7%) experienced an MI after surgery compared with 355 (7.1%) in the placebo group. However, aspirin patients were somewhat more likely to experience major postsurgical bleeding than those who received placebo (hazard ratio, 1.23; P=0.04), P 0.04), the researchers reported.

intervention”—a group largely absent from the trial population.

“Further progress in perioperative medicine may depend on the implementation of strategies that successfully address one pathophysiological mechanism of perioperative myocardial infarction without being limited by another.”

Is prevention of postoperative MIs an unrealistic goal for clinicians? Dr. Sessler said no. “It’s possible that these heart attacks are related to surgical responses resp that are unmodifiable, but thaat’s not

Data Support ‘Calculated Strategy’

my guess,” Dr. Sessler told General Surgery News. “There are things that anesthesiologists can do to moderate those responses. We just don’t know how yet.

We’re working on it and eventually I think we’ll find some drug or treatment or anesthetic method that does reduce postoperative MI, but aspirin and clonidine are not the answer.”

Researchers will take another crack at the question with the POISE-3 trial, Dr. Sessler said. That study is still being designed.

In an editorial accompanying the journal articles, Prashant Vaishnava, MD, and Kim Eagle, MD, of the University of Michigan, in Ann Arbor, wrote that the results of the POISE studies “taken together offer credibility to a calculated strategy of decreasing heart rate while avoiding perioperative hypotension.”

However, they wrote, the studies do leave substantial uncertainty, “including best practice in those who have undergone any percutaneous coronary

‘If you can prove that your general surgery program is capable of training general surgeons, then it’s fine to have fellowships. But you should not have them if it’s taking away from the quality of your residency program.’

—William Cheadle, MD teach residents more in a shorter time period than ever, said David J. Cole, MD, chair of surgery at the Medical University of South Carolina, Charleston.

“The training paradigm, the Halstedian model that we still have some significant version of today, is largely a

time-based model. Do your time, we hope you’re good.

That’s how it’s been. The challenge now is to switch to a competency-based model.”

A competency-based model requires flexibility but flexibility does not exist under the current system, he said. One option may be to develop a program in which residents spend the first three years learning core surgical principles, after which they move to a more specialized track.

“No matter what model we use, my hope is that the continual drumbeat of work-hour restriction doesn’t continue. There have been very positive benefits of the 80-hour workweek [but] the most recent changes are now hurting the people that were trying to help, which are the junior residents,” Dr. Cole said.

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GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

Will Hospitals Be Ready To Get Smart?

B Y K EELY S AVOIE

P

hysicians routinely scrutinize their patients’ medical information to make clinical determinations, but the process is labor-intensive, replete with redundancies and prone to human error.

New research, in combination with mobile medical monitoring techniques, now points to the possibility of a smart alert technology that could revolutionize

patient management—if hospitals can adapt to it.

California researchers have found that a single metric in patients undergoing total knee arthroplasty (TKA)—use of opioid analgesia before admission—strongly predicts the need for additional postoperative pain management and extended stays in the hospital. That’s proof, they said, that selected data points have the power to flag patients who may require additional interventions.

“This is not novel. We have a lot of data to show that patients who require pain medication are going to be more challenging to manage postoperatively,” said Bassam Kadry, MD, clinical assistant professor of anesthesiology, perioperative and pain medicine at Stanford University School of Medicine, in Stanford, Calif., who presented the findings at the 2013 annual meeting of the American Society of Anesthesiologists (abstract 2261). “We know that the best intervention to control

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pain is early intervention; but in the hospital environment, coordination of early intervention is itself a challenge.

For these TKA patients, the management of their pain is administered after the fact, even though we have a good idea of who will require additional support even before surgery.”

In the latest study, Dr. Kadry and his colleagues examined the records of 1,611 TKA patients, 1,122 patients undergoing total hip arthroplasty (THA) and 169 patients undergoing total shoulder arthroplasty (TSA). They found that patients who had used opioids before surgery (including methadone, fentanyl, oxycodone [≥40 mg] and morphine [≥60 mg] stayed in the hospital significantly longer than those who had not taken the painkillers. The median length of stay was 0.55 days longer for TKA patients using opioids (P<0.0001), 0.57 days longer for THA patients (P=0.013) P and 0.9 days longer for TSA patients (P<0.0001).

After analyzing the method of anesthesia, the researchers found that TKA patients with preadmission use of opioids who received combined general and regional anesthesia had a 0.8 day longer stay in the hospital (P<0.0001) than opioid-naive patients.

Using diagnostic codes, the Stanford researchers determined that most of the patients taking opioids before surgery were doing so to treat chronic pain.

Dr. Kadry said he envisioned using these selected data points, such as preadmission opioid use by TKA patients, to develop algorithms similar to those used in the financial sector to detect credit card fraud and arbitrage. The algorithms could send smart alerts to physicians warning them of potential problems even before they become clinically evident.

“The idea is that we are trying to emulate how [a] physician analyzes information for a particular diagnosis,” Dr. Kadry said. “How do you optimize filters and alerts to give you accurate signals and limit both false-positives and false-negatives?

We want to develop technology that could look [and] analyze data for ‘fingerprints’ of patients that fulfill the same set of criteria that we would use to make diagnoses as physicians.”

One of the first steps to establishing such a system is to define the clinically relevant data points that can flag patients who are likely to require interventions.

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“The data we use must be ‘vital’—valid, important, timely, actionable and low-cost,” Dr. Kadry explained.

But before such systems can be put in place, another major hurdle must be cleared: the collection and integration of those data.

Outdated monitoring systems remain one of the biggest obstacles to implementation of integrated data systems and smart alert technology in health care settings.

Most monitors used in hospitals do not store, integrate or share the data they generate. If medical monitoring devices store data at all, it is on their manufacturers’ own private networks.

Collecting the data and connecting and integrating those networks is prohibitively expensive and complicated.

“Medical devices today—most of them—live in the world of kingdoms.

Each company has its own kingdom,” said Leo Montejo, MD, founder and CEO of WiCis, a company that manufactures wearable mobile health, or “m-health,” devices. “These systems haven’t changed in 20 years.”

M-health devices, in contrast to the monitors used in most health care settings today, are expressly designed to store and share data seamlessly across many different platforms. With m-health devices, multiple medical parameters such as blood glucose, temperature and electrocardiography—and medical information such as prescriptions and medical history—can be shared across multiple platforms, just like fitness information can be shared through social media with devices like Fitbit or Nike+.

Dr. Montejo said he expected consumers to usher in an m-health revolution in the next several years that will force recalcitrant health care providers to adopt m-health devices. “It’s not going to be driven by the hospitals,” he said. “They are way behind the curve on this.” But changes in health care delivery ultimately may force institutions to make the leap.

“The reality is that a lot of the processes in health care have a lot of complexity, and variability will never go away,” Dr. Kadry said. “Developing a system that can balance standardizing processes, minimize variability, recognize opportunity and leverage smart alerts to drive change is key.”

Changes in health care payment structure will put additional pressure on hospitals to streamline services and minimize complications, because pay will be based on quality of care, not quantity, he added.

“I think the tipping point is going to come when clinical outcomes determine a bigger chunk of our incomes,” Dr. Kadry said.

“Eventually, this is going to happen. It’s just a matter of when is going to be the right time.”

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History of Lap Colectomy: An Approach Still Awaiting Widespread Use B Y V ICTORIA S TERN

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n October 1990, an elderly woman came to see Dennis Fowler, MD. She had several critical issues, including severe lung disease and a tumor resting in the middle of her sigmoid colon.

Dr. Fowler, an assistant clinical professor of surgery at the University of Missouri, Kansas City School of Medicine at the time, sat with his patient and her son, discussing treatment options. Dr. Fowler was reluctant to perform surgery because of the woman’s obstructive lung disease.

The patient, however, kept insisting that she would rather die from an operation than leave the cancer inside her.

Dr. Fowler told her about a new technique that he and several colleagues had been investigating over the summer. It involved taking out a section of the colon laparoscopically. He had trialed the technique in the pig lab, but the procedure had never, to his knowledge, been attempted in a human patient.

“After numerous discussions, the patient said she wanted this new procedure,” Dr. Fowler said.

On Oct. 19, after receiving three prototypes of a laparoscopic intestinal stapler from US Surgical, Dr. Fowler performed the first laparoscopic sigmoid colectomy. He used one stapler to ligate the mesentery and two to transect the colon intraperitoneally. He then created a small muscle-splitting incision in the left lower quadrant of the abdomen to remove the specimen and completed the anastomosis intracorporeally with a circular stapler.

Dr. Fowler was astonished by the patient’s progress. “Her recovery was amazing considering that she had such serious obstructive lung disease,” Dr. Fowler recalled. “I realized there might be a real benefit to having colon surgery performed laparoscopically.”

Laparoscopic Colectomy Beginnings As laparoscopic cholecystectomy gained popularity in the late 1980s, physicians started looking for the next homerun for minimally invasive surgery (MIS).

“The way we started was very innocent,” said Miami-based general surgeon Moises Jacobs, MD, recollecting his first laparoscopic colectomy case in June 1990.

The patient had a particularly “floppy colon,” Dr. Jacobs recalled, and consequently he could mobilize everything using one small incision. Dr. Jacobs and colleagues Harold Goldstein, MD, and Juan Carlos Verdeja, MD, placed four trocars in the abdominal cavity and,

‘I didn’t just jump off a cliff without a parachute.

I took the idea to the lab, worked out issues, bounced ideas off colleagues, and consequently have had minimal problems.’

—Morris Franklin, MD

using cautery, mobilized the white line of Toldt and the hepatic flexure. Through a small incision in the right lower quadrant, they exteriorized the colon, completing the first laparoscopic-assisted right hemicolectomy. The woman went home four days after surgery.

“We knew there must be something to this new technique,” Dr. Jacobs said.

Dr. Jacobs’ foray into laparoscopy began with cholecystectomy. In December 1989, he and his colleagues began performing laparoscopic cholecystectomies using a two-handed approach.

“We were doing two-handed surgery from the very beginning, and as a result, it was easier for us to transition into more complex surgeries,” Dr. Jacobs said.

When Dr. Jacobs became interested in applying laparoscopic techniques to colon surgery, he worked intensively in the pig lab to hone his skills until completing his first laparoscopic colectomy in June 1990.

After this success, Dr. Jacobs began investigating a variety of techniques for laparoscopic colon surgery with colleagues, including Dr. Verdeja and colorectal surgeon, Gustavo Plasencia, MD (Arch ( Surg 1994;129:206-212; Dis Colon Rectum 1994;37:829-833).

“These surgeons knew this was going to be the next big deal,” said Morris Franklin, MD, director of the Texas Endosurgery Institute. “They made significant contributions early on when it really counted.”

Halfway across the country in San Antonio, Dr. Franklin was also exploring laparoscopic surgery. In 1988, Dr.

Franklin, alongside urologist William Schuessler, MD, and gynecologist Thierry Vancaillie, MD, started investigating laparoscopic pelvic lymph node dissection for prostate cancer, a demanding procedure they eventually mastered and began teaching to urologists worldwide.

Dr. Franklin saw laparoscopic cholecystectomy as a better teaching tool for laparoscopy. He and Dr. Schuessler began performing up to 15 cholecystectomies a day. They also received institutional review board approval from their hospital to explore new more advanced laparoscopic techniques, and completed the first distal prostatectomy, splenectomy and one of the first hiatal hernia repairs.

Dr. Franklin soon developed an interest in colon surgery. He and his colleagues spent every weekend for 18 months in the pig lab and any additional free moments developing their skills.

In August 1990, Dr. Franklin performed his first laparoscopic colectomy. Several months later, in April 1991, he did the first completely laparoscopic right hemicolectomy.

“I tried to do it right,” Dr. Franklin said. “I didn’t just jump off a cliff without a parachute. I took the idea to the lab, worked out issues, bounced ideas off colleagues, and consequently have had minimal problems.”

Richard Whelan, MD, recalls Dr. Franklin’s unique abilities. “Dr. Franklin set the bar in the early days and he still does today,” said Dr. Whelan, professor of surgery and chief of surgical oncology at St. Luke’s-Roosevelt Hospital in New York City. “His skill set is

hard to match.”

Perhaps the first person to perform a laparoscopic colectomy was a gynecologist named David Redwine, MD, in the late 1980s, Dr. Franklin noted.

Several other general surgeons ventured into laparoscopic colon surgery early as well. In 1990, Garth Ballantyne, MD started visiting US Surgical on Tuesday afternoons to practice laparoscopic colectomies on pigs with fellow surgeon Patrick Leahy, MD. In late 1990, Dr. Leahy resected a proximal rectal cancer laparoscopically with the EndoGIA® (US Surgical) and in February 1991, Dr. Ballantyne did his first laparoscopic colectomy at Yale University. Another general surgeon, Joseph Uddo, MD, performed an entirely laparoscopic right hemicolectomy in July 1991.

The Technique Spreads Dr. Fowler presented on his first laparoscopic sigmoid resection at the Society of American Gastrointestinal and Endoscopic Surgeons meeting in April 1991 (Surg Laparosc Endosc 1991;1:183-188).

“I had an overwhelming response from people all over the world,” Dr. Fowler said. “Not many surgeons knew what had been done, and were eager to engage in training programs to learn the procedure.”

As with laparoscopic cholecystectomy, interest in laparoscopic colectomy prompted surgeons to initiate weekend training courses. By November 1991, Dr. Ballantyne had organized courses for US Surgical. Around that time, Ethicon

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had arranged laparoscopic colectomy workshops, run by Steven Wexner, MD, of Cleveland Clinic, Weston, Fla. The industry competitors invited many of the same faculty to their courses, and this core group of surgeons soon branched off into US Surgical and Ethicon camps.

Several industry leaders, namely Lee Cohen, head of laparoscopic marketing and technology at US Surgical in Norwalk, Conn., and Nicholas Valeriani, president of Ethicon Endo-Surgery for many years, supported and pushed the advancement of laparoscopic technology and education. “I often referred to Ms. Cohen as the queen of laparoscopy,” Dr. Ballantyne recalled.

On the global front, Dr. Franklin traveled to Australia, New Zealand and South America in the early 1990s to introduce laparoscopic colectomy to surgeons. Drs. Jacobs and Plasencia also taught some of the first international courses in laparoscopic colectomy.

“International surgeons, such as [Australians] Russell Stitz, MD, and Leslie Nathanson, MD, who went back home after these courses are now leaders in laparoscopic colorectal surgery,” said Dr. Franklin.

Even with training, however, many surgeons struggled to learn the new techniques. Dr. Ballantyne recalled surgeons’ ambivalence to laparoscopic colectomy. “When we surveyed the attendees [of the US Surgical course], many said, ‘Thanks for a great course, Garth, but you’ve convinced me that laparoscopic colectomy is too hard to do and I’ll never do one.’”

Laparoscopic colectomy is not as easy as laparoscopic cholecystectomy largely because it involves navigating at least two, and often all four, quadrants of the abdomen.

“The majority of surgeons didn’t want to learn laparoscopic colectomy because it was much harder than open surgery,” Dr. Whelan said.

Laparoscopic colectomy was also different from laparoscopic cholecystectomy because patients didn’t demand that their colectomy be completed laparoscopically. “Surgeons, even now, don’t as often feel pressure from patients to do their colectomy laparoscopically,” Dr. Fowler said.

Dr. Jacobs noted that the low volume of laparoscopic colectomy cases by general surgeons in the United States made it harder for surgeons to gain experience.

“I think the low volume of cases slowed down the adoption of laparoscopic colectomy,” he said. “But what almost halted its evolution was the concern over tumor recurrence.

Safety Concerns Halt Spread In 1994, worries about the safety of the

procedure emerged. A study by Berends et al in The Lancett reported that three of 14 patients (21%) undergoing laparoscopic colectomy had tumor recurrence at the trocar wound sites (1994;344:58).

Subsequent data have shown unambiguously that when the procedure is performed correctly, there is no increase in tumors recurrence at the incision.

“A surgeon can prevent a portsite recurrence simply by doing good, clean surgery,” said Dr. Franklin who found that the quality of surgical technique directly influenced the incidence of port-site recurrences (Surg Endosc 2001;15:121-125). “After 3,500 cases, I haven’t had a single tumor implant at the trocar site.”

Before the study was ultimately published in 2004, a group of laparoscopic surgeons worked diligently to verify the safety of laparoscopic colectomy.

“Despite the resistance, we persisted,” Dr. Jacobs said. “My colleagues and I had been doing laparoscopic colectomy for four years already and didn’t have any bad results.”

In 1991, Dr. Jacobs and colleagues completed a series of 20 laparoscopicassisted colon resections (Surg Laparosc Endoscc 1991;1:144-150), and independently, Dr. Franklin and colleagues performed 51 laparoscopic colectomies ((Ann Surgg 1992;216:703-707). Both studies showed the technique was safe.

Several years later, Dr. Franklin pub-

‘I had an overwhelming response from people all over the world. Not many surgeons knew what had been done, and were eager to engage in training programs to learn the procedure.’

—Dennis Fowler, MD But even the suggestion that tumors implanted in laparoscopic incisions more often than in open incisions led some major academic institutions and colorectal societies to limit or even ban laparoscopic colectomies.

“At Columbia University, senior surgeons stopped us from doing laparoscopic surgery and colorectal societies were against laparoscopy because of the lack of data,” said Dr. Whelan. “In addition, many older surgeons felt threatened and didn’t want to see any laparoscopic surgery.”

Surgeons who continued to perform laparoscopic colectomies experienced considerable backlash from the surgical community.

“Several of us were threatened by colleagues,” Dr. Fowler said. “Sometimes action was taken against us to reduce our privileges or turn patients against us.”

The resistance to laparoscopic colectomy reveals a lot about human nature, Dr. Jacobs said. “Some surgeons [who performed open surgery] didn’t want to lose patients and money to this new technique.”

It took 10 years before a definitive randomized controlled trial (RCT) created a large-scale shift in people’s thinking about laparoscopic colectomy (N Engl J Medd 2004;350:2050-2059). The COST [Clinical Outcomes of Surgical Therapy] trial, which began in 1994, involved 48 institutions and 872 patients with colon cancer randomly assigned to open or laparoscopic-assisted colectomy. Recurrence rates in surgical wounds were less than 1% in both groups, and the overall survival rate at three years was almost identical.

lished a five-year prospective randomized trial comparing open and laparoscopic approaches to colon cancer and found the laparoscopic procedure offered similar oncologic resections and better recovery than open surgery (Dis Colon Rectum 1996;39:S35-46).

In 1996, James Fleshman, MD, Anthony Senagore, MD, and Heidi Nelson, MD, reported retrospective data from the COST study, showing the same 1% rate of tumor recurrence at the wound sites in laparoscopic and open colectomy (Dis Colon Rectum 1996;39:S53-S58).

In 1998, Jeffrey Milsom, MD, from Cornell University, performed a prospective RCT comparing laparoscopic and open techniques in 109 patients undergoing bowel resection for colorectal cancers or polyps. Dr. Milsom showed an advantage in the laparoscopic group in terms of recovery time and return to bowel function, and found no port-site cancer recurrences in the laparoscopic group ((J Am Coll Surgg 1998;187:46-54).

That same year, Antonio M de Lacy, MD, from Barcelona, also published a prospective randomized trial comparing laparoscopic-assisted and open colectomy for colon cancer, revealing similar results, and in 2002, published a follow-up showing a slight survival benefit in the laparoscopic group (Surg Endoscc 1998;12:1039-1042; Lancet 2002;359:2224-2229).

These studies not only confirmed that laparoscopic colectomy was as effective as open for curing cancer, but that laparoscopic colectomy conferred greater benefits to patients, including better cosmesis, fewer wound infections, less inflammatory response, decreased postoperative pain

and quicker return to normal activities.

“The only reason laparoscopic colectomy was eventually accepted was because of these trials,” said Dr. Whelan.

Current Landscape Despite compelling evidence of a benefit, many surgeons still do not offer laparoscopic colectomy to patients.

According to Drs. Whelan and Franklin, less than 30% of all colectomies are performed laparoscopically.

Over the next decade, as more surgical residents are trained in MIS techniques, laparoscopic colectomy may become more standard.

“Surgical residents are being exposed to laparoscopic colectomy, so the hope is that much of the future of resectional colorectal surgery will be minimally invasive,” Dr. Fowler said.

Still, making laparoscopic methods more widespread continues to be a challenge. Hand-assisted laparoscopic surgery (HALS), developed by Drs. Ballantyne and Leahy in 1993, represented one of the first attempts to bridge the gap between open and laparoscopic techniques. With HALS, surgeons make a slightly larger incision compared with laparoscopic surgery, but studies show that patients experience many of the same benefits (Dis Colon Rectum 2008;51:818-826).

“HALS is an enabling technology for colorectal surgery,” Ms. Cohen said.

“The procedure becomes much easier to perform when surgeons can insert their hand in the belly to feel the anatomy and tumor site, just like they do in an open case.”

Surgical robotics is another MISenabling technology. The da Vinci Robot, for instance, is designed to restore sensory deprivation and give surgeons more intuitive control of their instruments.

However, according to Dr. Wexner, the expense of the technology has limited its widespread use and studies have consistently failed to show that the robot is superior to laparoscopy despite significantly more time and expense.

“I think many surgeons are struggling with these laparoscopic techniques, which is why they use tools such as HALS and robotics,” Dr. Franklin said.

“However, I don’t think these tools are the answer. Mastering difficult laparoscopic techniques is about constant exposure, hard work and revision. I continue to modify my technique even today.”

Reflecting on the past 25 years of surgery, Dr. Jacobs recalls how laparoscopy gave him a new prospective on his profession. “I never wanted to be the first at anything but the benefits of laparoscopy became obvious when we saw how we helped patients,” he said. “It was truly exciting to be part of a change that revolutionized surgery.”

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Hypothermia During Surgery Affects Even Warmed Patients B Y M ICHAEL V LESSIDES SAN FRANCISCO—Despite forcedair warming, hypothermia is common and often prolonged in patients undergoing noncardiac surgery, researchers have found. The new study showed that patient temperatures below 35 C significantly increased hospital length of stay and transfusion requirements.

Perioperative hypothermia is associated with morbid myocardial outcomes, wound infection and coagulopathy— links that have prompted widespread guidelines for maintaining normothermia in surgery patients. Yet even with active warming during surgery, redistribution hypothermia and excessive heat loss combine to make many patients at least transiently hypothermic.

Although studies have documented the incidence of intraoperative hypothermia in a variety of populations, the new work is the first to detail intraoperative temperature patterns in a large general population of noncardiac surgical patients, according to the investigators. It is also the first to evaluate hospital length of stay and transfusion requirements over a broad unselected population.

“There are many randomized trials showing that mild hypothermia worsens outcome,” said Daniel I. Sessler, MD, Michael Cudahy Professor and chair of Outcomes Research at Cleveland Clinic, in Ohio. “Our observational study nonetheless provides novel information. First, the results generalize better. The randomized trials focused on small subsets of high-risk patients, whereas our analysis included a broad array of inpatient operations. Second, most of the randomized trials date to the 1990s, and medical practice has since changed considerably.

And third, the randomized outcome trials all compared passive insulation to forced-air warming. In our current analysis, all patients were actively warmed per the current standard of care.”

The investigators extracted data from the most recent visit of 143,157 of the institution’s patients scheduled for noncardiac inpatient surgery between April 1, 2005, and Feb. 15, 2013. Records were only included if the anesthetic lasted at least one hour, forced-air warming was used and core temperature was measured in the esophagus.

Rather than use final intraoperative temperatures to determine the incidence of hypothermia, the researchers used a time-weighted measurement of core temperature. The primary exposure was integrated area under the curve incorporating both duration and severity of hypothermic exposures into one value. Estimates were obtained for one-degree temperature bands ranging from 34 C to 37 C. “All previous studies were based on final intraoperative temperature,” Dr. Sessler explained. “But final temperature overestimates temperature in actively warmed patients. It is therefore also important consider the duration and severity of hypothermia. Our exposure index includes both considerations.”

Prolonged Low Body Temperatures As Dr. Sessler reported at the 2013 annual meeting of the American Society of Anesthesiologists (abstracts 1267, 1272 and 2230), 58,814 patients met all criteria. Approximately one-third had core temperature of 36 C or lower for at least one hour; 8% were below 36 C for more than three hours.

Perhaps most alarming, the researchers said, was that 5% of patients had core Quantiles – Top 5% – Top 10% – Q3 – Median – Q1 – Bottom 10% – Bottom 5%

Core Temperature, °C

38

37

36

35

0

1

2

3

4

5

6

Time After Induction, h Sample Size

14

60k 30k 0k

Figure. Body temperatures during surgery, including hypothermia.

temperatures of 35 C or lower for at least one hour. The incidence of hypothermia was greatest one hour after induction, and then progressively improved.

“Even with forced-air warming, our results indicate that a fair fraction of patients still become hypothermic,” Dr. Sessler said. “In fact, almost 10% of patients were distinctly hypothermic and remained near 35 C at the end of surgery.

This is a degree of hypothermia that has been shown to cause major complications in randomized trials.”

Furthermore, the analysis showed that both the duration of hospitalization and red blood cell transfusion requirements increased for patients whose core temperature dropped below 35 C. Tackling this issue, Dr. Sessler concluded, might involve actively prewarming patients or increasing the efficacy of intraoperative warming systems. “Heat transfer by most any cutaneous warming system is a linear function of surface area,” he said. “Simply increasing the surface covered by forced air, for example, will augment its efficacy.”

Co-investigator Andrea Kurz, MD, professor and chair of general anesthesia at Cleveland Clinic, agreed that proactive measures might help address the issue.

“These studies show that hypothermia still exists,” Dr. Kurz said. “There is a lot less [hypothermia] than there was 20 years ago. But despite the fact that most patients are now normothermic at the end of surgery, many still experience periods of intraoperative hypothermia.

Even short periods apparently worsen outcomes; we therefore still need to improve this aspect of our practice.”

Steven M. Frank, MD, associate professor of anesthesiology and critical care medicine at Johns Hopkins Medical Institutions, in Baltimore, said that although he was not surprised by the incidence of hypothermia found in the study, he found it hard to believe how rarely the vital sign has been studied.

“Ever since the late 1990s, we’ve recognized the importance of maintaining body temperature,” Dr. Frank told General Surgery News. “But everybody has been focused on the core temperature at the end of the procedure, and largely ignored what happens during the procedure. We don’t judge the quality of our care by looking at these vital signs just at the end of the case. So why should we not focus on temperature throughout the entire case as well? This is a big issue, and I’m glad Dr. Sessler and his colleagues examined what happens between the beginning and end of a case.”

Virtual Sepsis Unit Aids Early Detection B Y D AVID W ILD

A

“virtual sepsis unit,” constructed from ones and zeros, may help speed the identification of severe sepsis or septic shock in patients outside the ICU, new findings suggest.

During a three-month pilot study conducted at Mercy Hospital St. Louis, in Missouri, the telemedicinebased system identified all hospitalized patients who developed the complication, according to the researchers, who

presented the findings at the 2014 annual meeting of the Society of Critical Care Medicine (poster 1026).

Brian M. Fuller, MD, a sepsis expert who was not involved in the study, called the system “striking in its accuracy and in its ability to promptly detect patients. Electronic screening aids such as this could have a very positive impact, especially given the increasing number of sepsis patients, the abundance of data that clinicians are asked to interpret on a daily basis and the unacceptably high mortality rates for sepsis,” said Dr. Fuller, assistant professor of anesthesiology and emergency medicine in the Department of Anesthesiology at Washington

In the News

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

University School of Medicine, in St. Louis.

Sepsis occurs in 1% to 2% of all hospitalizations in the United States and affects at least 750,000 people. The cost of treating a single case of sepsis averages $22,100, and the condition takes a $17 billion toll on the nation’s health care budget each year (Crit Care Med 2001;29:1303-1310).

Lead researcher Steven Trottier, MD, a physician in the Department of Critical Care Medicine at Mercy Hospital St. Louis, said the system was designed to overcome a key obstacle to timely detection of sepsis patients. “What makes it difficult to recognize these patients early is that they are located in all parts of the hospital,” Dr. Trottier said.

The Mercy telemedicine program was previously limited to monitoring ICU

hospital’s rapid response team.

Between January and March 2013, when the program was piloted at Mercy Hospital St. Louis, the electronic system placed 11,650 patients in the virtual sepsis unit. It triggered 3,240 alarms, of which the nurse identified 272 as septic shock or severe sepsis. Physician review found that 24 of these patients did not have severe sepsis or septic shock. No other cases of severe sepsis occurred at the hospital during the pilot period, Dr. Trottier said.

The researcher reported that the combination of telemedicine-based

TREATMENT

COST

monitoring and nurse verification had a positive predictive value of 91.2% in identifying septic shock or severe sepsis (95% confidence interval [CI], 87%-94.1%).

“The approach has a very low falsepositive rate, but it needs work to improve its specificity,” Dr. Trottier said.

“At present, the system cannot distinguish patients with systemic infection from patients with other inflammatory disease states resulting in organ failure, such as patients with acute trauma or severe burn.”

Dr. Trottier noted that his team did not document amount of time spent

$1.15 2

Single Shot 150 mg

(Per 30mL)

with epinephrine

ON-Q*

COMPARATIVE PAIN SCORES

(APPROX.)

Bupivacaine

attending to false alarms and that this would be an important cost–benefit consideration.

Dr. Fuller agreed that the system needs refining and should continue to undergo rigorous testing. “It would also be very interesting to have a detailed description of the team’s interventions and to know the clinical outcomes of patients included in this study,” he added. However, he said, the approach is “very interesting and the researchers should be commended.”

The telemedicine program will be implemented in 13 other Mercy Hospitals during 2014, Dr. Trottier said.

6

EXP 266mg 1

5

EXP 399mg 1

4

$231 Pump Costs3 $12 Drug Costs3

EXP 133mg 1

TOTAL KNEE ARTHROPLASTY (TKA)

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EXP 532mg 1

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EXPAREL ® 532mg (2 vials)

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patients, but the new system provides realtime monitoring of all of the hospital’s patients by an off-site team of “Mercy SafeWatch” nurses and physicians.

The system looks for patients meeting two or more risk factors for sepsis, including systemic inflammatory response syndrome, elevated lactic acid levels, hypotension and those with an order for blood cultures. Patients meeting the criteria are placed in the virtual sepsis unit. If they go on to meet predefined criteria for organ failure, the system triggers a severe sepsis alarm. A Mercy SafeWatch nurse immediately verifies the alarm and then notifies the

DAY 1

DAY 2

†Data compiled from studies referenced. Goyal VAS scores converted from 100 point scale to 10 point scale.

DAY 3

15

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In the News

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

Some Surgeons See Potential for Google Glass in OR, Education A New and Divisive Technology Finds Some Fans in the Surgical Community M ONICA J. S MITH

S

till in its infancy, Google Glass has provoked both curiosity and controversy, praised as a reality augmenting, Best Invention by Time Magazine on the one hand, and criticized as a socially divisive, etiquette-broaching, fracas sparker on the other. A handful of surgeons among the initial users, however, are excited about the wearable’s potential to help them provide better care for their patients.

“I think it’s an amazing tool with amazing potential,” said Rafael Grossmann, MD, FACS. “It’s like having a smartphone in front of your eye. You can take a picture or do a video, tweet, text, get directions, conduct a search or have a live video call with anyone who has Internet connectivity.”

According to Dr. Grossmann, he was the first surgeon to use Google Glass in the operating room (OR) when he live-streamed a gastric procedure, with the patient’s permission, to an invitation-only Google Glass Hang-out in a neighboring room last June.

“I streamed my view of the operation to an iPad where physicians or students could ask me about the procedure. They were with me virtually, as we do with telemedicine. It lasted just a few minutes, but it was great,” said Dr. Grossmann, a general, trauma, advanced laparoscopic and robotic surgeon in Maine.

The following day, a surgeon in Madrid live-streamed a chondrocyte procedure.

Since then, surgeons from India to Indiana have been experimenting with Google Glass in the OR. Although they acknowledge its limitations—there are privacy issues to consider, it can be slow to respond to voice commands and the current model of Google Glass is not designed for use in surgery—they foresee a future for the technology as a teaching tool, communications facilitator and information provider.

Like Glass’s other 10,000 or so beta testers, known as Google Glass Explorers, Dr. Grossman was given the opportunity to purchase the product based on his tweeted response to #ifihadglass. Since then, he has become something of an evangelist for Glass, speaking at TEDx talks and using health care social media to spread the word (Twitter handle @zgjr, blog at Rgrosssz.com).

“Until people understand it, they think [Glass] is just some silly gadget,” he said.

“Once they try it, it’s a complete change of opinion.”

He proposes that Glass could radically change health care and medical education, integrated to telemedicine protocols as well as coupled with electronic medical record platforms to optimize the flow and accuracy of data management, potentially decreasing medical errors, lowering costs and improving medical care overall.

Google Glass is an optical headmounted display that sits over the right eye, with built-in Bluetooth, GPS and microphone. Looking at the display is roughly equivalent to viewing a 24-inch monitor from six to eight feet away. Dr. Grossman described the experience of wearing it as similar to consulting a rearview mirror while driving.

“In reality, it’s not always on. Like in driving, you’re looking forward; if you need to look backward, you glance at the mirror.”

Is the OR the Perfect Place for Glass?

It’s not clear yet where Google Glass will be socially welcome. Although many Explorers report enthusiastic interest from the people around them, the device has provoked ire in others who see it as a symbol of the separation between haves and have-nots.

Some businesses, concerned about their patrons’ comfort and privacy, have banned Glass from their premises.

Within the OR, however, proponents of the technology foresee using it to reference imaging studies during a procedure without taking their eyes off the patient, to communicate with the patient’s family waiting for news, and to consult with another surgeon in real time while providing a first-person point of view of what’s going on.

Seattle trauma surgeon Heather L. Evans, MD, considers the restricted and controlled environment of the OR an ideal setting for Glass. Currently, she uses a separate consent form when she asks patients if they would be willing to have their elective procedure or a portion of it recorded. So far, none of the 12 to

‘If it’s [a procedure] we do all the time and this is a way for me to show other providers how we do it or how they might solve a problem, then I think it’s really important to use [Google Glass].’

—Heather L. Evans, MD

Rafael Grossmann, MD, wearing Google Glass, an optical head-mounted display with built-in Bluetooth, GPS and microphone. Dr. Grossman proposes the technology could have major upsides for health care and medical education. “Until people understand it, they think [Glass] is just some silly gadget. Once they try it, it’s a complete change of opinion.”

15 patients she’s asked have said no.

“They’re all interested in it and want to know about it,” Dr. Evans said.

At this point, she is trying to figure out the most appropriate uses for Glass in the OR. “In the future, I could see using this as an adjunct to or even a replacement for the text-based operative note. But it’s not something I would use for every operation. If it’s a procedure I know will be not very interesting, there is not the same level of importance to apply [Glass,]” she said. “On the other hand, if it’s something we do all the time and this is a way for me to show other providers how we do it or how they might solve a problem, then I think it’s really important to use it.”

She has also used Glass to assemble instructional videos from the first-person point of view. “Last week we made a movie with two Glass units and a cell phone. In three hours, we had a fully completed video to instruct providers on how to do pelvic immobilization using a bed sheet and four Kocher clamps.”

[View pelvic immobilization video at https://www.youtube.com/watch?v=5bY yySzIMlM&feature=youtu.be] Dr. Evans does not wear Glass during

other components of patient care, and she does not wear it around her hospital, Harborview Medical Center. “I made that deliberate decision for a couple of reasons,” she said. “I wanted to figure out how to use it safely within the appropriate restrictions, observing privacy and security issues as well as common courtesy.”

Beyond exploring of the potential for Glass in surgery, Dr. Evans has found the device particularly helpful in navigation. “It’s extremely useful for directions, whether I’m walking, riding my bike, taking public transportation or driving.”

Long a technology enthusiast and early adopter, she was first in line for the Palm Pilot and iPhone. Dr. Evans has become more critical of her involvement with technology since she started using Glass; she recently took a family vacation during which she did not look at email for five days.

“I don’t think I would have realized I needed to do that without this exploration I’ve been doing,” she said.

“It’s really made me question when is it appropriate to use technology.

I’ve been asking myself that question quite a bit.”

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Seeking Satisfaction With EHRs B Y B EN G UARINO

W

ith increasing frequency, doctors and patients are finding a third party crowding the examination room: the electronic health record (EHR). To some practitioners, EHRs are a boon, offering electronic prescribing, notes that are more legible and remote access to patient files. But to others, the systems are barriers to effective communication, demanding that attention be split between patients and computers.

A spate of recent studies reflects just how varied physician responses have been to EHRs. Last November, IDC Health Insights surveyed 212 clinicians and found that 58% felt neutral, dissatisfied or very dissatisfied with EHRs. Additionally, RAND Corporation reported in October on several factors contributing to physician dissatisfaction with EHRs, such as interference with patient care, poor usability and the large amount of time consumed by data entry.

“An EHR is a source of both promise and frustration, which stems from a mismatch of expectation and reality,” said Anil Makam, MD, assistant professor in the Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, who specializes in health care information technology. “It’s not like installing Microsoft Windows,” he said. “These things are not ready out of the box.”

For users who are learning how to implement EHRs in practice, the adoption process can be costly and disruptive.

For many physicians, the switch from paper records to electronic equivalents can be “very, very difficult,” said Lawrence Kosinski, MD, chair of the American Gastroenterological Association’s Practice Management and Economics Committee.

Of more than half of the health care providers who reported being neutral or dissatisfied in the IDC Health Insights survey, 85% reported that EHRs result in a loss of productivity and 66% said the diminished time cut into patient visits.

At his practice in Elgin, Ill., Dr. Kosinski can see up to four patients per hour while simultaneously entering data into EHRs. The key is to position the computer and the patient to form a tight line of sight, he said, and to maintain frequent eye contact.

And as he types, he will read back information to his patients.

Dr. Kosinski’s interest in medical databases spans 30 years. He designed his own electronic medical system in 2003. When the meaningful use requirements of the Medicare and Medicaid EHR Incentive Program were established in 2010, Dr. Kosinski and his colleagues at Illinois Gastroenterology Group switched to

a commercial system, NextGen Ambulatory EHR. Although commercial systems enable physicians to meet the requirements for meaningful use incentives, vendors do not always design EHR systems with gastroenterologists in mind. Instead, Dr. Kosinski said, many systems are aimed at primary care doctors, who make up the largest slice of the EHR market. For gastroenterologists, whose records often require a higher level of detail, using these systems can be like trying “to fit a round peg in a square hole,” he said.

In some cases, physicians may overlook features that can optimize EHR use. With systems such as Epic, clinicians can optimize the EHR system by customizing their own note templates and order sets. “This reduces the number of clicks or words you have to type,” Dr. Makam noted.

“Instead of reinventing the wheel,” he said, a gastroenterologist who frequently sees patients with peptic ulcer disease, gastrointestinal bleeding or inflammatory bowel disease, for example, could create templates that automatically populate with the necessary information.

In the future, EHRs will emphasize configurability over customizability, Dr. Kosinski said.

“Vendors are moving toward a one-sizefits-all product,” he said, to stay competitive.

The 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10), which Dr. Kosinski called “the big elephant in the room,” may pose problems for EHR developers. By Oct. 1, 2014, all EHR systems must support ICD-10 codes to remain compliant with meaningful use. For EHR vendors scrambling to update their systems, he said, “2014 will be like Y2K.” Beyond 2014, however, the outlook for EHRs trends toward the positive.

“The potential for EHR technology to enhance communication between physicians, patients and health care teams is unparalleled,” said Ellen J. Scherl, MD, associate professor in the Division of Gastroenterology and Hepatology at Weill Cornell Medical College, New York City.

And if clinicians can turn data in EHRs into actionable information through decision-support systems and predictive analytics, Dr. Makam said, the functionality of these systems could greatly improve. This is “a huge advantage we’re just beginning to tap into,” he said.

But without increased interaction between clinicians and vendors, the promising future of EHRs may never come to fruition. “The successful evolution of the EHR is dependent on physicians’ input,” Dr. Scherl said.

Drs. Kosinski, Makam and Scherl reported no conflicts of interest.

Telemedicine Shows Promise, With a Few Issues to Iron Out B EN G UARINO

I

t was nighttime in Berlin, Md., when a patient was admitted to Atlantic General Hospital in early February, with a suspected diagnosis of necrotizing fasciitis. Given the rarity of the flesh-eating bacterial infection, the ICU nurse sought the opinion of a critical care physician to corroborate the diagnosis. One obstacle: No specialist was at hand.

Despite this, the nurse was successful—thanks to telemedicine, a doctor could make a confirmatory diagnosis from more than 100 miles away.

The level of detail afforded by telemedicine is a far cry from grainy blackand-white security camera footage, thanks to advances in video conferencing technology and data streaming capabilities. As the technological barriers fall, telemedicine is poised to become increasingly widespread; however, several hurdles remain, particularly with respect to reimbursement and clinician adoption.

“I think we are at step one of a very, very long race,” said Brendan Carr, MD, assistant professor of emergency medicine at the University of Pennsylvania’s Perelman School of Medicine, in Philadelphia.

Even in these early stages, telemedicine’s lens can capture a wide range of specialties. At Mercy Hospital in St. Louis, the telemedicine program includes areas of care such as pediatric neurology and endocrinology, as well as pulmonology and dermatology.

“We are using telemedicine across the continuum of care, from the inpatient setting to the outpatient clinic setting and then into the home setting,” said Wendy Deibert, RN, BSN, vice president of Mercy Telehealth Services. “You can create all kinds of paths down the telemedicine road.”

Patients seem to be responding positively. “The patients are the easy ones,” Ms. Deibert said. “They love being able to go to their hometown to see a doctor from wherever. They really don’t mind the video perspective.”

Ms. Deibert offered the example of a patient who lived in Arkansas and had a cardiology procedure performed in Missouri; via telemedicine, he was able to have a postoperative visit in his hometown. “When we asked him about it afterward,” Ms. Deibert said, “he was almost in tears, saying: ‘My daughter just got chemotherapy

yesterday, and if I would have had to go to St. Louis, I would have been away from her for two to three days.’”

A recent study published in Critical Care Medicine evaluated the quality of care for pediatric patients who visited five rural emergency departments (2013;41:2388-2395). Through a chart review, the investigators found that quality of care was highest for patients who received consultation by telemedicine, intermediate for patients who received consultation by telephone and lowest for patients who did not receive consultation.

Likewise, a survey of the patients’ parents revealed that parental satisfaction was highest for the telemedicine consultations.

“In our experience, patients are very satisfied with the consultation [through] telemedicine,” said Madan Dharmar, MBBS, PhD, a pediatric telemedicine specialist at the University of California, Davis Children’s Hospital, and an author of the report in Critical Care Medicine. “Overall, patients seem to receive telemedicine very well.”

Telemedicine, Dr. Dharmar said, “changed how we are able to deliver our medical care” by helping to close the gap “between an underserved population and a medically served population.”

Unique Issues for Clinicians In contrast to patients, winning over clinicians may prove to be a more difficult challenge. “Anecdotally, we have had plenty of resistance because [telemedicine] is new and change is hard,” Dr. Carr said.

Clinicians who frequently consult patients using telemedicine may

‘We are using telemedicine across the continuum of care, from the inpatient setting to the outpatient clinic setting and then into the home setting.

You can create all kinds of paths down the telemedicine road.’

—Wendy Deibert, RN, BSN

In the News

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

Consultation Compensation Another aspect of physician resistance stems from the uncertainty of compensation for telemedicine calls. On the website of the American Telemedicine Association (ATA), CEO Jonathan Linkous wrote that a question he has been asked most frequently during his 20-year experience is: â&#x20AC;&#x153;How do we get paid for telemedicine?â&#x20AC;?

Reimbursement for telemedicine consultation, from an insurance perspective, varies from state to state. As of February 2014, 21 states have introduced bills that would mandate provider coverage for telemedicine, according to the ATA, which tracks the state legislature addressing telemedicine reimbursement. Medicaid coverage of telemedicine, which also differs by state, depends on where the consultation occursâ&#x20AC;&#x201D;a health care system on the receiving end of the video conference must be deemed â&#x20AC;&#x153;ruralâ&#x20AC;? to be eligible for coverage.

Better Outcomes Telemedicine also can save money in other ways, such as decreasing errors or length of stay. Dr. Dharmar and his col leagues evaluated physician-related medication errors by analyzing the charts of 234 pediatric patients. They compared the rates of medication errors based on the type of consultation: phone, telemedicine or no consultation (Pediatrics 2013;132:1090-1097).

Pediatric patients who received telemedicine consultation as part of their care had lower odds of medication errors than patients receiving phone consultation

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encounter unique licensing and credentialing problems. â&#x20AC;&#x153;We never think about where [patients] are when theyâ&#x20AC;&#x2122;re on the phone,â&#x20AC;? Dr. Carr said. But with telemedicine, state lines may come sharply into focus.

Mercy Telehealth Services covers five states: Arkansas, Kansas, Missouri, Oklahoma and South Carolina. Some of those states, such as Arkansas, Missouri and South Carolina, have compacts that recognize out-of-state nursing licenses. Still, â&#x20AC;&#x153;youâ&#x20AC;&#x2122;ve always got to pay attention to the state lines,â&#x20AC;? Ms. Deibert said. â&#x20AC;&#x153;It takes a lot of work to get a physician licensed in a different state, anywhere from three months to a year,â&#x20AC;? she said. Both Ms. Deibert and Dr. Dharmar noted that proponents of telemedicine comprise some of the voices in the call for universal medical licensing.

Telemedicine also raises issues of privacy for the patient and the physician. â&#x20AC;&#x153;Weâ&#x20AC;&#x2122;re pretty far away from figuring out how you make this HIPAA-compliant on both sides,â&#x20AC;? Dr. Carr said.

(odds ratio, 0.19; P<0.05) or no consultation (odds ratio, 0.13; P<0.05).

Implementing telemedicine can increase efficient use of resources at health care systems. Preliminary study findings, Dr. Dharmar said, indicate that telemedicine could save tens of thousands of dollars due to more informed transfer decisions. From the perspective of a tertiary care hospital with limited ICU beds, he said, â&#x20AC;&#x153;telemedicine can enable health care systems to prioritize ICU care to those who need the higher level of care, and also help local hospitals in caring for those admitted in their facility.â&#x20AC;?

A critical component of telemedicine is that the technology enables information to spread from clinician to clinician.

It can take up to 17 years for a medical discovery to transition into common practice, Dr. Carr said, referring to a review that assessed the lag time between research and integration (Pediatr Ann 1998;27:581-584). â&#x20AC;&#x153;Waiting two decades to get the word out is probably not the goal,â&#x20AC;? Dr. Carr said. By offering their expertise to other physicians via telemedicine, specialists can help â&#x20AC;&#x153;bend the dissemination and implementation curve.â&#x20AC;?

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Surgeons’ Lounge

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

Coverage of the Jagelman/ Turnbull International Colorectal Disease Symposium Held in February 2014, at the Marriott Harbor Beach, Fort Lauderdale, Florida All articles by Steven B. Perrins Jr., MD, PGY-3, Cleveland Clinic Florida, Department of General Surgery, Weston, Fla.

Current Evidence on Laparoscopic TME for Rectal Cancer A Message From the Symposium Director Steven D. Wexner, MD, PhD (Hon), FACS, FRCS, FRCS(Ed) Professor and Chair, Department of Colorectal Surgery Cleveland Clinic Florida, Weston

One of the hot topics during our recent 25th Annual David G. Jagelman/35th Annual Rupert B. Turnbull International Colorectal Disease Symposium was optimizing outcomes in colorectal cancer (CRC) surgery. Several sessions included presentations about evaluation and management of patients with CRC, in which new techniques and fresh emerging data were presented. I have selected five of the myriad excellent lectures to feature in this issue of The Surgeons’ Lounge.

Antonio de Lacy, MD, of Barcelona, Spain, was the first surgeon to publish a large randomized controlled trial comparing laparoscopic and open colectomy for colon carcinoma. In that landmark study, Professor de Lacy showed us clear evidence to support laparoscopic resection. During our symposium, he definitively demonstrated the value of laparoscopic total mesorectal excision.

Mariana Berho, MD, director of the Center for Pathology and Laboratory Medicine at Cleveland Clinic Florida in Weston, Florida, is one of the world’s foremost authorities on CRC histopathology.

She convincingly revealed the wide variability in the evaluation of the total mesorectal excision specimen and in reporting the results. She also demonstrated to us how, by improved specimen assessment and synoptic result reporting, improved prognostic information can be determined.

Matthew Kalady, MD, from the Department of Colorectal Surgery, Cleveland Clinic Foundation in Ohio, is an acknowledged authority

on molecular markers and genetic signatures. In his lecture, Dr. Kalady discussed the current and newly developing options for using these tools to improve our assignment of patients to adjuvant therapy.

David Dietz, MD, another colorectal surgeon from Cleveland Clinic Foundation, presented the OSTRiCh Consortium (Optimizing the Surgical Treatment of Rectal Cancer) initiative. He previously had described to audiences at the American College of Surgeons (ACS), the Society of Surgical Oncology and Digestive Disease Week, the huge variation in outcomes of treatment in patients with rectal carcinoma. He reviewed the vast improvements realized in Europe by the implementation of Centers of Excellence programs, and showed us the efforts of the OSTRiCh group to realize similar improvements in North America.

Lastly, Frederick L. Greene, MD, from the Carolinas HealthCare System, Charlotte, and past chair of the ACS Commission on Cancer and editor in chief of the American Joint Committee on Cancer (AJCC) staging manual, delivered the annual David G. Jagelman oration on “Quality Benchmarks in Colorectal Cancer Surgery.” His theme was perfectly interwoven with the other topics in that he offered a lucid current status report on how we can best evaluate our results and offer the most accurate information to our patients.

Steven D. Wexner, MD Program Co-Director

Antonio de Lacy, MD, chief of gastrointestinal surgery, Hospital Clinic, Barcelona, reviewed the evidence supporting laparoscopic total mesorectal excision (TME), which results in improved survival and lower recurrence rates. The current standard of care for rectal cancer is complete excision of the rectum with adequate lymphatics and an intact fascia of the mesorectum. Quality of mesorectal excision is the most reliable prognostic indicator of, and one of the key factors in, successful treatment. According to Dr. de Lacy, the standard definition of completeness of TME is a smooth mesorectal specimen with no defects, no coning and smooth circumferential excision at the margin. An incomplete mesorectum and any specimen with irregularity of the mesorectal surface, moderate coning of the specimen, and lack of visibility of the muscularis propria at any site except for the insertion of the levator muscles are considered incomplete (Figure 1).

In terms of the minimally invasive approach to treating rectal cancer, Dr. de Lacy noted that the difficulty lies in the arduous learning curve. A search of Medline and Embase from 1988 to 2010 revealed seven studies, including 5,000 cases completed by 19 surgeons (Dis Colon Rectum 2012;55:1300-1310). These reports suggest a learning curve of 90 to 150 cases for laparoscopic TME. The steep learning curve notwithstanding, there is evidence to suggest that laparoscopic TME could become the standard of care, according to Dr. de Lacy.

A 2008 meta-analysis that included 12 trials, with more than 3,000 patients, showed that the open and laparoscopic approaches for rectal cancer yielded similar outcomes in terms of incisional hernia, wound infections, tumor recurrence and overall mortality (Cancer Treat Rev v 2008;34:498-504). Similarly, the COLOR II trial evaluated patients from 2004 to 2010, providing insight into short-term outcomes in a randomized controlled trial. The study included more than 1,100 patients, and the authors concluded that results were similar between the laparoscopic and the open approaches in terms of completeness of resection, with positive margins seen in 10% of cases in both groups and similar morbidity and mortality rates (Lancet Oncol 2013;14:210-218).

What is the reality in clinical practice? The National Health Registry in the United Kingdom contains data on 70,000 colorectal resections, with 10% of cases performed laparoscopically in 2006 and 28% in 2008 (Br J Surg 2013;100:553-560). In Germany, in 2012, Mroczkowski et al reported that of 18,000 patients undergoing surgery for CRC, only 9.2% were approached laparoscopically, with a 12% conversion rate (Colorectal Diss 2012;14:1473-1478). Luján et al reported that in Spain, 30% of 5,000 rectal cancer patients underwent laparoscopic TME, with a 17% conversion rate (Br J Surgg 2009;96:982-989).

Figure 1. Complete versus incomplete In summary, Dr. de Lacy dissection. recommended the laparoscopic approach for colon cancer, although he did stop short of a firm recommendation for rectal cancer. He suggested that the colorectal community continue to monitor long-term oncologic results, evidence of better short-term results, and at the very least, equal or improved longterm outcomes.

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Improving Efficacy of Adjuvant Therapy Using Molecular Markers and Genetic Signatures

The Synoptic Pathology Report: Partnership With Your Pathologist in Predicting Patient Prognosis

Matthew Kalady, MD, the Mrausse-Lieberman Chair in Colorectal Surgery Mariana Berho, MD, Department at Cleveland Clinic Ohio, discussed the role of adjuvant therapy using molecular of Pathology, Cleveland Clinic markers and genetic signatures. The treatment paradigm that colorectal surgeons Florida, Weston, noted that pathology and oncologists face regularly is based on imperfect clinical or pathologic staging. He reports are the strongest determining asked whether there are genetic and molecular markers that can be used to develop factors for oncologic management, and tailor individual treatments. The literature notes hundreds, if not thousands, and therefore the accuracy of the of potential markers, ranging from microRNA to stem cells, to gene mutations, to findings is crucial. She discussed single-nucleotide polymorphisms, but most result in minimal clinical use. What are methods of providing a standardized the most practical markers currently used and what is the future of molecular markers pathologic assessment of colon and as tools for specifically tailoring treatment regimens? rectum specimens and stressed that From a practical application, KRAS S is one of the most well-established markers the pathology report must be accurate, in cancer research. This gene codes for the KRAS protein, a signaling protein for complete and easy to understand the RAS pathway, which activates many transcription factors in the cell nucleus, in order to implement appropriate resulting in cell growth and proliferation. If KRAS S is mutated, it can be constituently treatment. Creating a complete and turned on, resulting in uncontrolled cell growth. This mutation has been associated easy-to-understand report is relatively with worse prognosis and poorer overall survival for patients with colon and rectal easy, Dr. Berho noted. However, cancer. Clinically, the ability to block the receptor for KRAS downregulates this producing an accurate report that is growth, and currently there are monoclonal antibodies (cetuximab [Erbitux, Bristolconsistent in terms of descriptors and Myers Squibb] and panitumumab [Vectibix, Amgen]) that serve this role as specific a methodology of reporting has been, receptor blockers. Dr. Kalady noted that a KRAS S mutation is a prognostic marker until recently, virtually nonexistent. that predicts response to antibody adjuvant therapy; it can be used to detect patients Dr. Bertho stressed the importance of who are not potentially responsive to specific therapies. Accordingly, all patients, the pathologistâ&#x20AC;&#x2122;s ability to recognize regardless of stage, should undergo testing for the KRAS S gene mutation to help a specific disease and competence in determine initial therapy. determining the variables that define A second molecular marker is microsatellite instability (MSI; also known as that disease. mismatch repair deficiency), which is the result of a loss in the function of mismatch How do pathologists perform when repair (MMR) genes such as MLH1, MSH2, MSH6 and PMS2 (the four most complying with report requirements? common). With defective genes, genetic errors accumulate, resulting in repetitive Decades ago, data revealed that sequences that lead to MSI. In all, 15% to 20% of colon and rectal cancers are pathologists often missed important microsatellite-unstable, and the majority of these cases occurs through a somatic prognostic indicators such as vascular methylation at MLH-1 (85%). A minority is associated with MMR mutation/Lynch invasion, which prompted the call syndrome (15%) (Figure 2). The sentinel study of this genetic defect was first published for standardized reports. In 1996, the in The New England Journal of Medicinee in 2003 by Ribic et al. These authors studied College of American Pathologists the effect of MSI on 5-fluorouracil treatment (N Engl J Medd 2003;349:247-257).

(CAP) created a synoptic checklist, Patients who had high levels of MSI were found to have a correlation with Lynch or a systematic method of reporting syndrome; these patients had a better prognosis but had little benefit from 5-FU pathologic findings, that provided treatment in stage II or III disease (J ( Clin Oncoll 2010;28:3219-3226). Dr. Kalady pathologists with specific requirements noted that all patients, therefore, should undergo MMR and MSI-H genetic testing needed for the management of patients to potentially determine if 5-FU would be beneficial as adjuvant therapy. with colon and rectal disease. Today, Looking to the future, Dr. Kalady noted that thamidylate synthase (TS) is a a pathology report must follow a cellular enzyme responsible for providing thymidine to the cell for DNA synthesis, format that includes required data. and that 5-FU binding to TS leads to cell death by blocking thymidine production.

For example, when commenting on Via this mechanism, TS is a potential target for further research. Additionally, gene tumor size, the pathology report must expression profiling can help confirm if specific genetic changes could 15%-20% of colon cancers determine clinical behavior of colon cancer, or a combination of changes not yet well understood that could Microsalellite determine behaviors and outcomes. instability Gene expression can potentially provide insight into patterns formed by specific cancers, which could then be used to determine treatment, response and prognosis. Gene expression also can be useful when evaluating adjuvant Germline MMR Somatic MLH1 chemotherapy, specifically differences mutation methylation in gene expression between stage II and II tumors that did not receive Lynch syndrome Sporadic adjuvant chemotherapy, to determine 15% 85% how to manage higher-stage tumors.

Dr. Kalady summarized that there Figure 2. MSI-H in colorectal cancer. is still much to learn about gene MSI-H, microsatellite instability high expression profiling and that work in this field has really only just begun.

MMR, mismatch repair

list measurements concurrently, and each diagnostic parameter should be listed on separate lines, to allow easier understanding and visualization.

The CAP has established a cancer committee with review panels for each type of tumor. Panels meet annually and include pathologists, clinicians, surgeons and nurses. They discuss changes in the TNM staging classification or adapt to any new recommendations. Any parameter included in the synoptic checklist is discussed, and protocols for each tumor are drafted and made public.

Currently, more than 20 years since the implementation of these synoptic reports, more than 2,000 surgical pathology reports have been formed to aid in the reporting of pathologic findings. Unfortunately, approximately 30% of all pathology reports are still missing one of the required elements: lymphovascular invasion and margin status (particularly circumferential margin status) ((Arch Pathol Lab Medd 1992;116:1113-1119). Current standards dictate that if pathology reports are missing important factors, a facility will be cited for this deficiency.

Creation of the synoptic reports has resulted in a decreased number of reports with missing data, an increased number of reported lymph nodes, and more accurate and thorough evaluation of the margins. These reports have enabled a standard quality of reporting between specialized pathologists (gastrointestinal) and nonspecialized pathologists.

Dr. Berho said, in summary, that although implementation of the synoptic report is clearly a step forward, the pathologist and the surgeon still have a long way to go to provide complete standardized care that will result in quality oncologic outcomes.

continued on page 22

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jcontinued from page 21

The OSTRiCh Initiative: Improving Care of Rectal Cancer David Dietz, MD, vice president, Department of Colorectal Surgery, Cleveland Clinic, Ohio, at the Digestive Disease Institute, reported on the current state of the OSTRiCh Consortium. OSTRiCh was established in 2011 and consisted of 17 centers. That number now has almost doubled to 30 centers. These centers represent a wide variety of health care environments, and each of these institutions is broadly represented in our surgical community.

The main goal of this consortium is to improve the quality and uniformity of rectal cancer care in the United States.

Why the name “OSTRiCh”? Because, according to Dr. Dietz, it represents the mindset of many institutions regarding rectal cancer care: There is wide disparity in the treatment of rectal cancer, and the image of the ostrich with its head in the sand often represents how facilities handle rectal cancer. Many centers in the United States report some of the best outcomes in the world, with high survival rates, low recurrence rates and a large percentage of patients achieving restored intestinal continuity. However, the OSTRiCh initiative was created to look beyond these high-performing centers in an attempt to discover what treatment regimens are offered at other centers and how that information can be made more uniform to benefit all patients.

In 2011, Ricciardi et al assessed hospital discharge data from 11 different states over a two-year period, during which time more than 7,500 proctectomies were performed by more than 2,600 surgeons.

The authors found that 40% of all surgeons performed onlyy nonrestorative procedures (abdominoperineal resection), with higher mortality rates and longer hospitalizations. Surgeons who performed restorative (low anterior resection) procedures were “specialized,” as they

typically performed more pelvic pouch and anorectal procedures (Dis Colon Rectum 2011;54:1210-1215). Another study by the same group evaluated rectal cancer procedures performed from 2002 to 2004 (Dis Colon Rectum 2011;54:207213). This included more than 20,000 proctectomies and evaluated data at the county level for 21 states. Surprisingly, only 20% of counties had a colostomy rate less than 40%. Dr. Dietz presented several studies reinforcing the large discrepancy in rectal cancer care; one study evaluated low-, medium- and high-volume centers and the percentage of patients seen at each (Table) (Int J Colorectal Dis 2013;28:191-196). The outcomes were striking, showing that low-volume centers treat roughly an equal number of patients as the few high-volume centers, but with significantly higher rates of mortality, longer length of stay and lower rates of sphincter preservation.

In summary, the quality of rectal cancer care in the United States varies greatly, and the vast majority of surgery for rectal cancer is performed by nonspecialists in low-volume hospitals.

The rates of permanent colostomy vary excessively, and there is suboptimal adherence to evidence-based guidelines.

Consequently, local recurrence rates and survival vary significantly throughout the United States.

Improving the quality of rectal cancer care must come from proper surgical technique in combination with evidencebased treatment and a multidisciplinary approach.

Significant evidence supports the use of multidisciplinary teams (MDTs) that provide improved outcomes in breast, head and neck, esophagus, and lung cancers. In 1995, the Calman-Hine Report established the definition of the MDT, including

a shift from generalist care to a cancer specialist approach. This includes the surgeon, medical oncologist, radiation oncologist, pathologist, radiologist and patient trackers. In the past 20 years, this concept has led to more patients being treated by fewer centers, but with better outcomes. It is this concept that the OSTRiCh Consortium is supporting and implementing for improved rectal cancer care.

In examining the current level of MDT care at the initial centers, it was noted that all surgeons were specialists ( A S C R S / S S O / S S AT / S A G E S members); all surgeons performed TME; all centers had an MDT; and 94% had regular MDT conferences.

However, further investigation found that the frequency of the MDT meetings varied greatly; only 20% of centers discussed every case; and the majority of centers discussed fewer than 50% of the cases. It also was seen that there was little standardized pathology

reporting, and radiological standards were inconsistent ((J Gastrointest Surg 2013;17:1863-1868).

For the future, trying to revise the current system may simply not be feasible, Dr. Dietz noted. It is likely that new cancer Centers of Excellence (CoEs) will need to be established, to facilitate implementation of standardization with clinicians and surgeons who meet the criteria for CoEs. OSTRiCh has proposed creation of CoE systems based on successful European models, to train and establish MDTs at specified hospitals, follow defined protocols,and prospectively collect data based on outcomes, and that are subject to peer review for accreditation. The potential benefit is quite impressive: a predicted involvement of more than 41,000 patients annually with a reduction in cost of more than $500 million and 6,000 lives saved. This is a model that is not only affordable, but also highly sustainable.

Table. Hospital Volume and Rectal Cancer Surgery Outcomes Hospital Volume Outcome

Low

Medium

High

P value

Yearly case volume (avg)

1-5

6-10

11-24

Number of hospitals

232

65

24

Number of patients

2,364

2,686

2,137

Mortality (%)

2.1

1.1

0.9

<0.001

Complications (%)

22

24

20

0.709

Sphincter preservation (%)

51

55

64

<0.001

Length of stay (days, mean) 9.7

9.2

8.8

<0.001

Source: California Office of Statewide Health Planning and Development Database (2000-2005). Int J Colorectal Dis 2013;28:191-196.

Jagelman Oration

Quality Benchmarks in Colorectal Cancer Surgery Frederick L. Greene, MD, FACS, former chairman of surgery at the Carolinas Medical Center, Charlotte, N.C. (1997-2012), member of the ACS Commission on Cancer, and founding member and past president of the Society of American Gastrointestinal and Endoscopic Surgeons, delivered the keynote lecture.

Dr. Greene discussed the use of quality benchmarks in colorectal surgery.

He began by noting that surgeons are practicing in unprecedented times, as pressure from a financial standpoint is

resulting in higher-quality benchmarks and accountability, never seen before.

As a result, monitoring of outcomes is becoming critical. In evaluating volume of services rendered, surgery is not the culprit; new technologies, imaging and testing are all noted to be the greatest drivers of cost in medical practice today. Quality of care, Dr. Greene said, was defined in 1999 by the Institute of Medicine as “providing patients with appropriate services in a technically competent manner, with good communication, shared

decision-making, and cultural sensitivity” (Cancer 2012;118:2571-2582).

So who provides this quality? It is provided by everyone involved in health care through education and training, and quality improvement on a local, regional and national level. Professional organizations, societies and quality organizations all help drive the goal of improved quality, in addition to defining quality benchmarks. These new benchmarks have been pushed forward since the 1999 Institute of Medicine report, “Ensuring Quality Cancer Care,”

that noted that patients were receiving a wide variety of care for cancer, with a gap in quality. This resulted in calls for a national quality-monitoring system.

The Commission on Cancer (CoC), of which Dr. Greene was a sitting member, was created to address these issues, and included surgeons and 52 professional organization representatives.

The CoC was a consortium dedicated to improving survival and quality of life for cancer patients through standard setting, prevention, research, education and the continued on page 24

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jcontinued from page 22 monitoring of comprehensive quality care. Cancer programs in U.S. hospitals make up roughly 25% to 30% of all programs, but care for more than 70% of all patients (Figure). The CoC has taken information from the local level and disseminated it to the roughly 1,500 hospitals providing cancer care.

One of the quality measures evaluated for CRC is the use and effectiveness of adjuvant chemotherapy, which has been measured and monitored for more than 10 years. In addition, the “12-node” rule is known throughout the CRC world as a reasonable benchmark for accurate diagnoses. It is now possible to take one’s own data and compare them with all other hospitals in the CoC. Regular revisions to quality measures are made to include additional benchmarks. For rectal cancer, the latest benchmark involves chemoradiation considered or administered within three months preoperatively, or within 90 days postoperatively for AJCC stage II or III rectal cancer.

Hospitals are held accountable for attaining quality benchmarks. The CoC compiles quality and outcome data, which allows for comparison with regional and national data. This compilation of data will enable comparison of short- and long-term outcomes. The CoC five-year survival data for lung, breast, prostate and colon cancers will provide an adjusted survival report to evaluate additional risk factors. Furthermore, reporting for factors such as in-and-out migration (a patient beginning treatment in one institution and finishing elsewhere) will be monitored; race, insurance status, distance traveled for care and days to first treatment are all tracked in order to provide benchmarks for potential improvement.

With the availability of reports and data to hospitals and insurance companies, it becomes essential that surgeons define criteria for selecting quality measures.

Dr. Greene noted that for a quality measure to have an impact, it must have a variation with the potential for improvement, and needs to be scientifically acceptable, reliable, valid and precise; a quality measure also must be usable and have both statistical and clinical meaning; and finally, a quality measure must be feasible, meaning

Hospital with accredited programs

Hospital without accredited programs

Treated elsewhere

Diagnosed and treated in accredited programs

that implementation must be achievable.

In his discussion, Dr. Greene suggested surgical issues that surgeons might address with their respective institutions. Hospitals use privileging committees that evaluate laparoscopic experience. Should hospitals require a minimum number of cases performed annually to continue to provide that service? Should each surgeon be held accountable for the number of lymph nodes obtained? Preoperatively, has there been appropriate endoscopic work prior to any surgical intervention? Was patient informed consent obtained?

Are surgeons discussing smoking cessation before surgery? Each of these benchmarks, at the very least, should be discussed if not implemented as possible methods of assuring improved quality, according to Dr. Greene.

There are three pillars of quality of care: “structure,” the attributes of the health care system; “process,” what we actually do for our patients; and “outcome,” the change in a patient’s health status as a result of the process. Aspects of each pillar in the setting of rectal cancer should be discussed at the level of the institution.

In evaluating structure, surgeons need to examine the hospital accreditation, annual case volume, specialist availability and the presence of an MDT; the process should include effective imaging after neoadjuvant therapy and attaining an adequate TME specimen with appropriate standardized pathology reporting; and finally, an outcome should be evaluated with 30-day

mortality, 60-day mortality, local recurrence rates and long-term outcomes. Taking each of these items into account, surgeons can improve their own institutions in the realm of rectal cancer care.

For institutions with low volume, does simply doing more cases result in improved quality? Certainly not: There is a variable relationship between volume and outcomes. Experience does allow for improvement with systems and technique, which often leads to improved outcomes; however, displacement of patients to high-volume centers creates limited access, and in doing so, deprives lower-volume hospitals of the opportunity to improve systems and processes of care.

Certainly, smaller hospitals and lower-volume surgeons can have excellent outcomes, and larger hospitals with high-volume surgeons can have poor outcomes, but the challenge is identifying both groups: Surgeons need to focus on the standards of quality rather than volume and outcome data; they need to achieve a level playing field of quality through the use of guidelines and a variety of commissions on care such as the CoC and OSTRiCh. In closing, Dr. Greene quoted a letter from Dr. Jagelman to the Archives of Surgeryy in 1981, noting that “in reality and, unfortunately, all too often, colon cancer surgery is performed in a less than adequate way, resulting in a high incidence of local recurrence and an unnecessarily high mortality’’ ((Arch Surg 1981;116:253).

New Drug Combo May Delay Aromatase Inhibitor Resistance B Y K ATE O’R OURKE SAN ANTONIO—In a Phase II study, adding dasatinib (Sprycel, BMS) to letrozole (Femara, Novartis) in patients with postmenopausal metastatic breast cancer doubled progression-free survival (PFS), but had no effect on clinical benefit rate. The results were reported at the recent San Antonio Breast Cancer Symposium.

“These findings suggest that dasatinib may inhibit the emergence of acquired resistance to aromatase inhibitor [AI] therapy,” said Devchand Paul, DO, PhD, a breast oncologist at US Oncology and Rocky Mountain Cancer Centers, Denver.

Dasatinib is an inhibitor of five tyrosine kinase families, including Src. Because studies have linked high levels of Src activity to breast cancer metastases to bone, investigators set out to test the combination of letrozole and dasatinib as first-line treatment for

metastatic breast cancer.

“Src regulates osteoclast-mediated bone turnover,” said Dr. Paul. “Several studies have shown that Src is important in enabling estrogen-receptor crosstalk with the HER2 family and other growth factor-signaling pathways, as well as other steroid hormone receptors, including the androgen receptor, leading to activation of MAP [mitogen-activated protein] kinase and PI3 [phosphatidylinositide-3] kinase pathways. Ultimately, this will affect transcription, DNA synthesis, proliferation and breast cancer cell survival.”

The trial enrolled 120 hormone receptor–positive, HER2-negative postmenopausal patients with metastatic breast cancer. Patients were randomized in a 1:1 fashion to receive letrozole monotherapy (2.5 mg orally once daily) or letrozole in combination with dasatinib (100 mg orally once daily) as first-line AI treatment. No prior AI therapy for metastatic breast

cancer was allowed, but patients could have received an adjuvant AI more than one year before study entry.

Investigators found no difference in clinical benefit rate, the study’s primary end point. However, the median PFS was 9.9 months in patients receiving letrozole alone and 20.1 months in patients receiving combination therapy. Dr. Paul said the combination therapy was well tolerated and that dasatinib may decrease the incidence of osteopenia in patients on AIs. “Previous studies have shown that fulvestrant or exemestane combined with dasatinib did not improve progression-free survival following progression on nonsteroidal aromatase inhibitor–pretreated patients compared with fulvestrant or exemestane alone,” said Dr. Paul. “These findings [with] the first-line letrozole dasatinib data suggest that dasatinib may be of benefit mainly in patients receiving initial aromatase inhibitor therapy.”

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Opinion

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

Vogl, NY...

Examining NSABP B32 Trial Should Have Asked ‘How Big Is the Detriment From Occult Nodal Metastases?’

immunologic staining for small numbers of cancer cells.

B32 Study Results in Detail B Y S TEVEN V OGL , MD

T

homas Julian, MD, associate director of the Allegheny Breast Center in Pittsburgh, presented the 10-year results of NSABP B32 at the San Antonio Breast Cancer Symposium on Dec. 11 (abstract S2-05). He correctly concluded that sentinel node biopsy, when skillfully done, is adequate treatment of the axilla if the node is negative on routine histologic examination, with no need for a completion axillary dissection. This was a randomized study of about 5,600 women designed to examine this point, and I believe it excluded a substantial benefit from axillary dissection in this population.

In B32, women who had negative sentinel nodes on routine exam (N=3,989) then had the same nodes subjected to immunohistochemistry (IHC) on two more slices. The NSABP then sought to answer the question of whether such examination for “occult” nodal metastases is worthwhile by looking at patient outcomes.

A short version of the results is that deaths at 10 years increased from 11% to 14.1% and disease-free survival (DFS) events increased from 22.2% to 26.9%, if two extra sections of each sentinel node stained for epithelial cells demonstrated metastatic breast cancer.

My assertion is that having even tiny amounts of breast cancer in axillary nodes cannott make the prognosis better.

Rather than approach the issue with the question of “Do occult metastases worsen the prognosis?,” I believe the question should have been, “How bad is it to have even minute involvement of axillary nodes?”

In other words, this study should have set out to exclude a predefined level of decline in prognosis (distant metastases or overall survival) associated with occult nodal involvement.

It seems unlikely that we will ever get an even larger randomized trial to answer this noninferiority question with sufficient statistical confidence. We should, therefore, examine the results of B32 carefully to draw what conclusions we can on when, and if, to conduct extraordinarily careful examinations of sentinel nodes by serial sectioning and

The population of women in B32 with negative sentinel nodes on routine histology had favorable clinical prognostic characteristics and excellent local and systemic therapy: 84% had primaries less than 2 cm in diameter; 80% of tumors were hormone receptor-positive; 87.5% were treated with lumpectomy; 82% had postoperative irradiation; 75.5% were aged 50 years or older; and

other prognostic factors, with a 25% reduction in DFS events (P=0.01). Isolated tumor cells and micrometastases increased the risk for DFS events similarly (29% and 23%, respectively).

DFS was 18% worse with the presence of occult nodal metastases if axillary dissection was added to sentinel node biopsy—a nonsignificant decrease from 76.4% to 69.9% at 10 years (P=0.2), with a nonsignificant 20% increase in first locoregional recurrences (4.2% to 6.3% at 10 years; P=0.52).

Pathologists should subject sentinel axillary nodes to careful examination if the risk for relapse or distant metastases based on known patient characteristics is sufficiently high such that knowledge of the worsened prognosis would change systemic therapy.

85% had postoperative systemic therapy.1 We do not know how many were HER2-positive, nor was histologic grade centrally reviewed.

About 16% of 3,268 patients with negative routine nodal histology on the sentinel nodes had metastases detected by IHC—11% isolated tumor cells (cell collections <0.2 mm in size); 4.4% “micrometastases” (nodal nodules 0.2-2 mm); and 0.4% had “macrometastases” (>2 mm) that were missed on routine H&E (hematoxylin and eosin) staining of the node.

Overall survival at 10 years dropped from 89% to 85.9% if the nodes had occult metastases discovered by more sections and IHC—a 37% increase in the rate of death. This was significant (P=0.03), but when adjusted for other prognostic factors, the rate of death increased only 26% and the P value was borderline significant (P=0.06). Isolated tumor cells increased the rate of death by 22% compared with no detectable nodal metastases on IHC, whereas micrometastases (0.2-2 mm) increased the rate of death by 43%. Survival among women with occult metastases in the sentinel node was unaffected by the addition of axillary dissection in this study (the subject of the randomization), with slightly more deaths in the dissection arm (47 vs. 43, of about 300 women in each arm )—a difference that was both trivial and not statistically significant.

DFS at 10 years went from 77.8% to 73.1% if the initially negative sentinel nodes had occult metastases: a 27% reduction in DFS (P=0.02). This remained significant when adjusted for

Occult Nodal Disease and Local Control Recurrences in the breast and draining nodes increased from 3.9% to 5.3% if occult axillary nodal involvement was present, a 32% increase that was not significant (P=0.17). Axillary recurrences were very rare in the entiree study population—0.4% even in those women who did not have an axillary dissection. Among women with occult axillary nodal involvement, first recurrence in the axilla without axillary dissection (n=300) was 1.7%, but went down to 0.6% with axillary dissection (n=316).

Most women (87%) in the B32 trial were treated with lumpectomy and breast irradiation that included the lower axilla, in part accounting for the very low axillary recurrence rates.

B32 Nodal Exam Techniques Somewhat Underestimated Occult Nodal Involvement The experimental protocol used in B32 to detect occult disease in the negative sentinel nodes on routine exam included IHC staining on two extra sections. A 54-case subset of B32 patients evaluated exhaustively at the University of Vermont demonstrated that this technique missed many positive nodes with occult disease. In this very small series for which nodes were sliced very thinly to detect collections of isolated tumor cells (ITCs) up to 0.18 mm in size, the frequency of positive blocks increased from 6% to 11.4%, positive nodes from 8% to 12.3%, and positive

cases from 17% to 26%.2 If one extends these numbers to the overall B32 study population, the group of women negative for occult metastases (who had only two slices taken from each sentinel node) was likely contaminated by approximately 11% with women whose nodes actually had undetected occult metastases. Had these women, with a likely worse prognosis, been accurately assigned, then the group negative for occult metastases would have done better, and the study might have shown a bigger survival difference in favor of the absence of occult nodal metastases.

Careful Examination of IHC Thin Sections of Sentinel Nodes Will Change Therapy Dr. Julian’s conclusion at SABCS was that careful “routine” IHC examination of the sentinel nodes is not recommended. I fear this will be misinterpreted to mean it should never be done, and hospital histology laboratories will cease to offer this service. Pathologists should subject sentinel axillary nodes to careful examination if the risk for relapse or distant metastases based on known patient characteristics is sufficiently high such that knowledge of the worsened prognosis would change systemic therapy. Control of the axilla is not the issue; systemic relapse and death are the concerns. This assumes the patient could tolerate the systemic therapy that would be given if higher risk is discovered.

Based on the B32 results, occult disease in the sentinel node leads to worse outcomes. Knowing the sentinel node has breast cancer in small amounts would be useful in some higher-risk circumstances such as: • The patient is young or middleaged with a small triple-negative tumor who would otherwise not get adjuvant therapy, but is fit to tolerate it.

• The patient has a small HER2positive tumor. This has a worse prognosis than a small HER2-negative tumor.

• The tumor is big (2-5 cm) and hormone-receptor positive with a low or intermediate recurrence score.

Until we have the results of the ongoing RxPonder trial, standard therapy for such patients could be considered to include adjuvant chemotherapy.

Absent an involved node, many experts now still advise no adjuvant therapy for a HER2-positive primary tumor

Opinion

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

less than 6 mm in size (Eric Winer, MD, Dana-Farber Cancer Institute, personal communication, December 2013). Nodal involvement makes the prognosis considerably worse for small HER2-positive tumors.3 In an analysis

by Manuela Campiglio, PhD, of Italian women with T1 tumors treated with trastuzumab (Herceptin, Genentech) and chemotherapy, the hazard rate for relapse was 3.4 for nodal involvement, 3.1 for negative hormone receptors, and 2.9 for high tumor grade in this patient population. Primary size did not matter, although the number of primaries less than 5 mm was quite small (N=41) in this series.

In B32, the NSABP did monumental work defining the safety and efficacy of sentinel node biopsy for women with breast cancer. If the 37% increase in the risk of death that accompanies occult involvement of the sentinel node would be enough to merit a change in systemic therapy to a regimen that is more effective and whose greater toxicities are now justified by the higher risk for death, then this technique should remain available to surgeons and medical oncologists in every hospital across the country.

The costs are small compared with the genetic tests we routinely order and

Anatomic Staging is Still Important: “Occult” Sentinel Nodal Metastasis in NSABP B32 • Occurs in 16% of women with negative sentinel nodes on routine histology.* • Lead to increased risk of systemic relapse.** • Increases hazard rate of death by 37%.

• Increases hazard rate of recurrence, new primary or death (inverse of DFS) by 27%.

• Very rarely leads to local recurrence in the axilla.

Careful examination of the sentinel axillary nodes should remain available as a technique for clinicians when the increased risk of systemic relapse would change systemic adjuvant therapy: Small HER2-positive and triple-negative cancers in women who could tolerate enhanced systemic therapy, and perhaps big tumors with low and intermediate recurrence scores.***

we think it will help our patients. If we do not support the value of such testing in print, CMS and the insurance industry may refuse to pay for very careful nodal examination. More annoying, but not as bad, they may force us to divert our efforts from patient care to convincing high-school dropouts, sitting in front of computer screens, that such testing is of value for each patient we think it will help.

References 1.

2.

* And about another 9% if sought by very thin serial sections.2 ** Compared with “truly negative” nodes. *** Or similar results on other genomic prognostic tests.

3.

the drugs we routinely administer. If inconvenient at a local level, this testing could be done at referral laboratories, as indeed was done at the University of

Vermont in NSABP B32.2 Breast physicians must act now to protect and preserve our ability to very carefully examine sentinel nodes when

Krag DN, Anderson SJ, Julian TB, et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial.

Lancet Oncol. 2010;11:927-933, PMID: 20863759.

Weaver DL, Le UP, Dupuis SL, et al. Metastasis detection in sentinel lymph nodes: comparison of a limited widely spaced (NSABP protocol B-32) and a comprehensive narrowly spaced paraffin block sectioning strategy. Am J Surg Pathol. 2009;33:1583-1589, PMID: 19730364.

Campiglio M, Sandri M, Sasso M, et al.

Small HER2-positive breast carcinomas: Prognostic factors to consider in deciding on adjuvant trastuzumab treatment. Presented at: San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Poster P4-12-06.

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GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

A Tale of Two Nations

$ (U.S.)

A Comparison of Health Care In the United Kingdom and the United States: Which Country Gets It More ‘Right’?

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n January 2012, while on a train traveling from Stratford-upon-Avon, Ellen Smucker-Green, an American studying in England, suddenly felt abdominal pain so severe that she lay on the floor cradling her knees for an hour until the train reached Oxford.

Once off the train, she rushed to the accident and emergency department (A&E). After a cursory examination, the A&E doctor thought she might have gallstones but would need a general practitioner (GP) to refer her for an ultrasound to confirm.

“The GP I saw told me to wait for another attack before recommending an ultrasound because if my gallbladder wasn’t in serious enough trouble, he said he couldn’t pass me on to a surgeon,” Ms. Smucker-Green recalled.

So she waited. Her next attack in May 2013 was more debilitating than the last and landed her in the hospital again. This time her GP sent her for an ultrasound, which showed her gallbladder was severely inflamed and packed with stones. She needed surgery urgently.

By the time Ms. Smucker-Green had a laparoscopic cholecystectomy in August 2013, she required codeine almost full time to control the pain, had numerous attacks requiring hospitalization, lost more than 20 pounds and had to take a leave of absence from her PhD program. During the wait, her condition worsened and a relatively simple procedure became significantly more complicated.

Ms. Smucker-Green could have shortened her wait time after her attack in Oxford, and potentially avoided the complications, by traveling home to the United States for surgery.

“With good insurance, she probably would have had all of the tests, and undergone elective laparoscopic surgery within a few weeks,” said John Maa, MD, president of the Northern California Chapter of the American College of Surgeons. “If she were uninsured, she would have had to go to a county medical hospital, and might have waited months for an operation. But at least the decision to schedule an operation would clearly have been made immediately.”

However, in the United States, Ms. Smucker-Green’s greater access to surgical care would have come at a significant financial burden. The national average for laparoscopic cholecystectomy is about $11,400, ranging from $6,100 to $30,400, according to estimates collected from New Choice Health. When looking at hospital charges, prices tend to balloon. Average prices for laparoscopic cholecystectomy often fall between $17,054 and $58,553, but can reach as high as $170,000 at some institutions.

In the United Kingdom, cost is rarely a factor for patients requiring medical care. Patients pay next to nothing out of pocket for a cholecystectomy through the National Health Service (NHS), and the small percentage of people who have private care can expect to pay between £4,000 and £6,895 (U.S. $6,700-$11,550) across the United Kingdom, according to quotes from various hospitals and clinics.

A major advantage of the NHS is that “the costs of

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Adjusted for differences in cost of living.

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Figure 2. Cost-related access barriers in 2013a a

Did not fill/skipped prescription, did not visit doctor with medical problem and/or did not get recommended care.

Source: 2013 Commonwealth Fund International Health Policy Survey in eleven countries.

care and insurance never seem to enter the picture for patients,” said Dr. Maa. “In the United States, if the patient were uninsured, the costs of a deductible, coinsurance and hospital bill could have been very serious factors in the timing of surgery.”

Treatment Balancing Act Although Ms. Smucker-Green’s difficult experience may not represent the norm in the United Kingdom, it serves to highlight the cracks in both the U.K. and U.S. health care systems.

When comparing the medical care in these two countries, there appears to be a fundamental trade-off between individual and population health, and a careful balance

between resource allocation and cost containment.

“The United States is a revenue-driven health care system that incentivizes use and high costs while the U.K. focuses on population-level health, which means lower costs but often also underuse,” said David Flum, MD, MPH, professor in the Schools of Medicine and Public Health, and director of the Surgical Outcomes Research Center at the University of Washington, Seattle.

Data compiled by The Commonwealth Fund that compare wait times and costs across 11 countries reflect these trade-offs (Figures 1 and 2). A 2013 survey found that Americans boasted among the shortest wait times for elective surgery, whereas patients in the United Kingdom reported some of the longest. More

In the News

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

specifically, 68% of U.S. respondents needing any type of elective surgery said they waited less than one month and 7% waited at least four months, whereas 59% of U.K. respondents waited less than one month and 21% waited four months or more (Figure 3).

“For a gallbladder operation, I’d be very surprised if patients in the United States had to endure wait times that meaningfully impacted their lives,” said Dr. Flum.

In terms of cost, the Commonwealth survey found that, compared with 11 other countries, patients in the United States are the least likely to access care because of costs, whereas those in the United Kingdom don’t tend to face cost-related access problems. In 2013, 23% of U.S. respondents had issues paying or were unable to cover their medical bills for a range of treatments (42% for uninsured, 15% for insured), and 37% reported forgoing care in the past year because of cost (63% for uninsured, 27% for insured), whereas almost no respondents in the United Kingdom reported similar problems.

“In general, patients in the United States can expect to pay more for care than anywhere else in the world,” said David Squires, senior researcher at The Commonwealth Fund in New York City. “I think it’s fair to say that, at least in the public’s eye, cost-control mechanisms in the NHS haven’t undermined access to needed care to the same degree as high costs have in the United States.”

Part of the problem is the United States spends more on health care than any other country. In 2011, U.S. health care spending reached nearly $8,500 per capita compared with almost $3,400 in the United Kingdom, according to data from the Organization for Economic Cooperation and Development.

“This higher spending is mostly due to the fact that we have higher prices,” said Mr. Squires.

Issues in the United Kingdom arise largely because the growing demand for treatment is outstripping the availability of doctors and the shrinking NHS budget.

Although the NHS has largely delivered on its promise to guarantee patients care within 18 weeks after a referral (and less time for urgent cases), as of October 2013, about 169,000 patients experienced longer delays, a 22% increase from the previous year. Almost 3 million people in England have been waiting for operations or other hospital treatments since August 2013, according to 2014 data from the National Audit Office (NAO).

“The challenge of sustaining the 18-week waiting standards is increasing, against a background of an increasing number of patients being referred to trusts, the financial pressure on the NHS and the need to make efficiency savings,” wrote Amyas Morse, head of the NAO, in a statement.

Such lengthy wait times may be detrimental to patients. For Ms. Smucker-Green, delaying surgery meant she not only needed additional A&E visits, but also had to endure a more complicated surgery because of a rogue gallstone, which required a larger incision, prolonged the procedure and resulted in an overnight hospital stay and two postoperative infections.

During the wait for surgery, “many patients progress to needing an emergency operation, due to infections, gallstone pancreatitis or other gallstone-related complications,” said Dr. Maa. A growing body of research supports the idea that delaying surgery “causes more harm to patients’ health and costs more for patients and the health care system,” said Kurinchi Gurusamy, MBBS, MRCS, PhD, lecturer in surgery, University College London & Royal Free Hospital.

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Figure 3. Wait times for elective surgery and specialist appointments, 2010.a a b

Base: needed to see specialist in past two years.

Base: needed elective surgery in past two years.

Source: 2010 Commonwealth Fund International Health Policy Survey in 11 countries.

For patients with biliary colic, there is no medical reason to delay surgery, said Dr. Gurusamy. However, he noted, early surgery for biliary colic is not always possible.

“In a state-funded health care system, the aim is to maximize the health of the whole population using the available resources. Because of this, early laparoscopic cholecystectomy is rarely performed for biliary colic in the NHS [because of preferences given to cancer operations], while it is almost always possible in the private setting,” he said.

Early surgery is also generally recommended for patients with acute cholecystitis. In a review, Dr. Gurusamy reported that patients with acute cholecystitis did best when they had surgery within one week of symptom presentation (Br J Surgg 2010;97:141-150).

Delaying surgery for acute cholecystitis appeared to have no advantages and resulted in significantly longer hospital stay.

“Early surgery in the setting of acute cholecystitis has been demonstrated in several randomized studies worldwide to be beneficial,” said Dr. Maa, adding that the time off work, risks for further complications and death, and quality of life clearly are worsened with a delay.

However, Dr. Maa said, although patients with acute cholecystitis should undergo surgery promptly, the comfort level of surgeons for operating in the setting of acute inflammation is quite variable.

“Some surgeons will offer surgery immediately, while others may try to treat the patient with antibiotics and discharge them home with a plan to perform surgery months later. This [variability] makes the data quite confusing,” he said.

Delaying surgery also can place an unanticipated financial burden on the NHS. A 2010 review found that early laparoscopic cholecystectomy saves approximately £820 per patient (U.S. $1,375) and results in better quality of life than delayed laparoscopic cholecystectomy (Br J Surg 2010;97:210-219). Another study, which examined the costs associated with laparoscopic cholecystectomy at a hospital in England in 2009, reported that 23.7% of patients (37 of 156) were admitted with recurrent gallstone-related symptoms while on the wait list. The cost per episode of admission was £946, totaling £44,462 for all patients (or approximately U.S. $74,400).

“This is a significant amount of money that could theoretically have been used to operate on these 37 patients early, thereby preventing the morbidity,” the

authors concluded. However, they pointed out, it’s difficult to know which patients will experience recurrent symptoms and develop more serious complications.

Thus, when balancing patient needs with limited resources, it’s hard to know which patients would benefit most from earlier surgery.

Although there are major downsides to delaying surgery, some critics feel that the opposite problem exists in the United States. “Americans may be having surgery when they don’t necessarily need it,” Dr. Flum said.

A particularly striking example occurs with colon surgery. Current guidelines recommend that patients not have a laparoscopic colectomy to prevent future episodes of diverticulitis, but in practice, the number of Americans having their colons removed due to diverticulitis has tripled in the past 15 years.

Some evidence suggests that cholecystectomy may also be performed too often. According to data compiled by the California Health Care Foundation from 2005 to 2009, there is wide variability in the rates of cholecystectomy in California. For instance, residents of one region were 3.5 times more likely to receive a cholecystectomy (more than twice the state average) compared with patients in another region.

In fact, with a fee-for-service system and short wait times, some patients may undergo surgery for the wrong diagnosis, which is both costly and harmful to patients. A recent analysis of malpractice claims in the United States put the percentage of unnecessary operations as high as 10% to 20% for some specialties, including cardiac and spine procedures.

“In the U.S., we’re seeing incredible use of marginally helpful interventions that are highly reimbursed,” Dr. Flum said.

So, which health care system is better? “The takehome is there are pros and cons of both systems but neither is getting it just right,” Dr. Flum said.

Comparing the U.K. and U.S. health care systems involves examining the complex interplay of costs of care, access to resources and time.

“In the U.S., we emphasize access and time, but patients are often left alone to bear the costs,” Dr. Maa said. In the United Kingdom, however, the emphasis is on cost and access, often at the expense of time.

This oversight can result in long wait times, protracted symptoms, complications and impaired quality of life.

“What we’re seeing is that you likely can’t prioritize all three equally at once,” Dr. Maa said.

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OMAHA

jContinued from page 1 Seattle, and it was over.

43-8, Seattle. Omaha! Omaha!

Manning said he wasn’t embarrassed, but you could tell he was humiliated. In sports, there’s just no way to get around a spanking.

Not so in politics, where reality is what you say it is. President Obama has been audibilizing like crazy trying to salvage the Affordable Care Act (ACA), his prized legislation upon which he has staked his legacy.

The rollout was a disaster, even comical for an administration that prides itself on its techno-savvy. The billion-dollar website “healthcare.gov,” that took longer to build than to wage and win World War II, didn’t work … at all.

Omaha! Omaha!

“Imagine you want to buy this unbelievably great product from your favorite big box store, but you can’t because it’s so good everyone else wants it at the same time, so the cash registers crash.”

Apparently, no one told the president that you don’t spike the ball when you fall on it in your own end zone, but the playing field of politics has shifting goal posts.

I could relate to the president’s optimism. Down 22 to zip at the start of the second half, I still thought Denver would come back to win, until Seattle ran the second half kickoff back for a touchdown. In 10 seconds, I finally got it.

But not the president. “It’s just a glitch, like Apple maps. We’ll fix it, and buying health insurance will be like shopping on Amazon. It’ll cost you less than your monthly phone bill.”

Then 4 million people lost their insurance because their policies didn’t conform to ACA minimal standards, despite repeated assurances that if you liked your insurance, you could keep it.

Omaha! Omaha!

“I never said that,” the president said. Everyone went under the hood for instant replay and there he was, 58 times, with irrefutable visual evidence to the contrary.

Omaha! Omaha!

The president clarified that if you like your insurance, you shouldn’t. “The ACA protects people against bad-apple insurance companies that rip you off ” by selling deficient policies at cut-rate prices.

The president is a scrambler and could not be boxed in by “settled law.”

He would not take a knee on the issue of canceled policies. Then former president Bill Clinton ran onto the field, saying Congress should honor the president’s pledge and restore canceled policies. President Obama dug in and said he would veto any such legislation, but Omaha! Omaha! The very next morning

Unlike disinformation abundantly provided by insurance companies with every transaction, meaningful metrics of comparison will be available on the Internet to help consumers locate and evaluate providers, and to consummate needed financial transactions

the president proudly announced that he restored the canceled policies on his own by directing the insurance companies to reissue and honor them, even if no premiums were paid, since no one knew if healthcare.gov’s payment module was functional.

Wow! Omaha! Omaha! Who knew that the president had nationalized the insurance industry?

One would have thought that the insurance industry would have been screaming for a penalty flag for getting blindsided by a president who seemed to be playing by his own rules, but apparently it took House minority leader Nancy Pelosi’s advice to heart and knew exactly what was in the bill before it decided if it liked it or not. Provisions 1341 and 1342 of the law provided for perpetual annual federal bailouts if, for any reason, underwriting losses exceeded revenue.

If anyone ever doubted that insurance companies are champions of risk management, insuring themselves against

the mendacity of those with whom they conspired to get the ACA passed should remove any doubt.

Despite efforts to control the narrative, by February it appeared that the president had more to worry about than the other team. The Congressional Budget Office—the nonpartisan agency that verified the president’s claim in 2009 that the ACA would create two million jobs, reduce premiums by 40% and not add a dime to the debt— announced that the equivalent of 2.5 jobs would be lost due to the ACA. Apparently, it came as a surprise to some that employers, especially those with fewer than 50 employees, like private practice doctors’ offices, would shrink their workforce if they were forced to buy health insurance for employees.

Now the president was audibilizing the audibles. The employer mandate was delayed beyond the interim elections to minimize political fallout. Then the employer mandate for large employers

was delayed, twice. Average citizens were beginning to wonder why it was necessary to frantically change the original game plan when everyone had more than four years to think about it.

As usual, The New York Timess could be depended on for clarification and coverage. It informed those pedestrian folks who thought the ACA was about health care cost, quality and access that its real purpose was to end “the insurance trap” that kept people in jobs they didn’t like just to maintain coverage. Omaha!

Omaha! The ACA became the second Emancipation Proclamation. No one needed to work. In Senate majority leader Harry Reid’s words, we were free to pursue our dreams. Batiking is my passion. Yours?

Despite the president’s nifty brokenfield running and audibilizing, bad news continued to mount. Prominent hospitals were opting out of the ACA; and those that did not, like the Cleveland Clinic, were trimming jobs to account for expected reductions in per diems from the insurance plans offered on the exchanges. For every story of a patient grateful for insurance coverage for the first time, there were other patients who thought that they had insurance but were being turned away from hospitals because coverage could not be verified.

To recapture the narrative, the president took extraordinary measures. He reassured Charles Barkley on radio that future generations would thank him for Obamacare. He went on Ellen [DeGeneres’ television show] who told him how much everyone appreciated what he had done. He endured the camp fecklessness of Zach Galifianakis on “Between Two Ferns” to tell the young Internet audience to “grow up” and accept some responsibility for themselves by buying insurance because “you never knew when an old basketball injury would flare up.”

The First Lady advised young “knuckleheads” to get on the exchanges. Even Lebron took his prodigious talents to the airways to cajole.

But as of March 1, 29 days before the enrollment deadline, more people had actually lost their insurance due to ACA than had enrolled in the exchanges, and the majority was for an expanded Medicaid program. It seemed like the only success was keeping 26-year-olds on their parents’ policies, but that seemed to be counterproductive to the goal of getting young healthy people to buy their own policies that they didn’t need to put the program on sound financial footing.

The moral underpinning of the ACA was shaken when the Kaiser Family Survey revealed that the uninsured weren’t buying. People who believed that being uninsured meant you had no access to care were bewildered. Not so the uninsured, who knew how to navigate the

Opinion

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

vast network of local and state facilities, academic centers, charitable organizations and the general hospital grid where EMTALA laws protected their access to care. Less than 20% of the uninsured saw the wisdom of substituting what they had for monthly premium notices. The dirty, closely guarded secret that provided the moral basis for the ACA was out of the bag: Being uninsured and having no access to health care are not the same thing. In fact, studies emerged demonstrating that for certain conditions, like trauma, the uninsured got better care than the insured who wound up at Level II trauma centers, while the uninsured got shipped to Level I centers and better outcomes becausee they were uninsured.

The unkindest cut of all, of course, was that the healthy 18- to 30-yearolds were not signing up either, and had no intention of doing so, even though the beefed-up IRS was poised to collect “personal responsibility payments” if proof of insurance did not accompany tax returns (although to quash a potential open revolt, the administration is slowly leaking that they have no plans of rigorous enforcement, a decidedly different message than the one sent when the IRS hired 16,000 new agents for enforcement). It seems that this demographic had wised up to the other dirty, closely guarded secret of ACA: The financial stability of the ACA depended on young healthy people buying expensive coverage that they didn’t need to underwrite the larger health care needs of older people. Already burdened with Medicare and Social Security payroll deductions that many believe will not be there for them because of the government’s $17 trillion debt, young people sniffed out another generational transfer of wealth, and balked.

Why go through this painful recapitulation of the ACA? Is there really anything to be gained in watching the game film of a 43-8 smackdown, other than maybe trying to get the ones with eight points to admit defeat? It’s politics. That won’t happen.

In my professional lifetime, private practice ran itself into the ground because every doctor wanted to be a millionaire.

To control that, managed care stepped in, first with HMOs and then PPOs. Patients hated HMOs because of narrow networks. Ezekiel Emmanuel, one of the chief architects of the ACA, must have been in diapers during the HMO debacle because he’s now claiming in a New York Timess editorial that narrow networks ensure quality because they’re easy to control and doctors and patients love them. PPOs expanded choice; but to pay for them, deductibles and copays have risen every year. It was only natural that at some point, the government would get its chance to run health care

that has been the holy grail of every biggovernment advocate for 75 years. An enormously popular president provided that opportunity, but incompetence squandered it.

So what will fill the vacuum now that government has DQ’d itself, even if it hasn’t come to grips with its own failure yet? Personally, I’ve always thought that the government should just write a trillion-dollar check every year to Kaiser and say, “Here, you take care of everyone.” Kaiser could do it and do it reasonably well, without a million new federal employees in dozens of newly created

The dirty, closely guarded secret that provided the moral basis for the ACA was out of the bag: Being uninsured and having no access to health care are not the same thing.

federal agencies and departments.

The second option isn’t a coherent plan, but an evolving organic system that already is developing and will accelerate.

The conventional wisdom was that the government intentionally designed a public–private hybrid health system guaranteed to fail to facilitate implementation of a completely centralized governmentrun health system. They miscalculated, and people won’t be begging government to step in anytime soon. They will find their own solutions at a fraction of the cost with a smartphone and a search see OMAHA page 32

Optimizing the Prevention and Management of Postsurgical Adhesions To participate in this FREE CME activity, log on to

www.CMEZone.com and enter keyword “MN125” Release date: December 1, 2012

Chair

Jon Gould, MD Chief, Division of General Surgery Alonzo P. Walker Chair in Surgery Associate Professor of Surgery Medical College of Wisconsin Senior Medical Director of Clinical Affairs Froedtert Hospital Milwaukee, Wisconsin

Faculty

Michael J. Rosen, MD Associate Professor of Surgery Division Chief, General Surgery University Hospitals Case Medical Center Cleveland, Ohio

Statement of Need Adhesions are the most common complication of abdominopelvic surgery, developing postoperatively in 50% to 100% of all such interventions. They can lead to serious medical complications, substantial morbidity, high monetary costs, large surgical workloads, dangerous and difficult reoperations, and an increasing number of medicolegal claims. An official definition of the Sponsored by

Expiration date: September 1, 2014 condition has not been established, and an unequivocally effective prevention method has not been identified. A standardized classification for adhesion assessment and scoring also is lacking, as are guidelines for diagnosis and management. To close these gaps, clinician education is necessary.

Goal The goal of this educational activity is to provide surgeons with up-to-date, clinically useful information concerning the prevention and management of postoperative adhesions.

Learning Objectives 1 Review the pathophysiology and complications of postoperative adhesion formation.

2 Summarize current strategies used to prevent postoperative adhesion formation.

3 Describe the various types of barrier materials used to prevent postoperative adhesion formation.

Intended Audience The intended audience for this educational activity includes general surgeons, vascular surgeons, colon and rectal surgeons, critical care surgeons, surgical oncologists, trauma surgeons, and thoracic surgeons.

Supported by an Educational Grant from

Estimated Time for Completion: 60 minutes Course Format Monograph (print and online)

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Medical College of Wisconsin and Applied Clinical Education. The Medical College of Wisconsin is accredited by the ACCME to provide continuing medical education for physicians.

Designation of Credit Statement The Medical College of Wisconsin designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. t Physicians should only claim credit commensurate with the extent of their participation in the activity.

Method of Participation There are no fees for participating in or receiving credit for this activity. To receive CME credit, participants should read the preamble and the monograph and complete the post-test and evaluation. A score of at least 70% is required to complete this activity successfully.

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Opinion OMAHA

jContinued from page 31 engine, and two or three apps like Waze to help them find their way.

Ironically, the president was actually on to something when he said buying health insurance should be like shopping on Amazon. He was half right. He should have said buying health care, not just insurance, should be like shopping on Amazon, and it will be. He couldnâ&#x20AC;&#x2122;t execute because heâ&#x20AC;&#x2122;s on the wrong team: The government has conclusively demonstrated to everyoneâ&#x20AC;&#x2122;s satisfaction, turnover after turnover, fumble after fumble, that it canâ&#x20AC;&#x2122;t execute, which is surprising given its access to limitless capital and human resources. Itâ&#x20AC;&#x2122;s almost as if the government purposely ignored assets from the private sector that would have guaranteed success, at least in the enrollment process. That alone explains why politicians, bureaucrats and academics canâ&#x20AC;&#x2122;t build anything that works. That they donâ&#x20AC;&#x2122;t understand that to be true, and had almost no trepidation taking on something so large that it would frighten, dislocate or unsettle half the civilian population proves how utterly incapable they are of governing.

The private sector already has everything that would have been required to accomplish a seamless rollout that could have been expanded to implementation, payment, self-assessment and revision had government actually been interested in something other than increasing its size, reach and control. Young people, who are tech natives, want to buy certain aspects of health care directly via the Internet, but they only want to buy what they want and when they want it. They want the appropriate platform that will allow them to buy health care like plane tickets and Birkenstocks. When they want shoes, though, they donâ&#x20AC;&#x2122;t want to contribute to a shoe fund.

The health delivery system based on the Internet will not require enrollment or initiation fees. Restricted access is a concept antithetical to the Internet culture.

Users can move in and out when the need arises. They can comparison-shop for an MRI and pay $700 cash instead of being charged $8,200 so the insurance company can tell them on their six-page statement that they saved $7,000 by being a member. Unlike disinformation abundantly provided by insurance companies with every transaction, meaningful metrics of comparison will be available on the Internet to help consumers locate and evaluate providers, and to consummate needed financial transactions.

Those who believe that the delivery of health care requires a high level of government intervention and regulation do not understand how the Internet works.

The Internet is the regulatory system because unlike government or insurance

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

companies that are opaque, it is transparent. Because it is transparent, choices get winnowed, like on a search engine.

Favorable experiences get amplified and move to the top of the list if replicated.

It is no accident that the companies that have succeeded in the Internet universe, like Amazon, are always the best. Do you think that the cost of a hospital bed or a pill would rise by more than 10% annually for 30 years in a transparent and competitive marketplace conducted on the Internet, where price reflected proven quality?

If Kaiser doesnâ&#x20AC;&#x2122;t want the universal health care gig, give it to Jeff Bezos.

The Internet, when used for commerce, is anti-inflationary because it eliminates the middleman. Insurance companies, government and large complex hospital systems are middlemen with bloated bureaucracies that have insinuated themselves between doctors and patients, exacting from both a tithe to cover the costs of their own expanding needs that have little relationship to specific health care transactions. The insurance companies justify their take as matchmakers between doctors and patients who, through various mechanisms of coercion, have found themselves in the same cage.

They also claim to add value to the system as resource management experts and prudent fiduciaries of premium dollars. They do neither effectively. Internet algorithms reward efficiency and penalize waste and advertise success that attracts further usageâ&#x20AC;&#x201D;for free.

The smoldering IRS and National Security Agency issues didnâ&#x20AC;&#x2122;t help the marketing of the ACA because the potential abuse of power by the government undermined public trust in its programs. The perception of young people is that they donâ&#x20AC;&#x2122;t need intermediaries to get what they need, especially if they canâ&#x20AC;&#x2122;t trust them.

Health care transactions most likely will become part of the exploding social economy that directly connects providers and consumers. Hertz and Avis have a lot to worry about with Uber and Lyft.

Airbnb could quickly kill segments of the hotel business by connecting travelers with people ready to put them up in their homes for a fraction of the price of a hotel room, and you donâ&#x20AC;&#x2122;t have to worry about being next to the ice maker. Vested interests are scrambling to use government and regulatory authority to kill these emerging businesses similar to the battles that Tesla is fighting because the company refuses to sell through dealerships. There is little doubt in my mind who will win that battle. Twenty-five years ago, my money would have been on vested interests because there was no mechanism to connect directly with goods and services. Today, in an Internet social economy, bye bye insurance companies, and absent coercion, bye bye government. They will

When Joe Citizen realizes that he can get a CBC like a pizza from Dominoâ&#x20AC;&#x2122;s for one-tenth the price and hassle we have all become accustomed to, the agents and T-men will be run out of Dodge like the rustlers that they are. go down kicking and screaming because neither one wants to get shut out of a $2 trillion to $3 trillion portion of the economy that provides endless opportunity to tax, regulate, politicize, and most of all, grow the size and reach of government.

However, when Joe Citizen realizes that he can get a CBC like a pizza from Dominoâ&#x20AC;&#x2122;s for one-tenth the price and hassle we have all become accustomed to, the agents and T-men will be run out of Dodge like the rustlers that they are.

If the health care consumer needs any guidance navigating to the provider of choice, it wonâ&#x20AC;&#x2122;t come from insurance companies or government exchanges, who have everything but the consumerâ&#x20AC;&#x2122;s best interest at heart. Companies like Castlight, appropriately named (it went public on the NYSE in early March, priced at $12 and opened in the low $30s), will proliferate and provide guidance to highdeductible consumers who are spending their own money to buy specific health services.

The ACAâ&#x20AC;&#x2122;s failure will have another ironic twist that should delight the reader. When the unholy cabal made up of the insurance industry, hospital consortiums, Big Pharma and government got together to scheme how to sell ACA to the public so they could divide up the booty from 40 million new paying customers, notably absent were doctors and patients. Predictably, patients were promised the moon to get their support, and doctors were publicly vilified as cash-hungry predators to convince the frightened public that it needed government to protect them from their own doctors. The strategy sold the plan to a public weary of managed care and ready for government intervention. But the government bungled badly, and is now using all its resources to convince everyone that you can actually enroll â&#x20AC;&#x153;easy-peasyâ&#x20AC;? as senior presidential advisor Valerie Jarett put it, as if being able to enroll were the purpose of the law and had anything to do with actually getting care.

In the vacuum created by the ACAâ&#x20AC;&#x2122;s failure, as the public begins to understand that there was little more to it than rehashed HMOs with narrow networks run by the government instead of the insurance companies, frustrated patients

may fall back into the waiting arms of physicians, who always have been the only ones with any real genuine interest in their well being. Physicians should be able to use the Internet platform to connect directly with patients without the poisonous interference of insurance companies and government, both experts in designing delivery systems that alienate patients from doctors, and vice versa. The Frankenstein that they created in their own image, the electronic medical record, did the same thing: It literally made the physician turn her back on the patient, while in the same room, ostensibly providing care, to satisfy the unrelated needs of the payors and regulators. The insurance-and-governmentâ&#x20AC;&#x201C;free physician will have great appeal to the modern young patient attracted to concepts like free range and biosustainability that promote a natural world without harmful additives that contaminate without serving any real purpose. Doctors and patients should be able to find each other just like men and women do on Christian Mingle, J-Date and Farmers Only. If that sounds stupid to you, would you rather make the match yourself, free, based on personal preference or pay an insurance executive with a million-dollar salary to do it for you?

The â&#x20AC;&#x153;conciergeâ&#x20AC;? movement is a step in the right direction because it is based on a private covenant between patient and doctor without outside interference, but I hate the name because it sounds exclusionary and rich. It doesnâ&#x20AC;&#x2122;t have to be.

Instead of â&#x20AC;&#x153;concierge medicine,â&#x20AC;? letâ&#x20AC;&#x2122;s think of a better name that is inclusive, free of government and insurance company intrusion, and protects the sacred bond between doctor and patient.

How does â&#x20AC;&#x153;private practice of medicineâ&#x20AC;? sound to you? I think it has got the Bronze Plan beaten by a mile.

The country has been through a lot with the ACA. The government could have enlarged Medicaid and provided a pool for patients with pre-existing conditions without the big grab, but apparently the temptation to control all aspects of health care was irresistible. I can only think of the quaint quatrain that I learned as a kid: Humpty Dumpty sat on a wall, Humpty Dumpty had a great fall.

All the kingâ&#x20AC;&#x2122;s horses and all the kingâ&#x20AC;&#x2122;s men Couldnâ&#x20AC;&#x2122;t put Humpty together again.

I never knew what it meant. Now I do. â&#x20AC;&#x201D;Dr. Cossman is a vascular surgeon in â&#x20AC;&#x201D; Los Angeles, California.

khorty@mcmahonmed.com.

Opinion

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

VAP Definition Unrepresentative of Ventilator-Associated Infections B Y B EN G UARINO

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neumonia, a well-known complication of mechanical ventilation, may represent only a fraction of the nosocomial infections that affect ventilated patients, researchers have found. Bacterial cultures taken from a pediatric ICU revealed a higher rate of pathogenic infection than reports of ventilator-associated pneumonia (VAP) suggest.

“The results challenge the conventional definition of VAP,” said Andrew Beardsley, MD, a critical care pediatrician at the Indiana University Health System in Indianapolis, who presented the results of the study at the 2014 annual meeting of the Society of Critical Care Medicine.

Dr. Beardsley and his colleagues analyzed patient records at Indiana University Health’s Riley Hospital for Children, where clinicians routinely use bronchoalveolar lavages when they suspect ventilated patients have acquired infections.

From January 2011 through June 2013, more than 2,000 pediatric patients required mechanical ventilation at Riley, totaling 20,114 ventilator-days. Clinicians performed 313 bronchoalveolar lavages on the second day of admission or later. From these lavages, 160 cultures tested positive for pathogenic bacteria.

During the same 30-month interval, the hospital reported eight cases of VAP, for a rate of 0.40 instances of VAP per 1,000 days. This rate falls within the estimated national incidence of VAP, which ranges from 0.0 to 4.4 cases per 1,000 ventilator-days, according to a 2012 report by the Centers for Disease Control and Prevention’s (CDC) National Healthcare Safety Network.

But when the incidence of VAP at Riley was compared with the incidence of pathogenic bacteria cultures, the authors found the rate of positive cultures—roughly eight per 1,000 ventilator-days—was about 20 times higher than that for VAP. “There are a lot of patients who have infections that aren’t categorized as such in VAP reporting,” Dr. Beardsley said.

Although the database indicated positive pathogenic cultures, it would be difficult to relate the study’s results to clinical outcomes, Dr. Beardsley said. But ongoing efforts aim to determine when such infections are clinically relevant and help inform best management strategies.

The CDC, in order to facilitate hospital reporting and surveillance, requires clinicians to corroborate a series of symptoms before diagnosing VAP. Before a pediatric case of VAP can be reported to the National Healthcare Safety Network, for example, a chest x-ray must confirm the presence of pneumonia.

But a problem with relying on chest x-rays to diagnose pediatric patients is that it can be very difficult to distinguish between atelectasis and pneumonia in children, said Jennifer Muszynski, MD, assistant professor of pediatrics in the Division of Critical Care Medicine at the Ohio State University College of Medicine, in Columbus. The chest walls of infants and small children are more compliant than those of adults, and if small areas of the lungs collapse, it can look “just

like pneumonia,” said Dr. Muszynski, who was not involved with the research.

The level of specificity of the classification system is another restriction, Dr. Beardsley said. “No matter how many signs or symptoms of infection are present, if there is no chest x-ray change, you exit the algorithm.”

For adult patients, the strict definition of VAP now falls under a broader category of ventilator-associated events, a change enacted in January 2013. To be classified

as a lower-tier ventilator-associated event, a chest x-ray is not required; the diagnosis is instead based on increases to the daily minimum fraction of inspired oxygen or positive end-expiratory pressure.

“The CDC has recognized the current definition may not be adequate,” Dr. Muszynski said. “What they’ve tried to do is to objectively quantify clinical worsening, as opposed to using chest x-ray findings or other nonspecific signs or symptoms of pneumonia.”

Rationale, Reversal, and Recovery of Neuromuscular Blockade Part 1: Framing the Issues Case Study Harold is a 74-year-old man undergoing a video-assisted right upper lobectomy for stage I non-small cell lung cancer.

Current Symptoms • Dyspnea • Coughing with hemoptysis • Chest pain Vital Signs • Height: 177.8 cm (70”) • Weight: 65 kg (143 lb) Signi¿cant Medical History • Hypertension • Chronic obstructive pulmonary disease (moderate) Current Medications • Metoprolol succinate ER 50 mg/d • Tiotropium bromide inhalation powder Laboratory Results • 2-cm lesion in right upper lobe revealed on chest computed tomography (CT) scan; malignancy con¿rmed with needle biopsy • No abnormal bronchopulmonary or mediastinal lymph nodes; brain CT, isotopic bone scan, abdominal ultrasonography negative for distant metastases • Forced expiratory volume in the ¿rst second: 43.6% of predicted value (1.44 L) • Carbon monoxide diffusing capacity: 71.7% of predicted values (20.19 mL/min/mmHg) • Cardiac ultrasonography: normal pulmonary artery pressure (22 mm Hg) At induction, Harold receives propofol 1.5 mg/kg and rocuronium 0.6 mg/kg. During the procedure, movement of the diaphragm interferes with surgery.

This activity is jointly sponsored by Global Education Group and Applied Clinical Education.

Supported by an educational grant from Merck.

Applied Clinical Education is pleased to introduce a new interactive 3-part CME series featuring challenging cases in neuromuscular blockade.

Each activity will present a clinical scenario that you face in your daily practice. After reading the introduction to the case, consider the challenge questions, and then visit www.CMEZone.com/nmb1 to ¿nd out how your answers stack up against those of our multidisciplinary faculty panel.

Access the activities on your desktop, laptop, or tablet to explore the issues surrounding safe, effective, neuromuscular blockade and reversal via a unique multimedia learning experience and earn 1.0 AMA PRA Category 1 Credit.™ Participate in the coming months as well to complete the whole series and earn a total of 3.0 AMA PRA Category 1 Credits.™ This activity’s distinguished faculty Jon Gould, MD Glenn S. Murphy, MD Chief, Division of General Surgery Alonzo P. Walker Chair in Surgery Associate Professor of Surgery Medical College of Wisconsin Senior Medical Director of Clinical Affairs Froedtert Hospital Milwaukee, Wisconsin

Clinical Professor, Anesthesiology University of Chicago Pritzker School of Medicine Director Cardiac Anesthesia and Clinical Research NorthShore University HealthSystem Evanston, Illinois

Challenge Questions 1. What would you do next?

2. What potential postoperative risks does this patient face?

Access this activity at www.cmezone.com/nmb1

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Opinion ELEPHANT

jContinued from page 1 anecdotally noticed that a patient, who survived a wound infection, did not seem to ultimately live as long as expected. But I did not yet see the elephant.

Then in late 2013, at a multidisciplinary breast conference, the case of a 50-year-old obese, diabetic, woman with a long history of smoking was presented.

The patient had a 2-cm invasive breast cancer and insisted on bilateral mastectomy, a sentinel node biopsy and tissue expanders. We all recognized that her risk for infection was “high.” We argued that perhaps she should only have the mastectomies and sentinel lymph node biopsy as a first operation, and the expanders at a later time. Then I remembered my similar patient who did not live a long life after her wound infection, and I vaguely began to see the elephant in the operating room.

Was there a connection between wound infection and long-term survival after infection in breast cancer surgery? I was unaware of any link. I searched the Internet for, “cancer surgery and postoperative infection and survival,” limiting my search to more recent studies (2000 and after). After several searches I only found four relevant articles. Our librarian used those articles to look for other citations. Once I reviewed those articles—and there are not many—I clearly saw the elephant in the operating room.

Patient pain and suffering from any infectious complication after surgery, as well as the massive costs, have been well documented. But the awareness of the reduction in disease-free survival because of postoperative infectious complications has not diffused among surgeons. The evidence for blood transfusion reducing survival, along with colon cancer surgery, has diffused among surgeons. Quoted references below will support the argument that postoperative infection after breast, colon, stomach, liver, lung and head and neck cancer surgery decreases long-term survival.

Breast Cancer One of the early articles I noted was “Postoperative Wound Complications and Systemic Recurrence in Breast Cancer,” by Murthy et al (Br J Cancerr 2007;97:1211-1217). In this study, “1,065 patients diagnosed with operable primary invasive breast cancer between 1994 and 2001 were assessed for development of systemic recurrence according to whether or not a wound complication occurred after surgery, with a median follow-up of 54 months (range 15-119).

There were 93 wound complications (9%). There was a statistically significant greater risk of developing systemic recurrence in patients with wound problems

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

than those without (hazard ratio [HR], 2.87; 95% confidence interval [CI], 1.97-4.18; P<0.0001). This remained in a multivariate analysis after adjustment for case mix variables, including Nottingham Prognostic Index (NPI) and estrogen–progesterone receptor status.”

The article indicated that in the “good prognostic group,” the systemic recurrence-free survival at five years (95% CI) was 93.1% in patients with wound complications and 98.2% in patients with no wound complications. In the moderate prognostic group the systemic

Salient Points •

Patient pain and suffering from any infectious complication after surgery, as well as the massive costs, have been well documented. But the awareness of the reduction in disease-free survival because of postoperative infectious complications has not diffused among surgeons.

•

In the “poor prognostic group” the systemic recurrence-free survival at five years was 61.3% without postoperative infection versus 46.3% with infection.

•

Surgical complications after immediate breast reconstruction are related to preoperativelyidentifiable factors that can be used to accurately risk stratify patients, which may assist with counseling, selection and perioperative decision making. The low versus very high infection risk was 7.14% versus 27.02%.

•

In patients with infectious complications after surgery for colorectal cancer, the survival rate was more than 50% lower than in patients without infections.

•

The presence of postoperative complications was an independent factor associated with a worse overall survival and a higher overall recurrence rate in colorectal cancer patients. Also, there is a significant association between colorectal anastomotic leak and reduced long-term cancer-specific survival.

•

Multivariate analysis demonstrated that age, preoperative comorbidity, blood transfusion, tumor depth, nodal involvement and postoperative infection correlated with overall survival in gastric cancer.

•

High-quality surgical technique to minimize complications will improve the prognosis of hepatocellular carcinoma.

•

Postoperative complications, particularly of a major infectious type, are strong negative predictors of long-term survival in lung cancer patients.

•

Host–tumor interactions under surgical stress may act synergistically as potent tumor growth factors, and may thus influence long-term survival. Controlling surgical insults and/or regulating perioperative inflammatory responses may therefore lead to new therapeutic approaches for controlling disease recurrence.

•

Intravital microscopy showed that cancer cells adhered directly on top of arrested neutrophils, indicating that neutrophils may act as a bridge to facilitate interactions between cancer cells and the liver parenchyma.

•

The Risk of Surgical Site Infection in Cancer scoring system improves risk stratification of cancer patients and identifies those who may benefit from more aggressive or novel preventive strategies.

•

Delayed breast reconstruction is more reasonable in patients at high risk for postoperative infection.

•

If surgeons accept the notion that postoperative infection reduces survival, then certain algorithms in surgery should be modified.

recurrence-free survival at five years was 82.2% versus 89.6%. In the poor prognostic group the systemic recurrence-free survival at five years was 61.3% without postoperative infection versus 46.3% with infection. Smokers at the time of diagnosis were more likely to develop metastatic disease than the nonsmokers after adjustment for other factors.

Fischer et al recently published the article “Risk Analysis and Stratification of Surgical Morbidity After Immediate Breast Reconstruction” ((J Am Coll Surgg 2013;217:780-787). In the article, the authors reported that the following conditions were associated with complications: autologous reconstruction (odds ratio [OR], 1.41; P<0.001), American Society of Anesthesiologists physical status >3 (OR, 1.25; P P=0.004), class I obesity (OR, 1.38; P<0.001), class II obesity (OR, 1.91; P<0.001), class III obesity (OR, 1.70; P<0.001) and active smoking (OR, 1.46; P<0.001). The authors concluded that, “surgical complications after IBR [immediate breast reconstruction] are related to preoperatively identifiable factors that can be used to accurately risk stratify patients, which may assist with counseling, selection and perioperative decision making.” The patients were stratified according to risk for infection, with 7.14% of patients falling in the lowrisk category and 27.02% in the veryhigh-risk category.

Colorectal Cancer Turning to cancers of the colon and rectum, the next article I noted was, “Correlation Between Postoperative Infections and Long-term Survival After Colorectal Resection for Cancer,” by Nespoli et al (Tumorii 2004;90:485-490). In this study, Dukes’ stage (P=0.048) P and occurrence of postoperative infectious complications (P=0.011) P were independently associated with outcome. The authors reported: “In patients with infectious complications, the survival rate was more than 50% lower, than in patients without infections. We excluded emergency and palliative operations (intestinal bypass), elderly subjects, previous cancer, immunosuppressive therapy, severe organ dysfunction, and Dukes’ stage D and A because all of these factors may affect the long-term survival.”

There is further support published in the Annals of Surgical Oncology (2007;14:2559-2566) by Law et al in the study “The Impact of Postoperative Complications on Long-term Outcomes Following Curative Resection for Colorectal Cancer.” In this series of patients, “With exclusion of patients who died within 30 days, the median follow-up of the surviving patients was 45.3 months. The 5-year overall survival was 64.9%, and the overall recurrence rate was 29.1%. The presence of postoperative complications was an independent factor associated with a

Opinion

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

worse overall survival (P=0.023; P HR, 1.26; 95% CI, 1.03-1.52) and a higher overall recurrence rate (P=0.04, P HR, 1.26; 95% CI, 1.01-1.57). The presence of postoperative complication not only affects the short-term results of resection of colorectal cancer, but the long-term oncologic outcomes are also adversely affected.”

In 2011, Mirnezami et al published a very convincing study in the Annals of Surgery: “Increased Local Recurrence and Reduced Survival from Colorectal Cancer Following Anastomotic Leak” (2011;253:890-899). The authors examined the long-term oncologic effects of anastomotic leakage (AL) after restorative surgery for colorectal cancer by performing a search of studies published between 1965 and 2009. They evaluated local recurrence, distant recurrence and cancer-specific survival. In all, the analysis included 21,902 patients from 21 studies, including 13 prospective nonrandomized studies, one prospective randomized study and seven retrospective studies. The authors reported the following results: “For rectal anastomoses, the odd ratios (OR) of developing a local recurrence when there was AL was 2.05 (95% CI, 1.51-2.8; P P=0.0001). For studies describing both colon and rectal anastomoses, the OR of local recurrence when there was an AL was 2.9 (95% CI, 1.784.71; P<0.001). The OR of developing a distant recurrence after AL was 1.38 (95% CI, 0.96-1.99; P P=0.083). Long term cancer specific mortality was significantly higher after AL with an OR of 1.75 (95% CI, 1.47-2.1; P P=0.0001).” The authors concluded “AL has a negative prognostic impact on local recurrence after restorative resection of rectal cancer. A significant association between colorectal AL and reduced long-term cancer specific survival was also noted.” No association between AL and distant recurrence was found in this particular study.

The evidence that postoperative infectious complications decrease survival in cancer patients is compelling, and should resonate with all physicians caring for these patients.

After Hepatectomy for Hepatocellular Carcinoma” [HCC] ((J Surg Oncol 2011;104:814-821). In this study, the authors compared results of patients with complications (177) and those without complications (199) after hepatectomy for liver cancer. Clinical data, surgical outcome, and long-term survival of patients were analyzed retrospectively. The authors concluded that “postoperative complications (major or minor) are one of prognostic indicators in hepatectomy for HCC, and further stressed that “high quality surgical technique to minimize complications will improve the

prognosis of HCC.”

Laryngeal Cancer The theme continues with the paper “Prognostic Significance of Postoperative Wound Infections After Total Laryngectomy” (Head Neck 2012;34:1023-1027)

by Gonzalez-Marquez et al. The authors analyzed 129 patients with previously untreated laryngeal or hypopharyngeal squamous cell carcinoma who underwent a total laryngectomy with a minimum follow-up of 24 months. Fifty-seven patients (44%) developed a see ELEPHANT PAGE 36

Gastric Cancer Turning to another cancer, Tsujimoto et al published the following article in Annals of Surgical Oncology: “Impact of Postoperative Infection on Long-term Survival After Potentially Curative Resection for Gastric Cancer” (2009;16:311318). They concluded: “Patients with complications due to postoperative infection had significantly more unfavorable outcomes compared with those patients without postoperative infection. Multivariate analysis demonstrated that age, preoperative comorbidity, blood transfusion, tumor depth, nodal involvement, and postoperative infection correlated with overall survival.”

GSN Video Arcade Share your knowledge, show off your skills, speak to your colleagues.

General Surgery News is calling for video submissions to feature in our new Surgical Video Arcade, on one of the most viewed websites in surgery.

Send us your contribution to surgical education or discussion, such as ÜYÚd][lmj]Ú ÚÜÚÚYfÚafl]j]klaf_Ú[Yk]Ú ÚÚÚÚÜÚYÚÚna\]gÚghafagfÚÚÚÚÚÜÚgl`]j

Liver Cancer In 2011, Okamura et al published the paper “Prognostic Significance of Postoperative Complications

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GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

ELEPHANT

jContinued from page 35 wound infection. The study showed that the only parameters significantly associated with a worse disease-specific survival in these cases were nodal extracapsular invasion (P<0.001) and surgical wound infection (P=0.02).

P

Lung Cancer Further support of the role of infection on survival was detailed in â&#x20AC;&#x153;Influence of Postoperative Infectious Complications on Long-term Survival of Lung Cancer Patients: A Population-based Cohort Studyâ&#x20AC;? in the Journal of Thoracic Oncologyy (2013;8:554-561). In this article, Andalib found an overall 30-day postoperative complication rate of 58.2% in a group of 4,033 patients. They noted a major infectious complication (pneumonia, empyema, or mediastinitis) in 378 patients, and concluded that â&#x20AC;&#x153;postoperative complications, particularly of a major infectious type, are strong negative predictors of long-term survival in lung cancer patients.â&#x20AC;?

Possible Mechanisms As I mentioned earlier, there are not many other articles that I have found that document evidence of postoperative infection decreasing survival in cancer surgery patients. There are a few articles that attempt to explain the mechanism. One is â&#x20AC;&#x153;Perioperative Host-Tumor Inflammatory Interactions: A Potential Trigger for Disease Recurrence Following a Curative Resection for Colorectal Cancer,â&#x20AC;? by Mike et al (Surgery Today 2008;38:579-584).

The authors of this paper â&#x20AC;&#x153;investigated whether host-tumor interactions are causal or consecutive clinical factors associated with surgical stress that influences the long-term survival after a curative resection of colorectal cancer. A Medline/ PubMed search was conducted to identify the relevant articles investigating the factors related to surgical stress and their effects on the long-term survival after a curative resection of colorectal cancer.

The intraoperative state is defined as a cytokine storm in which ongoing local cytokine production occurs at the site of the tumor, thus further enhancing the autocrine cytokine loop for angiogenic factor production. The postoperative state is defined as tissue regeneration in which surgery-related clinical events enhance the systemic induction of inflammatory cytokines, which in turn synergistically exaggerate the local activation of tumor growth factors.

Host-tumor interactions under surgical stress may act synergistically as potent tumor growth factors, and may thus influence long-term survival. Controlling surgical insults and/or

regulating perioperative inflammatory responses may therefore lead to new therapeutic approaches for controlling disease recurrence.â&#x20AC;?

More granular explanations of potential mechanisms were elucidated in the following articles: â&#x20AC;˘ â&#x20AC;&#x153;The Neutrophil Elastase Inhibitor Sivelestat Suppresses Accelerated Gastrointestinal Tumor Growth via Peritonitis After Cecal Ligation and Punctureâ&#x20AC;?

(Kumagai et al. Anticancer Research 2013;33:3653-3659).

The authors concluded: â&#x20AC;&#x153;Intra-abdominal inflammation induced by cecal ligation puncture (in mice) enhances the growth of subcutaneously implanted tumors, while perioperative administration of sivelestat (neutrophil elastase inhibitor) suppresses tumor growth by affecting systemic inflammation.â&#x20AC;? â&#x20AC;˘ â&#x20AC;&#x153;Neutrophils Promote Liver Metastasis via Mac-1-Mediated Interactions with Circulating Tumor Cellsâ&#x20AC;? (Spicer et al. Cancer Researchh 2012; 72:3919-3927).

The authors summarized their findings: â&#x20AC;&#x153;Although circulating neutrophils are associated with distant metastasis and poor outcome in a number of epithelial malignancies, it remains unclear whether neutrophils play an active causal role in the metastatic cascade. Using in vivo models of metastasis, we found that neutrophils promote cancer cell adhesion within liver sinusoids and, thereby, influence metastasis. Neutrophil depletion before cancer cell inoculation resulted in a decreased number of gross metastases in an intrasplenic model of liver metastasis. This effect was reversed when inflamed neutrophils were inoculated with cancer cells.

In addition, early adhesion within liver sinusoids was inhibited in the absence of neutrophils and partially restored with a short perfusion of isolated activated neutrophils. Intravital microscopy showed

that cancer cells adhered directly on top of arrested neutrophils, indicating that neutrophils may act as a bridge to facilitate interactions between cancer cells and the liver parenchyma. The adhesion of lipopolysaccharide-activated neutrophils to cancer cells was mediated by neutrophil Mac-1/ICAM-1. Our findings, therefore, show a novel role for neutrophils in the early adhesive steps of liver metastasis.â&#x20AC;?

Surgical Decision Making and Informing Patients The article â&#x20AC;&#x153;Development and Validation of a Novel Stratification Tool for Identifying Cancer Patients at Increased Risk of Surgical Site Infection,â&#x20AC;? by Anaya et al describes a prospective cohort study of 503 patients undergoing elective operations at a tertiary cancer center ((Ann Surgg 2012;255:134-139) to assess postoperative surgical site infections (SSIs). The authors used multivariate logistic regression analyses to identify predictors of SSI from which they created a scoring system called Risk of Surgical Site Infection in Cancer (RSSIC). SSI incidence after 30 days was 24%. Significant predictors of SSI included preoperative chemotherapy (OR, 1.94; 95% CI, 1.16-3.25), cleancontaminated wounds (OR, 2.1; 95% CI, 1.24-3.55), operative time more than two hours (OR, 1.75; 95% CI, 1.01-3.04) and equal to four hours (OR, 2.24; 95% CI, 1.22-4.1). The authors also determined predictors according to surgical site, including the groin (OR, 4.65; 95% CI, 1.69-12.83) and head/neck (OR, 0.12; 95% CI, 0.02-0.89). The authors concluded: â&#x20AC;&#x153;SSIs are common following cancer surgery. Preoperative chemotherapy, in addition to other common risk factors, was identified as a significant predictor for SSI in cancer patients. The RSSIC [scoring system] improves risk stratification of cancer patients and identifies those that may benefit from more aggressive or

novel preventive strategies.â&#x20AC;?

This report from the Annals of Surgery noted a 30-day SSI rate of 24%. Even if the wound infection rate is 5%, the life span of those patients may be compromised. And survival is shortened more than any benefit from chemotherapy or radiation. With regard to simultaneous breast surgery and reconstruction, surgeons must inform their patients about the risk for infection and the resulting chance of decreased long-term survival.

Delayed reconstruction is more reasonable in patients at high risk for postoperative infection. If the chance of a wound infection in a high-risk patient were 25%, which might decrease long-term survival by 25%, would you advise using expanders at the same time as mastectomy? What percent risk for infection would you accept and still insert expanders? Now do you see the elephant?

As far as colon surgery, surgeons should inform patients of the risk for infectious complications and the consequences. The first step is to get surgeons on board just as they have accepted the risk for transfusion in colon cancer surgery. If surgeons accept the notion that postoperative infection reduces survival, then certain algorithms in surgery should be modified.

Sometimes a surgeon does a low-anterior resection and considers adding a loop ileostomy, because he or she is not â&#x20AC;&#x153;sureâ&#x20AC;? about the anastomosis. If the survival of that patient is reduced because of a leak, the decision for a loop ileostomy should be easier.

Perhaps earlier recognition of infection will promote earlier treatment and higher long-term survival. In the future, modulators of the immune response will also help treat infectious processes. The evidence that postoperative infectious complications decrease survival in cancer surgery patients is compelling, and should resonate with all physicians caring for these patients. Will patients realize that if they have an infection, their life span will be shortened? Should that be part of informed consent? These are uncomfortable questions for us, but they will be addressed, especially because some of us will deal with these questions on a personal level. Hopefully this article will help alert surgeons that there is an elephant in the operating room. â&#x20AC;&#x201D; â&#x20AC;&#x201D;Dr. Goldfarb is program director, Department of Surgery, Monmouth Medical Center, Long Branch, New Jersey.

He is an advisory board member for General Surgery News.

khorty@mcmahonmed.com.

In the News

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

Study Stresses Need for Assessing Family Cancer History B Y B EN G UARINO

A

s many as one in 10 new cancer diagnoses are attributable to genetically inherited disease, according to the American Society of Clinical Oncology, and documenting family history of cancer can have a large effect on screening and preventive decisions. In a study published in the Journal of Clinical Oncology, investigators who reviewed medical records of patients with breast or colorectal cancer found that 79.8% included the cancer history of first-degree relatives, however, only 64.6% of records documented cancer history of second-degree relatives.

Clinicians should be pleased with the rate at which the cancer history of firstdegree relatives was documented, said Noralane Lindor, MD, a medical geneticist at Mayo Clinic in Scottsdale, Ariz., who was not involved with this research.

“This is a dramatic change from 10 to 15 years ago,” she said.

“These rates are higher than we thought we’d find, but there is room for improvement,” said Marie Wood, MD, co-author of the study and the director of the familial cancer program in the Hematology/Oncology Division at the University of Vermont in Burlington.

Analyzing the records of 10,466 patients diagnosed with breast or colorectal cancer, representing more than 200 cancer centers, the authors were able to determine the rate at which family history of cancer was recorded ((J Clin Oncoll 2014;32:824829). For patients with breast cancer as well as those with colorectal cancer, fewer than half of medical records documented the age of relatives at diagnosis.

“Providers do a good job of documenting first-degree family history,” Dr. Wood said, but are not as completely recording second-degree family history and are “not great” at reporting age. Age at cancer diagnosis is important, she said, as it can indicate hereditary cancer syndromes if diagnosis was made at early an age.

The rate at which providers recorded the history of first-degree relatives was significantly higher for patients with breast cancer than for those with colorectal cancer (81.2% vs. 77.4%, respectively; P<0.001); similarly, the records for patients with breast cancer also included history of second-degree relatives at a higher frequency (68.9% vs. 57.3%, respectively; P<0.001).

The difference in rates of family history between colorectal and breast cancer “reflects the knowledge gap between the two diseases,” Dr. Lindor said.

Patients tend to be more forthcoming about breast cancer than colorectal cancer, said Kevin Hughes, MD, the co-director

of Avon Comprehensive Breast Evaluation Center and a surgeon at Massachusetts General Hospital in Boston, who helped conduct the study. The difference may stem in part from a cultural taboo surrounding the discussion of colorectal problems, he said. “People don’t talk about their colons, usually, at the dinner table.”

The study also evaluated the rates at which doctors referred patients to receive genetic counseling or testing. For patients with breast cancer, 29.1% were referred,

“People don’t talk about their colons, usually, at the dinner table.”

—Kevin Hughes, MD

whereas of patients with colorectal cancer, 19.6% were referred for genetic counseling or testing (P<0.001).

But looking solely at the rates of referral for genetic tests may be deceptive. “It’s the right percentage of the practice,” Dr. Hughes said, “but not the right patients.”

Of the patients who met the criteria for referral, only 52.2% of those with breast cancer were referred for genetic testing or counseling, and 26.4% of individuals with colorectal cancer were referred.

“This paper highlights that we are missing candidates for genetic testing,” Dr. Wood said.

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Letters to the Editor A Medical Scribe?

To the Editor: [Re: â&#x20AC;&#x153;Do You Need a Medical Scribe?â&#x20AC;?

March, page 3] I agree with the reasons outlined

by Dr. Greene as to why the electronic health record (EHR) has taken away from the patientâ&#x20AC;&#x201C;physician relationship.

I have refused to work on a computer while with a patient unless I need to show them a film or in some other way interact with both the patient and EHR. The bond and trust we must build with patients and their families to treat complex diseases and perform surgery can only be gained by looking the patient and their families in the eye as you speak to them. Therefore, by necessity I complete most of my charting at night and on weekends. It is simply a fact of life in â&#x20AC;&#x153;modernâ&#x20AC;? medicine. There is no question that this detracts from my family life and quality time. These are the choices we all make. I have read about medical scribes for a while. It is clear that EHRs are no more efficient, faster, safer or even generate less paper than the old charting methods. Having said that, I embrace the access it gives us, the documentation, drawing, graphing and other information capabilities of the EHR. What Dr. Greene does not address is who should pay for a medical scribe and how they should be paid for. You cannot bill for them. Whether in a small practice or as part of a larger medical conglomerate, in most cases, the cost will

GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

come out of yourr pocket. You can argue the scribe may increase your efficiency enough to cover the added costs, but this remains to be seen. It is clear that this is the result of another unfunded mandate of medicine. Unlike other industries, we cannot pass this cost of doing business to any of our payers.

For now, I will continue to look my patients in the eye and leave the paper work (computer work) for later.

Michael S Bouton, MD, MA, FACS Fargo N.D.

The initial reason we started using scribes was because of the numerous EMR [electronic medical record] systems (yes, we have several and all are different) limiting the amount of time per patient and subsequently the number of patients seen per day. The singular downside was the initial time it took to train the corpsman up (not long because of their prior training and experience in corps school and in theater, respectively), and, of course, the surgeonsâ&#x20AC;&#x2122; desire to main-

tain the EMR albatross around our necks. No, thatâ&#x20AC;&#x2122;s not true. I made that last part up.

Eric E. Liedtke, MD Department Head, General Surgery Naval Hospital Lemoore Station, CA

Smoking Cessation Before Surgery

To the Editor: [Re: â&#x20AC;&#x153;Withhold Surgical Treatment for Smoking,â&#x20AC;? March 2014, page 4] Withholding elective surgical treatment is sometimes not only necessary but is in the patientâ&#x20AC;&#x2122;s best interest. Consider, as an example, a patient who Opinion Understand has vascular claudication, Omentum Su ing rg For Alzheim ery Explored does not exercise and is a Surg ical Pa er â&#x20AC;&#x2122;s Disease tients Show Hig her practicing tobacco addict.

Mor talit y Fr Hospital H om B ar ms This patient does not need elective surgery, although R the indication, â&#x20AC;&#x153;lifestylelimiting claudicationâ&#x20AC;? may be acceptable. If we, as physicians, commit to educating Study Prov our patients about the effects Bariatric D ides Snapshot of Rec en emog raph ics, Outco t of tobacco and the necessimes ty of progressive ambulation, D REPORT instead of rushing the patient off to the cath lab/operating room, the results may be 12 18 surprising. The key phrase is â&#x20AC;&#x153;elective operation.â&#x20AC;? We are not talking about the patient with resting ischemia who will

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To the Editor: In the Surgery Department of Naval Hospital in Lemoore Station, Calif., we have been using surgical scribes for nearly two years. Initially, the concept seemed only to displace work from the surgeon to a corpsman. However, it has been well received for many reasons. Rather than only taking vital signs and checking patients into the clinic, the corpsman have become fully engaged in patient care, which has empowered them and promoted esprit de corps. Surgical providers quickly realized we were mentoring our corpsman with each patient encounter as they were able to better comprehend patient preINSIDE sentations, pathology and treatment 6 decisions. This further fostered their interest in health care, and many are on track to become nurses and doctors, some with specific interest in surgery.

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GENERALSURGERYNEWS.COM / GENERAL SURGERY NEWS / MAY 2014

almost certainly lose a limb if not revascularized; those patients need treatment urgently if not emergently.

Natural history: 93% of patients with claudication will never need intervention if they are able to stop smoking.

If intervention is offered “electively” and the patient does not stop smoking, the effects of the intervention will be short-lived and the failure rate high.

If the patient stops smoking for good, guess what? It is a win–win situation for the patient and the medical system as a whole. Most patients who engage in a progressive ambulation program, stop smoking and generally change their habits and lifestyle away from cigarette centric, will never need intervention.

These patients are able to progressively attain the ability to walk two to three miles without painful claudication, as their bodies, including the arterial tree, undergo internal modification (collateralization of flow, better oxygen capacity, etc.). By successfully converting these patients to nonsmoking people with healthy attitudes, we not only treat the patient long-term without the risk for complications related to intervention, but we also save our health care system millions of dollars annually in unnecessary treatments.

I agree with Dr. Teitel, that we should never “… punish and harm individual patients by withholding surgical care …”, but I think that he takes the patient who smokes out of context and misplaces ideas of politics with doing the right thing for the patient.

Dr. Greene in no way suggested that we flush these patients down the drain because we don’t like smokers; he merely said what has been said before, that not everyone requires surgery immediately. The patient with claudication is better served by withholding “elective surgery.” It is greed that causes the physician to treat claudicants with surgery before attempting conservative measures. Recurrent ischemia, forces further intervention, producing a cycle of ischemia, treatment, failure, ischemia. This cycle is not good for the patient.

Primum non nocere.

Rick D. Pittman, MD Salem, Ore.

Surgeons and Substance Abuse To the Editor: [Re: Laparoscopic Techniques for Hernia Repair: A History of Ups and Downs, March 2014, page 6] Although the historical component of this article was interesting, I am disappointed with the inclusion of a quote from Dr. Ponsky equating the excitement of the emergence of laparoscopy with cocaine use. This analogy is not amusing and trivializes the profoundly negative effects of substance abuse on

our patients and society. Furthermore, with alcohol and substance abuse within our own ranks as surgeons, associating cocaine with innovative techniques and ideas is not appropriate in your general surgical newspaper. Please consider examining your article review process.

Robert Noll, MD, FACS Sacramento, Calif.

Financial Disclosures To the Editor: I read with interest the “On the Spot With Colleen Hutchinson” column featuring surgical robotics in the March

2104 issue (page 18). Question: where are the author disclosures? Given the controversial and divisive nature of this evolving topic, and the fact that industry (and one dominant surgical robotics company in particular) is keenly interested in the outcome, a statement of relevant financial relationships for each author needs to be on the first page of the article. Disclosing author conflicts of interest provides the reader with necessary context to the authors’ statements.

Mark A. Carlson, MD Omaha, Neb.

Editor’s Reply: Thank you to Dr. Carlson for pointing out this oversight. Here are the participant disclosures for the article “Surgical Robotics: On the Spot With Colleen Hutchinson”: Yuman Fong, MD: None reported.

Daniel Jones, MD: None reported.

Omar Kudsi, MD: Proctor for Intuitive Surgical Martin Makary, MD: None reported.

Frank Rosato, MD: None reported.

Noel Williams, MD: None reported.

BRIEF SUMMARY ®

ENTEREG (alvimopan) Capsules 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 [see Warnings and Precautions (5.1)]. ] 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 [see Warnings and Precautions (5.1) and (5.2)]. ] 1

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.

4 CONTRAINDICATIONS ENTEREG is contraindicated in patients who have taken therapeutic doses of opioids for more than 7 consecutive days immediately prior to taking ENTEREG [see Warnings and Precautions (5.3)].

5 WARNINGS AND PRECAUTIONS 5.1 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 [see Warnings and Precautions (5.2)].

5.2 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 [see Warnings and Precautions (5.1)].

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.

5.3 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. 5.4 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.

5.5 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.

5.6 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.

5.7 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.

6 ADVERSE REACTIONS 6.1 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.

7 DRUG INTERACTIONS 7.1 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.

7.2 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.

7.3

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.

7.4 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.

8 USE IN SPECIFIC POPULATIONS 8.1 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.

8.3 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 [see Clinical Pharmacology (12.3)].

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 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 [see Clinical Pharmacology (12.3)].

8.6 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 [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].]

8.7 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 [see Clinical Pharmacology (12.3)].

8.8 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 [see Clinical Pharmacology (12.3)].

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: g Two-year carcinogenicity studies were conducted with alvimopan in CD-1 mice at oral doses up to 4000 mg/kg/day and in Sprague-Dawley rats at oral doses up to 500 mg/kg/day. Oral administration of alvimopan for 104 weeks produced significant increases in the incidences of fibroma, fibrosarcoma, and sarcoma in the skin/subcutis, and of osteoma/osteosarcoma in bones of female mice at 4000 mg/kg/day (about 674 times the recommended human dose based on body surface area). In rats, oral administration of alvimopan for 104 weeks did not produce any tumor up to 500 mg/kg/day (about 166 times the recommended human dose based on body surface area).

Mutagenesis: g Alvimopan was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/−) forward mutation test, the Chinese Hamster Ovary (CHO) cell chromosome aberration test, or the mouse micronucleus test. The pharmacologically active ‘metabolite’ ADL 08-0011 was negative in the Ames test, chromosome aberration test in CHO cells, and mouse micronucleus test.

Impairment p of Fertility: y Alvimopan 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) was found to have no adverse effect on fertility and reproductive performance of male or female rats.

17 PATIENT COUNSELING INFORMATION 17.1 Recent Use of Opioids Patients should be informed that they must disclose long-term or intermittent opioid pain therapy, including any use of opioids in the week prior to receiving ENTEREG. They should understand that recent use of opioids may make them more susceptible to adverse reactions to ENTEREG, primarily those limited to the gastrointestinal tract (e.g., abdominal pain, nausea and vomiting, diarrhea).

17.2 Hospital Use Only ENTEREG is available only through a program called the ENTEREG Access Support and Education (E.A.S.E.) Program under a REMS that restricts use to enrolled hospitals because of the potential risk of myocardial infarction with long-term use of ENTEREG. Patients should be informed that ENTEREG is for hospital use only for no more than 7 days after their bowel resection surgery.

17.3 Most Common Side Effect Patients should be informed that the most common side effect with ENTEREG in patients undergoing surgeries that include bowel resection is dyspepsia.

ENTEREG and E.A.S.E. are registered trademarks of Adolor Corporation, a wholly owned subsidiary of Cubist Pharmaceuticals, Inc. Any other trademarks are property of their respective owners.

Manufactured for: Cubist Pharmaceuticals, Inc. Lexington, MA 02421 USA October 2013

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MAY 2014 MAY 2014 Brought g to You by y

REPORT Improving Precision and Accuracy in Laparoscopy Using the ENDOEYE FLEX 3D Articulating Videoscope T

he inception of laparoscopy marked a significant turning point in patient care. The transition from open procedures to a minimally invasive approach to surgery resulted in numerous benefits including minimal pain, less need for narcotic analgesics, fewer complications (eg, hernia and infection), less blood loss, shorter (and consequently less expensive) hospital stays, and

a faster recovery and return to normal daily activities.1-3 The indications for laparoscopic surgery quickly expanded to increasingly complex proceduresâ&#x20AC;&#x201D;gastrointestinal, gynecologic, and urologicâ&#x20AC;&#x201D;and more complicated patient populations.1,4,5 Although the integration of laparoscopy improved clinical outcomes and reduced costs, it offered limited

Faculty Ronald Clements, MD

Rami Lutfi, MD, FACS

Marc Singer, MD

Chief of Bariatric Surgery Professor of Surgery Vanderbilt University Medical Center Nashville, Tennessee

Chairman of Surgery Mercy Hospital and Medical Center Clinical Assistant Professor of Sugery University of Illinois at Chicago Chicago, Illinois

Colon/Rectal Surgeon Clinical Assistant Professor NorthShore University HealthSystem Evanston, Illinois

Brett Cohen, MD, FACS

Marcos Michelotti, MD

Todd Wilson, MD

Medical Director Memorial Health System for Advanced Laparoscopic and Bariatric Surgical Program Memorial Regional Hospital Hollywood, Florida

Assistant Professor of Surgery Loma Linda University School of Medicine Loma Linda, California

Assistant Professor of Surgery University of Texas Health Science Center Houston, Texas

Supported by

REPORT visualization and articulation—key elements of open surgery.

Mobility and dexterity associated with direct visualization in a 3-dimensional (3D) field were compromised.1 Surgeons found it necessary to adjust to the loss of depth perception inherent to operating in a 2-dimensional (2D) field and deferring to a video screen when operating on patients.1 The shift to laparoscopy required a new set of skills and more specialized training; consequently, this entailed a prolonged learning curve that increased the risk for complications.6-8 With the development of 3D laparoscopic systems, the benefit of depth perception was restored and the advances made through laparoscopy were recognized. However, widespread use of 3D was hindered by a lack of image brightness, inadequate image quality, and excessive fatigue and discomfort caused by the heavy active-shutter 3D glasses.9,10 Although robotic surgery restored high-quality 3D imaging and surgical dexterity, its adoption as a standard approach remained problematic particularly because of its size and associated expense.1,6,8 More importantly, clinical support on the practicality of robotic surgery remained preliminary.9,11 With the recent FDA clearance of the ENDOEYE FLEX 3D, the world’s first and only high-definition (HD), 3D articulating videoscope—surgeons are now able to operate with restored depth perception. The system’s articulating design allows surgeons to obtain critical views at ideal angles without sacrificing a level visual horizon (Figures 1 and 2). Additionally, its modular design enables surgeons to easily switch between 2D and 3D visualization. Preliminary research and clinical experience suggest that by enhancing visualization and precision, the ENDOEYE FLEX 3D system facilitates faster and more precise execution of laparoscopic

procedures, while shortening the learning curve for surgical tasks (Figure 3).12,13 Furthermore, integrating the EVIS EXERA III Universal Imaging System, with the ENDOEYE FLEX 3D videoscope into the surgical suite can improve efficiency through the standardization of surgical equipment, training, and service and biomed support.

This monograph discusses the benefits of integrating the ENDOEYE FLEX 3D system to improve efficiency and precision in laparoscopic procedures, level the learning curve, and potentially consolidate surgical technology through a universal platform.

Minimally Invasive Surgery With Limited Depth Perception With the advent of laparoscopy, surgeons are able to perform a variety of procedures through small incisions using trocars, rather than through foot-long incisions. Unlike with open surgery, laparoscopic surgeons use auxiliary visual cues to determine depth and where to position surgical instrumentation while referring to a 2D video monitor.7 “Laparoscopy has given surgeons the ability to perform through tiny incisions almost every surgery that once required a large incision,” said Brett Cohen, MD, medical director of the Memorial Healthcare System for Advance Laparoscopic and Bariatric Surgical Program. Laparoscopy has resulted in better outcomes, shorter hospital stays, and faster recovery times, while containing costs.1-3 In fact, laparoscopy became the gold standard for cholecystectomy even before evidence from prospective randomized controlled trials showed its superiority over open cholecystectomy.14,15

Figure 1. The ENDOEYE FLEX 3D Articulating Videoscope offers 100-degree angulation that can provide critical views and a level visual horizon.

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REPORT Although the approach is less invasive, the reduced depth perception inherent with laparoscopy poses a significant challenge for surgeons.16 Rather than visualizing the peritoneal cavity directly, laparoscopy incorporates the use of a 2D monitor. “In laparoscopy, you have to be a little farther from the area you’re operating on. The caveat is, the farther away you go, when you put the laparoscope in you’re looking at quite a distance and you get a very flat view,” explained Dr. Cohen. “Classic TV screens are 2D. We’re working on a 3D object within the body and a 3D procedure, but we lose our depth of field and have to get used to working in 2 dimensions,” Dr. Cohen said. “It has a lot to do with the feedback that comes through the instruments, and the eye adjusting to working with that depth of field.”

Challenges inherent to evaluating 3D structures in 2D increase the risk for complications related to a surgeon’s skill and experience. This includes risk for complications associated with pneumoperitoneum (eg, decreased cardiac output) and with the procedure itself.14 As the standard approach to cholecystectomy, laparoscopy was associated with an

increase in biliary injury, including misidentification of the bile duct and delayed stricture; whereas laparoscopic antireflux surgery led to lower wound, cardiac, and pulmonary complications, the most common intraoperative complications included perforations of neighboring anatomy, and pneumothorax; in laparoscopic inguinal hernia repair, intraoperative complications included injuries to the bladder, the epigastric vessels, and spermatic cord; and ureteric injury occurred in laparoscopic colectomy.14,17 For surgeons experienced in open surgery, laparoscopy involves a paradigm shift that requires an additional set of operative skills, with a prolonged learning curve, to handle surgical instrumentation while referring to a video monitor to judge positioning and depth.7 Recently, a study investigating the effect of 3D visualization on surgical skill and task performance in 3 different types of surgical approaches emphasized the importance of depth perception.18 The researchers assigned 34 surgeons with varying laparoscopic experience—about half were novices—to perform tasks testing their skills assessing spatial relationships, grasping and positioning, precision, dexterity, and hand–eye/hand– hand coordination, in both 3D and 2D.18 The results showed that the loss of 3D imaging and depth perception had a significant effect on the surgeons’ perception of the difficulty of a task, as well as on the time it took to perform it. Simpler tasks required 25% to 30% more time to execute, whereas complex tasks took as much as 75% longer to perform.18 The researchers concluded that the more complicated a task was, the greater the effect of 3D visualization on accelerating that task.18 Studies evaluating the learning curve for laparoscopy indicate that the rate of intraoperative complications appears to diminish with surgeon experience. In a 1995 study of the laparoscopic learning curve, 90% of bile duct injuries in laparoscopic cholecystectomy occurred within a surgeon’s first 30 cases,15 whereas a later study showed that the learning curve for laparoscopic inguinal hernia repair was about 50 cases.19 Training in laparoscopic techniques plays a crucial role in surgeons’ ability to master 2D visualization. Recent innovations recognize the benefit of minimally invasive techniques, as well as the efficiency and safety associated with 3D imaging. “In my opinion, being able to see structures and planes between organs easily and suture more accurately, adds value to the surgeon, and the value will translate to safe and more efficient moves,” said Rami Lutfi, MD, chairman of surgery at Chicago Mercy Hospital and Medical Center.

Integrating 3D Surgical Technology

Figure 2. The ENDOEYE FLEX 3D Articulating Videoscope provides depth perception using a 3D monitor (simulated 3D image shown).

3D visualization offers a number of benefits: enhanced depth perception yielding more precise spatial views of anatomy; faster and more accurate completion of tasks such as grasping, suturing, and dissecting; and an accelerated learning curve for the acquisition of surgical skills.7 “For me, better depth perception means better structure recognition, better plane recognition, and facilitates certain maneuvers, such as knot tying,” said Marc Singer, MD,

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REPORT a colon and rectal surgeon and clinical assistant professor at NorthShore University HealthSystem. 3D also may help in operations where access is challenging. “Any time we’re working at a great distance from the camera, such as deep in the pelvis, we experience some visual paradoxes that make conventional laparoscopy difficult. In colon and rectal surgery, there are parts of the operation, such as identifying the ureter, where I feel 3D really makes a difference,” Dr. Singer said.

Other 3D surgical technology generally comprises a rigid telescope and a camera head with right- and left-eye sensors; images are fed to the respective right and left sensors.

When all components are in alignment, the result is restored depth perception, but this is contingent on stability. If the surgeon, seeking a different angle of view, rotates only the telescope, the images fall out of alignment with the sensors and the 3D screen image is lost. The surgeon can compensate for this by rotating both the camera and telescope to view a point from a different angle, but this causes the images on the screen to rotate as well. To maintain orientation, the surgeon has to rotate his or her head, which can throw off equilibrium and create dizziness.20 Additionally, earlier 3D video

systems required surgeons to operate wearing bulky glasses—a potential inconvenience.21 With the introduction of robotic surgery, surgeons were equipped with the technology to tackle these shortcomings.

The da Vinci Surgical System (Intuitive Surgical) offers a number of advantages over conventional laparoscopy, including improved ergonomics and reduced tremor interference.8 Additionally, the da Vinci uses the EndoWrist technology, which offers 7 degrees of freedom and 90 degrees of articulation, while restoring dexterity and interpreting the surgeons’ hand motions with great precision and refinement.6,8,16,22 The most useful feature of robotic surgery, however, is the restoration of stereoscopic 3D vision through the use of a doublechanneled camera integrated in the surgical console.6 This allows surgeons to regain control over visualization and operate with more precision.

One study showed that surgeons using the 3D mode display on the da Vinci Surgical System completed suturing 65% faster than those who used the 2D mode.16 Additionally, the 3D mode resulted in enhanced speed and accuracy, particularly in knot-tying ability.16 As early as 2001, researchers showed that telemanipulator performance was enhanced by

Figure 3. The ENDOEYE FLEX 3D showed improved speed, accuracy, and precision for surgical tasks while helping to shorten the learning curve, based on testing using a simulated surgical model.

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REPORT the availability of 3D-National Television Standard Committee despite the surgeons’ familiarity with 2D systems and the fact that the 2D systems operated at an equal or better resolution than the 3D system. 23 Although the da Vinci system integrates 3D visualization, it may not be an ideal approach for some clinicians given the associated costs (initial cost: $1.7 million) and the need for additional staffing and training.6,8 Robotic surgery reinforces the importance of 3D visualization, and has provided a stepping-stone toward further advances in restoring surgical control to improve accuracy and precision.

ENDOEYE FLEX 3D: Enhanced Visualization and Articulation With the availability of the ENDOEYE FLEX 3D laparoscope, surgeons have an effective tool that applies 3D visualization and 100 degrees of articulation to maximize spatial

orientation. Using lightweight 3D glasses—a clip-on option is available for surgeons who already wear glasses—surgeons are equipped with a system that restores natural 3D that is transmitted through an HD 3D monitor. “The [ENDOEYE] system we’re using here is much more subtle and refined and you have a little more ability to manipulate it with the flexible technology,” Dr. Wilson said.

High-Definition Imaging The ENDOEYE FLEX 3D system uses a dual-lens system with distally located image sensors in which the right and left images are captured by separate lenses and processed by 2 CV-190 video processors that are integrated by the Olympus 3DV-190 to produce brighter, more light-sensitive images (Figure 4). The dual-lens, distal tip design increases the angle between left and right lenses, enhancing the perception of depth. The ENDOEYE FLEX 3D restores 3D visualization and provides greater depth perception and spatial view

Figure 4. The ENDOEYE FLEX 3D produces left and right image signals that are sent to left and right images processors and then integrated by the 3DV-190 3D Visualization Unit.

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REPORT edge of a plane and trying to see clearly what is happening at of anatomy compared with the rigid laparoscope. The qualthe edge farthest away. “But [with ENDOEYE], you start at the ity of depth perception is contingent on the angle between far edge of the plane and have your view go right over the top of the object and each eye. Some systems use a single-lens the object and look down on it. This truly mimics open surgery,” pupil system, in which a single image is split by a prism and he said. “With this system, you can do everything with one delivered to 2 sensors, which decreases the angle. The hand—one knob allows you to look left, right, up, down. You ENDOEYE FLEX 3D videoscope’s depth of field ranges from can lock it in place. You don’t have to use 2 hands to manipu18 to 100 mm, eliminating the need for manual focus adjustlate it, so the design is really quite ingenious.” ment. “The dimensionality is very impressive,” noted Ronald Marcos Michelotti, MD, assistant professor of surgery at Clements, MD, chief of bariatric surgery and a professor of Loma Linda University School of Medicine, recognizes that surgery at Vanderbilt University Medical Center. the articulating design enables surgeons Dr. Cohen has been using the ENDOto have more control in maneuvering withEYE FLEX 3D since Pembroke Memoriin the peritoneal cavity. “[The design’s] al Hospital became the first in the United ‘I think articulation is very flexibility makes procedures significantly States to adopt Olympus’s fully integrated less cumbersome, and makes the cam3D system in late 2013. “This 3D equipimportant for procedures era job a lot easier to accomplish,” he ment has given us back [the 3D] dimenwhere you need to look explained. sion,” he said. “With this dynamic 3D into deeper and curved Because the system is capable of recvisualization, the view is exceptional. It reating the same critical view as a stanmagnifies and clarifies the image incrediareas, like with hiatal hernia dard 2D 30-degree telescope, surgeons bly. The first time I used it, I told the [techrepair, when you need to can manage image integrity and orientanician] who operates our system, ‘this is tion when shifting to view an object from the biggest advent in laparoscopy since look around the spleen and a different angle. “The articulating scope the laparoscope.’” around the liver, and when can be used straight or angled, and it Using 3D visualization, surgeons have you need to dissect anagives you perspectives you just cannot more control of the instruments when get with a rigid laparoscope. It allows you handling layers of tissue, and can pertomical structures close to to look down on tissue as we do with open form challenging tasks, such as disseceach other.’ surgery, and to look under structures and tion, grasping, and suturing, faster and 12 around corners,” said Dr. Singer. with enhanced accuracy and precision.

—Marcos Michelotti, MD For very straightforward cases, such Recent data using a simulated surgical as appendectomy, a straight laparomodel indicated that surgeons were able to scope may be sufficient, but for more grasp 25% faster and with 80% fewer errors dynamic and complex procedures, such as colectomy, Dr. using 3D imaging. Results also showed that surgeons could disSinger believes the articulating laparoscope facilitates tremensect tissue 10% faster and suture 35% faster.12 “The goal in the dous perspective. “I think an articulating laparoscope should OR [operating room] is not to get through a system as quickly become the standard,” he said. “Rigid laparoscopy limits suras possible, but as safely as possible. That said, being able to geons and the perspective, while the articulating scope realsee the operation more clearly allows you to do things faster,” ly offers more flexibility because it can be used as a straight Dr. Cohen said. “For example, if you’re doing a gallbladder scope or an angled scope.” operation, you need to differentiate the main duct of the gall“Articulation adds value anytime you need to see over, bladder from the main duct of the liver. If you can see strucaround, or behind something,” Dr. Clements said. “It helps me tures with crystal clarity, magnified 10 to 15 times, it’s a lot in hiatal hernia repairs to get up into the mediastinum and be easier and safer.” out of the way of my instruments by having the camera above Unlimited Articulation the plane of where the instruments are looking down on it.” Dr. Michelotti agreed: “I think articulation is very important for proDespite the availability of other 3D laparoscopes before the cedures where you need to look into deeper and curved areas, ENDOEYE FLEX 3D, lack of articulation may have been one like with hiatal hernia repair, when you need to look around the of the drawbacks to them becoming standard in laparoscopy. spleen and around the liver, and when you need to dissect anaUnlike the conventional laparoscope, the ENDOEYE FLEX tomical structures close to each other.”

3D allows surgeons to view the entire peritoneal cavity by Dr. Cohen finds the articulating laparoscope especially benangulating in 4 directions—up, down, right, and left—up to eficial in certain types of procedures, and in certain types of 100 degrees and providing critical views of anatomy with a level patients. “In a Nissen fundoplication, part of the operation visual horizon. “Olympus put the camera at the very tip of the includes freeing up the esophagus as it cuts through the diarod, with a junction about 2 or 3 cm from the tip that allows it to phragm muscle into the belly, so we dissect high up in the articulate 100 degrees in every direction. You can look down, mediastinum above the diaphragm. Being able to have the up, left, right, go to a structure and look around the corner, or scope closer to the belly button and still use the articulating tip look right down on it,” Dr. Cohen said. to look all around the esophagus and in the mediastinum with Dr. Cohen likened this phenomenon to standing on one

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REPORT a clear, unobstructed view—we’ve never been able to do that before,” he said.

The articulating laparoscope also is helpful in procedures on obese patients. “Bariatric patients have a lot of fatty tissue.

Being able to bring the scope all the way up to the angle of His of the stomach and then flex the scope down to look at where the stomach attaches to the diaphragm—that’s something else we haven’t been able to do. Being able to look around the corner is new, and very advantageous,” Dr. Cohen said.

Alternating Dimensions and Advanced Visualization In cases where 2D would be preferable (eg, when accessing the abdominal cavity under direct vision through a trocar), the ENDOEYE FLEX 3D system’s visualization mode can be easily switched from 3D. Dr. Lutfi has found this feature useful when accessing the layers of the abdominal wall.

“I can put a straight zero-degree scope straight down through the abdominal,” he said. I go in through the optiview and go down through the abdominal wall layers under direct vision of the straight zero-degree scope almost touching the tissue— that’s 2D. Once I get inside the abdominal cavity and insufflate with gas, I switch to 3D.” Similarly, Dr. Clements has switched from 2D to 3D when inserting the visual entry trocar during bariatric surgery. “A short focal length, a centimeter or less, will require you to switch to 2D,” he said.

The system also includes narrow band imaging (NBI) technology, to enhance the visualization of vascular structures, such as capillaries, veins, and arteries, during laparoscopic and endoscopic procedures (Figure 5). Dr. Cohen finds this feature useful in distinguishing one tissue from another in Nissen fundoplications for reflux. “In this surgery, you have to wrap part of the stomach around the junction of the esophagus and

the stomach, and it has to be in a very specific spot—the GE [gastroesophageal] junction. In order to differentiate esophageal tissue from stomach tissue,” he said, “we use the NBI wavelength because it helps us identify the line very easily.”

Clinical Implications A number of advanced laparoscopic surgeons are reporting that, in their experience, the ENDOEYE system has shown a number of benefits specific to particular laparoscopic surgeries, as demonstrated by a series of in-house research studies conducted by a number of advanced laparoscopic surgeons.

In bariatric procedures, surgeons evaluated the positive benefits of the deflectable videoscope, the universal platform, and reported positive benefits including the restoration of depth perception. They found that the bird’s-eye view made it easier to check the angle of His, create the gastric pouch, identify the ligament of Treiz, and create the gastrojejunal anastomosis.23 Physicians also reported that the universal platform afforded the advantage of allowing them to check for bleeding and/or leaks on the staple line from the inside and that the restoration of depth perception added value in terms of dissection while creating the gastric pouch, particularly for the ability to view the back of the stomach.24 Additionally, suturing was eased by 3D visualization.24 In sigmoidectomy, surgeons found the deflectable tip gave them a potentially safer view for dissecting the mesenterium; in contrast working with conventional equipment in such a small area, the camera and energy device are close together, which often results in fogging of the camera’s tip.25 Observing structures in 3D also helped surgeons define the dissection plane, making dissection easier and faster.25 During the lateral dissection portion of the procedure, the articulating tip allowed

Figure 5. NBI enhances visualization of vascular structures including the capillaries.

NBI, narrow band imaging

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REPORT working in 3D when we’re doing fine dissection and intracorsurgeons to view critical structures from the optimal angle, poreal suturing, and when we’re working in deep cavities— even for the splenic flexure, which can be difficult to visualize such as the pelvis for a low anterior resection or the hiatus in using a rigid laparoscope. In theory, this could reduce the risk obesity surgery,” Dr. Lutfi said. “In cases such as large parafor splenic injury. As with mesenteric dissection, 3D visualizaesophageal hernia repair, depth perception is critical for fine tion made it easier to define the dissection plane for greater dissection up in the chest and suturing next to nearby critical precision and safety.25 structures; you want to see clearly where your scissor is cutWith rectal mobilization, the angulation allowed surgeons to ting and your needle is landing.” observe the sigmoid and rectum from multiple angles, enhancing the safety and precision of dissection, whereas 3D visualizaLeveling the Learning Curve tion allowed for a better view of the typically difficult-to-access 25 pelvic floor. The ENDOEYE system also made it easier to insert Surgery today is a far different specialty with more chalthe anvil into the circular stapler, thus assisting anastomosis.25 lenging patient populations and complex procedures; thus, training plays a crucial role in ensuring the optimization In hysterectomy, the ability to view structures from a variety of patient care. With innovation comes the need for skills of angles was tremendously beneficial. The articulating design assessment and opportunity to hone in on nuances and helped surgeons evaluate adhesions from the back and sides variations that accompany new instrumentation and techto make sure they steered clear of the bowel while taking 26 nique. Ideally, training should require a the adhesions down. When ligating utershort learning curve. With laparoscopy, ine arteries, being able to obtain an opti‘You definitely notice the however, studies have shown that there is mal front view made it easier to ensure difference right away, but a prolonged learning curve for surgeons the energy source was in the right place, to familiarize themselves with the minimalreducing the risk for bleeding. In colpotoit doesn’t feel unusual, and ly invasive 2D approach. 28 my, the articulating design gave surgeons there really is no learning a 360-degree view to avoid damaging surIn 2013, Mattar et al conducted a multicurve. It is as if you were rounding organs with the bipolar hook used domain global assessment of general surto separate the vagina from the uterus.26 gery graduate trainees entering accredited walking around with one surgical subspecialty specialties in North The utility of 3D visualization was eye closed, and suddenly America to investigate their level of readequally apparent in identifying the anatoyou open it. You don’t have iness by surveying their program direcmy (eg, preserving the uterine artery and tors. The survey included 46 quantitative ureter during dissection of the layer of to adjust to that.’ questions distributed across 5 domains broad ligament from the uterine cer—Brett Cohen, MD, FACS and at least 1 reflective qualitative quesvix). It also facilitated the division of the tion or domain. An analysis of laparoscopic adnexa of uterus and ligament, helpskills showed that nearly 33% of the training surgeons identify the surgical ees could not perform a laparoscopic cholecystectomy. Addiplane and ascertain how deep they are in the anatomy. 26 tionally, 26% were unable to recognize anatomical planes, Furthermore, 3D visualization greatly assisted in suturing, 30% were unable to manipulate tissue without causing trauhelping surgeons to see which way the needle is pointing.26 ma, and 56% were unable to suture. 29 In prostatectomy, the ENDOFLEX system made it easier to identify the plane between the urethra and dorsal vein For most surgeons, particularly residents, the challenge is complex, which could reduce risk for injury to the latter.27 It being able to translate 2D visualization into tangible imaging to carry out the different surgical processes—dissecting, graspalso appeared to make it easier to dissect prostatic pedicles 27 ing, and suturing. “It sounds crazy, but with laparoscopic surwhile preserving the neurovascular bundle. The system also gery we spend years teaching ourselves how to interpret a helped surgeons to suture as precisely as needed to create 2D image and convert that into 3D,” said Dr. Wilson, who is in the urethro-vesical anastomosis. 27 charge of laparoscopic and minimally invasive skills training for The perception of depth lends itself to any type of laparohis institution’s residency program. “I do a lot of research on scopic procedure. “You can gain benefit from 3D in any operthis very thing: How do we teach laparoscopic surgery to resation,” Dr. Clements said. “I find that even in something as idents?” he continued. “Of course, it depends on the individcommon as a laparoscopic cholecystectomy you gain beneual. In our current practices it takes every bit of a physician’s fits because you can see the triangle of Calot better than you surgical training, which is what they’ve already done through can see it in 2D.” Similarly, Dr. Cohen added, “Just because medical school, then 5 years of general surgery training. The a procedure is common doesn’t mean it’s simple. [3D] really majority of residents don’t feel comfortable with advanced helps you in a gallbladder operation, where you can’t always cases without doing a fellowship in minimally invasive suridentify the duct or the artery—this gives you a better view gery, and part of it is because of that [interpretation of the 2D than you’ve ever had before.” image],” he said. “[With the ENDOEYE system] you don’t have Some surgeons feel that the greatest value of 3D will be to learn to convert the image, so it’s inherent that that should seen in the most complicated types of procedures, making it translate into greater precision, greater speed, and should ultieasier to carry out some of the more demanding tasks of lapmately help us do a job we want to do better.” aroscopic surgery. “I think we will get the most benefit from

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REPORT Surgeons have found the adjustment to 3D requires minimal time. “You definitely notice the difference right away, but it doesn’t feel unusual, and there really is no learning curve,” Dr. Singer said. “It is as if you were walking around with one eye closed, and suddenly you open it. You don’t have to adjust to that,” Dr. Cohen added.

Dr. Clements found the adjustment was fairly instantaneous. “It was so easy, so intuitive. I wear safety glasses in the OR anyway, so instead of the safety glasses I just put on my polarizing glasses and that was it.” Dr. Lutfi agreed with his colleagues but acknowledged some initial frustration associated with the novelty of the laparoscopy. “I have seen a few surgeons get a little frustrated with the change in the way they look at things, but most [clinicians] are very impressed and are immediately able to adjust to it,” he said.

Dr. Michelotti suggested that surgeons using the ENDOEYE system position the monitor close for the best effect.

“The closer you have the monitor, the more of your visual field it occupies. With 3D, I think it’s crucial to have the monitor as close as possible so that you can appreciate the 3D depth perception in most of your visual field,” he said. Additionally, Dr. Michelotti observed that the images move much faster than they do with a standard laparoscope. “It takes a little time to get used to the controls of the camera,” he said. “You need to make sure you don’t overcompensate.”

Because the articulating laparoscope involves transitioning from the angled scope to the use of the flexible tip, less experienced surgeons may initially struggle with the ENDOEYE system. “I do a lot of single-incision surgery with a flexible-tip laparoscope, so I’m already familiar with [this

Figure 6. The ENDOEYE FLEX 3D is part of a universal platform to standardize equipment in the surgery suite.

It can be added to the Olympus EVIS EXERA III Universal Imaging System, which supports more than 100 different endoscopes.

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REPORT Standardizing Surgical Technology feature],” Dr. Lufti said. “Some of my residents struggle even with the 30-degree scope because they’re not used to it, as few of To Reduce Costs our faculty surgeons never made the switch to the angled scope.

Going from the angled scope to the flexible tip is a natural evoAs health care continues to focus on the need to contain lution but also a cultural change, and some people feel that it’s costs while optimizing patient care, opportunities to consolicumbersome. Once you adjust, however, it becomes comfortdate technology are essential. Because the ENDOEYE FLEX able. Residents in fact struggle going back to 2D laparoscopy 3D can be added to the Olympus EVIS EXERA III Universal after leaving their laparoscopic rotation with me.”

Imaging System, surgery suites are able to standardize equipDespite their established proficiency with standard 2D lapment, thus reducing the need for excess equipment in the aroscopy, experienced surgeons also may benefit from the confined space (Figure 6). Additionally, the ENDOEYE FLEX greater ease that 3D affords. Studies conducted in recent years 3D is part of a universal platform that supports more than 100 evaluating the effect of 3D laparoscopy on surgeons at various different endoscopes. “That is a huge advantage of this syslevels of experience—from medical students to advanced surtem. Olympus, as far as I am aware, is the only system that geons—using simulated surgical models found that most genallows you to plug all of your devices into one main compoerally performed faster and safer when they nent,” Dr. Cohen said. “If I was using [a were able to visualize tasks with restored competing system’s] laparoscope and I 7 depth perception. One study including wanted to use an endoscope at the same ‘3D helps us appreciate time, I would need a separate tower made both students and advanced surgeons depth, suture more accuby another company. With the ENDOfound that the use of a 3D system resulted EYE system and Olympus equipment, in fewer mistakes and faster execution of rately, see structures easily all I need to do is either unplug my lapatasks for all participants, and that the surand see the planes between roscope or plug the endoscope into the geons specifically saved time carrying out 30 same imaging tower and have both imagmore difficult tasks. organs better. That depth es up at the same time.” This approach Recently, Dr. Singer and his colleagues perception will translate into a reduces the capital investment, associconducted a formal study with a simulated safer and more efficient proated with asset management, its maintesurgical model comparing the performance nance, and training. of 12 residents as well as 12 attending surcedure, which is why people geons in their timing on a variety of tasks will eventually adopt it.’

Conclusion such as bead transfer, suturing, and tying.13 “[The 3D system] improved the time to Similar to how HD replaced standard —Rami Lutfi, MD, FACS complete each one of those tasks. So we definition, and 3-chip cameras replaced feel it has the potential to facilitate not just 1-chip cameras, the ENDOEYE FLEX training tasks, but also clinical use,” he 3D has the potential to become the gold said. “We have yet to show that, but in our lab we were realstandard for laparoscopy. As an articulating laparoscope with ly impressed with the impact of 3D on everyone for completing 3D visualization, the ENDOEYE FLEX 3D restores the ability very specific tasks that rely on very specific movements.” to access peritoneal cavity directly while adhering to a miniWhen it came to grasping, surgeons were able to complete mally invasive approach. the task 25% faster and with 80% fewer errors using 3D rather Dr. Lutfi believes that safety and efficiency will play a role than 2D technology. The pace of suturing, dissecting, and eyein reinforcing the importance of 3D laparoscopy and which letting were accelerated by 35%, 10%, and 15%, respectivesystem is integrated as the standard. “3D helps us apprecily, with the restoration of depth perception. In less-experienced ate depth, suture more accurately, see structures easily and surgeons, 3D technology significantly improved the learning see the planes between organs better,” he said. “That depth curve for both grasping and peg transfer.13 perception will translate into a safer and more efficient procedure, which is why people will eventually adopt it.” Patients, If ENDOEYE FLEX 3D proves to speed procedures and saves too, might be interested to know that that their surgeons are time in the OR, this will have many implications for cost savings using more advanced equipment that helps them do their job and safety. In the hands of experienced laparoscopic surgeons better, even if [patients] don’t completely understand how it who honed their craft before HD and 3D options were available, works. “Patients come to us for robotic surgery without realthe time savings may be negligible. But it may be tremendously knowing what the robot is or what advantages it provides,” ly useful in helping new surgeons tackle the laparoscopic learnDr. Lutfi said. “But I think being able to tell the patient we have ing curve. something that improves minimally invasive surgery and gives “I don’t think using the ENDOEYE would have much impact us better visualization and more accuracy will certainly help us for someone who has done thousands of cases and [has] overmarket the practice.” come the limitations of 2D laparoscopy,” Dr. Clements said. “But The preliminary data and experiences of those who have used it has really had an impact on the residents and first assistants the ENDOEYE FLEX 3D system using a surgical model suggest who help me do the cases. It cuts down on the delay of them it restores depth perception and enhances anatomical visualaccomplishing a task like picking up a suture, which they can ization; adds speed and precision to grasping, suturing, and do much faster in 3D.”

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REPORT dissecting; and levels the learning curve for surgeons-in-training as well as more experienced surgeons.

Those theories are being put to the test. “We need to keep an open mind and evaluate this technology thoroughly— and not make fast decisions about whether or not to adopt it,” Dr. Lutfi said. He and his team are currently assembling

a randomized controlled trial to evaluate speed, efficiency, errors of performance, suture handling, and soft tissue dissection in residents and in mid-expertise attending surgeons comparing 2D and 3D. “This will help us really answer those questions with certainty so that we have data to back up our decisions,” he said.

References 1. Ramirez PT, Soliman PT, Schmeler KM, dos Reis R, Frumovitz M. Laparoscopic and robotic techniques for radical hysterectomy in patients with early-stage cervical cancer. Gynecol Oncol.

110(suppl 2):S21-S24.

2. Randall J, Lord B, Fulham J, Soin B. Parastomal hernias as the predominant stoma complication after laparoscopic colorectal surgery. Surg Laparosc Endosc Percutan Tech. 2012;22(5):420-423.

3. Shabanzadeh DM, Sorensen LT. Laparoscopic surgery compared with open surgery decreases surgical site infection in obese patients. Ann Surg. 2012;256(6):934-945.

4. Kennedy GD, Heise C, Rajamanickam V, Harms B, Foley EF. Laparoscopy decreases postoperative complication rates after abdominal colectomy: results from the national surgical quality improvement program. Ann Surg. 2009;249(4):596-601.

5. Baumert H, Ballaro A, Dugardin F, Kaisary AV. Laparoscopic versus open simple prostatectomy: a comparative study. J Urol.

2006;175(5):1691-1694.

6. Sohn W, Lee HJ, Ahlering TE. Robotic surgery: review of prostate and bladder cancer. Cancer J. 2013;19(2):133-139.

7. Tanagho YS, Andriole GL, Paradis AG, et al. 2D versus 3D visualization: impact on laparoscopic proficiency using the fundamentals of laparoscopic surgery skill set. J Laparosendosc Adv Surg Tech A. 2012;22(9):865-870.

2001. http://www.ncbi.nlm.nih.gov/books/NBK6923/. Accessed March 24, 2014.

15. Moore MJ, Bennett CL. The learning curve for laparoscopic cholecystectomy. The Southern Surgeons Club. Am J Surg 1995;170(1):55-59.

16. Badani KK, Bhandari A, Tewari A, Menon M. Comparison of twodimensional and three-dimensional suturing; is there a difference in a robotic surgery setting? J Endouroll 2005;19(10):1212-1215.

17. Neri V, Ambrosi A, Di Lauro G, Fersini A, Valentino TP. Difficult cholecystectomies: validity of the laparoscopic approach. JSLS. 2003;7(4):329-333.

18. Wagner OJ, Hagen M, Kurmann A, Horgan S, Candinas D, Vorburger SA. Three-dimensional vision enhances task performance independently of the surgical method. Surg Endosc.

2012;26(10):2961-2968.

19. Voitk AJ. The learning curve in laparoscopic inguinal hernia repair for the community general surgeon. Can J Surg 1998;41(6): 446-450.

20. Kong SH, Oh BM, Yoon H, et al. Comparison of two- and threedimensional camera systems in laparoscopic performance: a novel 3D system with one camera. Surg Endosc. 2010;24(5):1132-1143.

21. Buchs NC, Morel P. Three-dimensional laparoscopy: a new tool in the surgeon’s armamentarium. Surg Technol Int. 2013;23:19-22.

8. Sinha R, Sundaram M, Raje S, Rao G, Sinha M, Sinha R. 3D laparoscopy: technique and initial experience in 451 cases. Gynecol Surg. 2013;10:123-128.

22. Shafer A, Boggess JF. Robotic-assisted endometrial cancer staging and radical hysterectomy with the da Vinci surgical system.

Gynecol Oncol. 2008;111(2 suppl):S18-S23.

9. Izquierdo L, et al. 3D advances in laparoscopic vision. Eur Urol Rev. 2012;7(2):137-139.

23. Falk V, Mintz D, Grunenfelder J, Fann JI, Brudon TA. Influence of three-dimensional vision on surgical telemanipulator performance.

Surg Endosc. 2001;15(11):1282-1288.

10. Yamauchi Y, Shinohara K. Effect of binocular stereopsis on surgical manipulation performance and fatigue when using a stereoscopic endoscope. Stud Health Technol Inform. 2005;111:611-614.

11. Yim GW, Kim YT. Robotic surgery in gynecologic cancer. Curr Opin Obstet Gynecol. 2012;24(1):14-23.

12. Olympus. Data on File; 2013.

13. Singer M, Endres J, Yetasook A, et al. Evaluation of 3-D laparoscopy to complete surgical skills task. Presented at: the 2013 Annual Meeting of the Society of American Gastrointestinal Endoscopic Surgeons (SAGES); April 17-20, 2013; Baltimore, MD. Poster P520.

14. Perugini RA, Callery MP. Complications of laparoscopic surgery.

In: Holzheimer RG, Mannick JA, editors. Surgical treatment: evidence-based and problem-oriented. Munich: Zuckschwerdt;

24. Bariatric procedures. Olympus. Data on File; 2013.

25. Left colectomy (sigmoidectomy).Olympus. Data on File; 2013.

26. Laparoscopic hysterectomy. Olympus. Data on File; 2013.

27. Prostatectomy. Olympus. Data on File; 2013.

28. McLachlan G. From 2D to 3D: the future of surgery? Lancet.

2011;378(9800):1368.

29. Mattar SG, Alseidi AA, Jones DB, et al. General surgery residency inadequately prepares trainees for fellowship: results of a survey of fellowship program directors. Ann Surg. 2013;258(3):440-449.

30. Storz P, Buess GF, Kunert W, Kirschniak A. 3D HD versus 2D HD: surgical task efficiency in standardized phantom tasks.

Surg Endosc. 2012;26(5):1454-1460.

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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, OLYMPUS, 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.

Copyright Š 2014, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

12

SR1316

DIslcosures: Drs. Clements, Cohen, and Michelotti reported no relevant financial disclosures. Dr. Lutfi reported that he is a consultant for Allergan, Inc, Ethicon Endo-Surgery, and Gore. Dr. Singer reported that he is a consultant for OLYMPUS and is on the speakersâ&#x20AC;&#x2122; bureau for Cubist Pharmaceuticals.

Dr. Wilson reported that he is a consultant for OLYMPUS and has received honoraria from Bard.

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MAY MAY 2014 2014

INTERNATIONAL EDITION

REPORT Clinical Advancements Using The ENSEAL® G2 Articulating Tissue Sealer D

espite the advances associated with laparoscopic surgery (eg, reduced blood loss and pain and a shorter hospital length of stay), its integration into practice continues to present challenges for surgeons performing general, colorectal, and gynecologic procedures.1-3 In particular, compromised access and visualization, as well as reduced tactile feedback with instrumentation, jeopardize the surgeon’s ability to seal vessels securely without potential risk for internal bleeding or damage to other tissues.3 Traditional vessel-sealing methods rely solely on compression through sutures, staples, and clips to maintain hemostasis.

Energy-based sealing devices were developed specifically to use heat and compression to provide a secure seal while decreasing the risk for bleeding.4 Of the available options, bipolar energy devices enable the current to only pass through tissue located between the instrument’s electrodes thus providing a high degree of precision in execution while minimizing the risk for damaging neighboring tissue4; however, some of these devices have proven to yield more adequate compression force and offer more control in delivering energy to the tissue.

The ENSEAL L® portfolio, marketed by ETHICON was developed to provide surgeons with bipolar energy-based

Faculty Ira Stanley Frye, MD Mclaren Medical Group Obstetrics and Gynecology McLaren Health Care Flint, Michigan Associate Professor Michigan State University College of Human Medicine East Lansing, Michigan Temple University School of Medicine Philadelphia, Pennsylvania

Alan M. Gillespie, MD, FRCOG Consultant Gynaecological Surgeon and Gynaecological Oncologist Sheffield Teaching Hospital National Health Service Foundation Trust Sheffield, United Kingdom

Guido Jutten, MD

Matthew F. Kalady, MD

Chief of Surgery Department of General Abdominal and Oncological Surgery AZ Klina Brasschaat, Belgium

Associate Professor of Surgery Department of Colorectal Surgery Cleveland Clinic Cleveland, Ohio

Supported by

REPORT vessel-sealing devices that provide reliable hemostasis while reducing the risk for thermal spread and vessel damage.5 Additionally, the ENSEAL L® devices are multifunctional and can be used to grasp, cut, dissect, spot coagulate, and to create an otomy. Since receiving FDA clearance in 2003, the ENSEAL L® product line has evolved to include a portfolio of dynamic devices, each with modifications based on surgeons’ feedback.

As the most recent addition to the ENSEAL® family, the ENSEAL L® G2 Articulating Tissue Sealer is the first advanced energy device that allows surgeons to use a perpendicular approach to vessel sealing when operating in challenging anatomy, which improves access and visualization, facilitates greater control during the procedure, and reduces the risk for internal bleeding and postoperative complications.

ENSEAL® Vessel-Sealing Technology ENSEAL L® devices were developed to provide surgeons bipolar energy-based instruments that can seal vessels up to 7 mm in diameter, as well as lymphatics. With proprietary features such as the I-BLADE® (a unique cutting mechanism that delivers uniform compression across the length of the jaw), Positive-Temperature Coefficient technology, and the offset electrode configuration, the ENSEAL L® system ensures reliable vessel sealing while minimizing thermal spread.6 The ENSEAL L® also allows surgeons to use different shaft lengths and jaw configurations (ie, straight and curved) based on procedure needs.7 The ENSEAL L® G2 platform expands the ENSEAL L® portfolio to include devices that further enhance the sealing experience through improved ergonomics, tactile feedback, and safety.7 The latest addition, the ENSEAL L® G2 Articulating Tissue Sealer, encompasses the ® ENSEAL L features while offering a flexible tool that allows for a perpendicular approach to vessel sealing. Having this ability improves visualization and access to targeted tissues, ensuring a strong seal that could reduce the risk for bleeding during gynecologic, colorectal, and general surgery procedures (Figure 1). ®

ENSEAL G2 Articulating Tissue Sealer As part of the ENSEAL L® portfolio, the G2 articulating device features both the I-Blade® and the Positive Temperature Coefficient to ensure uniform compression, reduce thermal spread, and minimize sticking. Compression begins once the I-Blade® advances to the tissue, delivered uniformly along the length of the jaw.8 “I can actually see the I-Blade® as it slides forward. Consequently, I know exactly where I am in the cutting process, and I can stop halfway through the procedure if I want because I know how far the device has traveled. This is not possible with [other energysealing] devices,” explained Ira Stanley Frye, MD, associate professor at Michigan State University College of Human Medicine and Temple University School of Medicine. To achieve superior vessel sealing with minimal thermal spread, the Positive-Temperature Coefficient technology regulates the temperature as it reaches 100°C and controls the flow of electric current.8 “This is actually one of the great advantages of the [ENSEAL L®] devices,” said Alan M. Gillespie, MD, FRCOG, consultant gynaecological surgeon and gynaecological oncologist at Sheffield Teaching Hospital. “When the tissue reaches 100°C, carbon fibers within the jaw of the device deactivate it to stop thermal transmission. Consequently, the opportunity for damage to nearby organs and surrounding tissue is greatly reduced. Also, the temperature at which the device functions is low compared with [other energy-sealing devices]. This is a feature that gives surgeons confidence that they are less likely to cause inadvertent thermal tissue damage.”

2

With the ENSEAL® G2 Articulating Tissue Sealer, surgeons are equipped with the latest vessel-sealing device possessing the latest advancements toward optimal vessel sealing.

The ENSEAL® G2 Articulating Tissue Sealer allows surgeons to take a perpendicular approach to sealing vessels up to 7 mm in diameter using 5-mm ports by means of 110 degrees of articulation with full 360-degree shaft rotation.5 Its articulating design facilitates access to tissues in deep or tight anatomical spaces and maneuvering around corners of organs and behind structures, resulting in greater control and stronger sealing.5 The ability of the ENSEAL L® G2 Tissue Sealer to articulate and thereby work around a curve is just one of several features that distinguish it from other surgical technologies (Figure 2). “The articulating feature allows me to reach around organs or follow their contours while dissecting, as with a bulky uterus,” Dr. Frye said. “Additionally, I can perform more difficult surgeries, perform more through a single incision, and even remove larger masses.” By giving surgeons more control in visualizing and accessing the anatomy, the G2 Tissue Sealing Device maintains hemostasis and minimizes the risk for complications. “This device provides consistent and reliable hemostasis. But it is its capacity to create a seal at a perpendicular angle to ensure that blood flow is completely interrupted what I find really innovative,” Dr. Gillespie said. “It really results in a significant reduction in the potential for bleeding.”

Because the ENSEAL L® G2 Articulating Tissue Sealer also provides tactile feedback, surgeons are able to assess the placement of the instrument with confidence. “The G2 device provides feedback similar to what I experience when I actually have an instrument in my hand. The articulation point is pliable, yet rigid, and that actually adds to the instrument’s safety. With this device, I can actually feel the tissue,” Dr. Frye explained. “It has a little ‘play’ so if I were to push in a bit too hard on the uterus with the tip, the potential for back bleeding is reduced and yet I’m still far away from the ureters because of the articulation.”

Benefits of a Perpendicular Approach To Vessel Sealing In laparoscopic procedures—general, colorectal, and gynecologic—the perpendicular approach to vessel sealing can play a significant role in reducing the amount of tissue manipulation needed to access a targeted area. In a recent white paper evaluating retroperitoneal tissue dissection and hemostasis, the authors concluded that applying a perpendicular approach to coagulation could improve visualization of the anatomy and provide strong vessel sealing with greater precision.9 Using the ENSEAL L® G2 Articulating Tissue Sealer, the perpendicular approach to vessel sealing is more than 28% stronger than vessels sealed at a 45-degree angle.5,10 “Laboratory studies have shown that a perpendicular seal as opposed to a seal

Figure 1. The ENSEAL® G2 Articulating Tissue Sealer.

REPORT made by an oblique angle is much stronger,” said Matthew Kalady, MD, an associate professor of surgery at the Cleveland Clinic. “When tissue is crossed at an oblique angle, the distance required to seal the vessel is also greater and requires more firings of the device.”

Efficient Operating Time The perpendicular approach has proven to be advantageous in optimizing vessel sealing. Using the ENSEAL® G2 Articulating Tissue Sealer has resulted in faster operating times.

“A perpendicular approach takes less time because less tissue is crossed and less tissue manipulation is needed,” Dr. Kalady explained. Additionally, a strong seal can help minimize the risk for postoperative complications. “A strong seal means better hemostasis, reducing the potential for bleeding and its associated complications,” said Guido Jutten, chief of surgery, Department of General Abdominal and Oncological Surgery at AZ Klina. “Using the G2 Articulating Tissue Sealer during colorectal and gastrointestinal procedures, I can transect soft tissue at a perpendicular angle in almost any situation that might arise, get a good seal in a short amount of time, minimize instrument exchanges, and reduce the overall procedure time.”

Additionally, because it is a multifunctional device, the ENSEAL® G2 Articulating Tissue Sealer, which cuts, dissects, and seals, eliminates multiple steps and the need for additional instruments. “I try to use the instrument as both a dissector and a vessel sealer so that I don’t have to do many instrument exchanges, which makes the process more efficient,” Dr. Kalady said.

Minimizing Incisions With optimal access during surgery, the ENSEAL L® G2 Articulating Tissue Sealer can reduce the need for additional ports. “Some of the greatest challenges in bowel surgery involve mobilizing the colon, in particular the hepatic and splenic flexures,” Dr. Kalady explained. “Because many instruments are unable to reach the targeted space or reach it without using extreme torque or angles, additional ports may be required to get the right angle to access that area. This new device actually allows me to articulate the instrument so that I can essentially work around a curve without having to adjust my position.”

In gynecologic procedures, such as hysterectomies, the ENSEAL L® G2 Articulating Tissue Sealer can have a significant affect in consolidating the number of incisions. “Hysterectomies performed using robotic laparoscopic technologies require five incisions,” Dr. Frye said. “Traditional laparoscopic hysterectomies

A

use three, one at the belly button, and one in each lower quadrant.

The ENSEAL L® G2 Articulating Tissue Sealer allows me to articulate the device up to 110 degrees. I can change the angle and bend the device and it still works properly. The end result is that instead of using several incisions throughout the abdomen, the procedure can be performed through one, hidden right in the belly button. The curve lets me reach around as though I were coming in from the side, thereby simplifying the procedure greatly. Needless to say, the patient is greatly pleased with the cosmetic outcome.”

The use of fewer ports also may help reduce costs. “Ports are expensive. The fewer ports used, the greater the cost savings,” Dr. Gillespie explained.

Improving Patient Recovery and Containing Costs The integration of the ENSEAL L® G2 Articulating Tissue Sealer adheres to the principles of minimally invasive surgery with safer procedures and faster recovery as well as containing costs. With more control over the procedure, surgeons can optimize outcomes with precision and accuracy while minimizing the number of incisions as well as the risk for complications. Dr. Frye was the first surgeon in the United States to perform a single-incision hysterectomy and bilateral salpingo-oophorectomy using the ENSEAL L® G2 articulating device. His patient underwent the procedure and was discharged within 24 hours without any complications. “The device is amazing,” Dr. Frye said. “The way I can articulate it with just movements of my thumb, I think, is revolutionary. This is a game changer.”

Using the perpendicular approach with the ENSEAL L® G2 Articulating Tissue Sealer may help contain health care costs associated with bleeding and other complications. “One of the most expensive aspects of surgery is managing complications. If a patient suffers internal bleeding, that patient will require transfusions, which can be dangerous as well as costly,” Dr. Jutten said. “A perpendicular approach to vessel sealing minimizes the chances of entrapping any extraneous tissue, which in turn reduces the potential for bowel damage,” he noted. “The end result is that the potential for bacterial infection is reduced, avoiding a serious complication.”

Operating Ergonomically In laparoscopic surgery, the lack of direct visualization and maneuvering of tissue using ports can be taxing on surgeons performing challenging procedures with limited access.3 “Surgeons are extremely vulnerable to back strain while performing surgical procedures,” Dr. Gillespie said. With the ENSEAL L® G2 Articulating Tissue Sealer, surgeons are equipped with an ergonomically flexible

B

Figure 2. (A) The ENSEAL® G2 Articulating Tissue Sealer seals and transects perpendicularly across the vessel. (B) The ENSEAL® G2 Articulating Tissue Sealer reaches around the anatomy, allowing for sealing at a perpendicular angle.

3

REPORT

device that articulates to optimize access and control during the procedure. “The way the handle fits the hand is impressive,” Dr. Frye noted. “Also, there are two rotating toggles on the device, one of which allows me to rotate the jaw 360 degrees; the other lets me articulate it 110 degrees. Combined, they let me access [areas] in the abdomen that are much harder to get to with other devices.”

The articulation itself makes the device easier to operate and it doesn’t require changing angles outside the body. “With the ENSEAL L® G2 Articulating Tissue Sealer, I don’t have to change angles from the outside of the body or the way that I’m holding the instrument because with the articulation I can change the instrument on the inside to hit the right turns and corners,” said Dr. Kalady. “It allows me to approach my target from a different angle, which results in a little less torque on the port, a little less torque on the instrument, and makes the procedure more comfortable for me.”

Additionally, Dr. Gillespie feels that this device can help to avoid awkward or uncomfortable positions in order to achieve an optimal approach. “This device helps maintain a better ergonomic position.

The result is less back strain and anything that reduces back strain is of benefit,” he said.

that the instrument moves the way it’s intended to move. So, there is a slight learning curve to using the instrument for the articulating feature,” he noted.

Shortening the Learning Curve

Conclusion

The idea of adopting a new device particularly for laparoscopic procedures can be daunting given the limited visualization and access to the anatomy. With the ENSEAL L® G2 Articulating Tissue Sealer, surgeons are able to apply previous training on the ENSEAL L® system; however, the articulating design might require some time for the surgeon to adjust to the device’s ability to rotate within the body while using fewer incisions. “The learning curve is not at all steep,” said Dr. Frye. “I just required a few cases in order to get used to the device.” Dr. Kalady has been using the device for the past few months. “As far as the learning curve goes, the general principles of using the ENSEAL L® instruments apply. In terms of vessel sealing, the difference is that it does take a little bit of time to get used to the articulation wheel and learn how to turn it so

For surgeons performing difficult laparoscopic procedures, the ability to have direct access with optimal visualization is critical.

As seen with earlier ENSEAL L® devices, the ENSEAL® G2 Articulating Tissue Sealer continues to feature essential elements of its signature technology—strong seal with minimal thermal spread— but provides further modifications, giving surgeons even more control when cutting, dissecting, and sealing tissue (Figure 3).

“Articulation is an add-on to an already high-quality product with important safety features. It simply adds further to its potential for greater use,“ Dr. Kalady said. These new developments will further enhance the vessel sealing experience for surgeons, providing an effective instrument with low risk for bleeding and postoperative complications.

References

6. Person B, Vivas DA, Ruiz D, et al. Surg Endosc. 2008;22(2):534-538.

4

7. Ethicon Endo-Surgery. ENSEAL G2 Tissue Sealer (Curved/Straight) Product Fact Sheet. http://www.ees.com/node/43144. Accessed March 24, 2014.

8. Ethicon Endo-Surgery. Energy Devices Portfolio. http://www.ees.com/ sites/default/files/generalsurgery_EES_Energy_Devices_Portfolio.pdf.

Accessed March 24, 2014.

10. Data on File. ENSEAL® devices tested in a benchtop study on 5-7mm porcine carotid arteries.

Disclosures: Dr. Frye reported no relevant financial disclosures. Dr. Gillespie reported that he is a consultant for and is on the speakers’ bureau of Ethicon Endo-Surgery. Dr. Jutten reported that he is a consultant for Ethicon Endo-Surgery. Dr. Kalady reported that he is a consultant for, is on the speakers’ bureau of, and has received honoraria from Precision Therapeutics.

Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Ethicon Endo-Surgery, 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.

Copyright © 2014, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

010507-140219

9. Brill AI, Stamos, MJ. http://www.ethicon.com/sites/default/files/ enseal-articulating-perpendicular-sealing-white-paper-13-1129.pdf.

Accessed March 24, 2014.

SR141

1. Ramirez PT, Soliman PT, Schmeler KM, et al. Gynecol Oncol.

2008;110(3 suppl 2):S21-S24.

2. Campagnacci R, de Sanctis A, Baldarelli M, et al. Surg Endosc.

2007;21(9):1526-1531.

3. Park A, Lee G, Seagull FJ, et al. J Am Coll Surg. 2010;210(3): 306-213.

4. Lorenzo ND, Franceschilli L, Allaix ME, et al. Surg Endosc. 2012; 26(10):2917-2924.

5. ENSEAL G2 Articulating Tissue Sealer. http://www.ethicon.com/ healthcare-professionals/products/advanced-energy/enseal/ensealg2-articulating. Accessed March 24, 2014.

Figure 3. The ENSEAL® G2 Articulating Tissue Sealer builds on the ENSEAL® platform but offers more versatility in cutting, dissecting, and sealing tissue.

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REPORT The Role of Multimodal Analgesia In General Surgery A Review of Clinical Data and Case-Based Presentations Featuring OFIRMEV V速 (acetaminophen) Injection Faculty Anthony Gonzalez, MD

Sonia Ramamoorthy, MD, FACS, FASCRS

Chief of Surgery Baptist Hospital of Miami Medical Director, Bariatric Surgery South Miami Hospital Assistant Professor of Surgery Florida International University College of Medicine Miami, Florida

Associate Professor of Surgery Chief, Section of Colon and Rectal Surgery Rebecca and John Moores Cancer Center University of California, San Diego Health System San Diego, California

Indication OFIRMEV V速 (acetaminophen) Injection is indicated for the management of mild to moderate pain; the management of moderate to severe pain with adjunctive opioid analgesics; and the reduction of fever.

Important Safety Information WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY Take care when prescribing, preparing, and administering OFIRMEV injection to avoid dosing errors which could result in accidental overdose and death.

OFIRMEV contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the recommended maximum daily limits, and often involve more than one acetaminophen-containing product.

Please see accompanying full Prescribing Information, including complete Boxed Warning.

To report SUSPECTED ADVERSE REACTIONS, contact Cadence Pharmaceuticals, Inc. at 1-877-647-2239 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Funded by

REPORT Introduction Effective pain management is a nationwide priority for health care organizations, practitioners, and policymakers. Over the past 2 decades, the suboptimal treatment of acute pain has become an important issue in health care, specifically in the postoperative setting.1,2 For example, The Joint Commission instituted pain management standards for the assessment and management of acute pain in 2001.3 The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey, also known as the CAHPS®, is the first national, standardized, publicly reported survey of patients’ perspectives on hospital care. Included in the HCAHPS survey are questions regarding pain management. The scores are available to the public and allow patients to compare hospitals in a meaningful manner.4 Patient satisfaction is an increasingly important outcome when considering perioperative analgesic regimens.

Unmet Need in Pain Management

Acetaminophen Concentration, mcg/mL

Despite the increased focus on pain management and the availability of effective analgesics and new mechanisms for delivering pain medications in the immediate postoperative period over the past 2 decades, the incidence of postoperative pain remains high. In a 2012 survey, approximately 85% of patients reported postoperative pain; of those, 65% reported moderate to extreme pain.5 These data are similar to those from a survey conducted in 1995 (65% vs 63% of patients reported moderate to extreme postoperative pain, respectively).1,5 Postoperative pain is associated with various complications and poor outcomes. Postoperative pain also is one of the most

Mean Plasma Acetaminophen Concentrations

25

20

IV acetaminophen 1,000 mg (n=6 ) Oral acetaminophen 1,000 mg (n=6) Rectal acetaminophen 1,000 mg (n=6)

15

10

5

0 0

2

4

Time, h

Figure 1. Acetaminophen plasma concentration over time.

Pharmacokinetic study. Efficacy was not assessed.

Based on reference 15.

2

6

common reasons for hospital readmission following discharge.6 Traditionally as well as currently in the US, monotherapy with opioids is used as the mainstay to treat postoperative pain. In a 2012 study analyzing data from 1,665,418 hospital patients, 72% of inpatients treated with IV pain medication received IV narcotic monotherapy.7 A 2012 retrospective analysis evaluated the odds of experiencing prespecified opioid-related adverse events (AEs). The use of opioid analgesia led to an increased risk for AEs, particularly gastrointestinal (GI) related (constipation and emesis).8 More severe AEs associated with opioid use include respiratory depression and sedation, both of which can put patients at risk for respiratory failure.9 These factors make pain management challenging in postoperative patients. In 2012, The Joint Commission published a Sentinel Event Alert that underscored the need for judicious and safe use of opioids in hospitals. Included in The Joint Commission’s recommendations were measures aimed at reducing the overall use of opioids, such as implementing a multimodal approach to perioperative analgesia.9

Multimodal Approach to Pain Management Acute postoperative pain is complex and multifactorial and may be optimally treated via a multimodal approach in the perioperative setting. With this approach, 2 or more analgesics acting by different mechanisms are administered when providing analgesia.10 Using different classes of analgesics, each with different pathways and receptors, multimodal analgesia can optimize analgesic efficacy by using lower doses of each of the respective agents, with the aim to reduce the risk for dose-related AEs.11 Multimodal analgesia may be implemented via a stepwise approach with non-opioids serving as the foundational agents given perioperatively for the management of pain with adjunctive opioids added as needed for moderate to severe pain.10,11 Over the past decade, multimodal analgesia has gained recognition as an effective strategy for the management of acute pain in the perioperative setting, and the concept is supported by numerous professional organizations. The American Society of Anesthesiologists (ASA),10 the American Society for Pain Management Nursing (ASPMN),12 the Agency for Healthcare Research and Quality (AHRQ),13 and The Joint Commission9 encourage a multimodal approach to perioperative analgesia.

Current ASA guidelines recommend that unless contraindicated, all surgical patients should receive an around-the-clock regimen of a nonopioid agent, such as acetaminophen, nonsteroidal anti-inflammatory drug (NSAID), or cyclooxygenase-2 selective NSAID (COXIB).

OFIRMEV® (acetaminophen) Injection Product Description Acetaminophen is a non-salicylate, non-NSAID, non-opioid analgesic and antipyretic agent. The precise mechanism(s) of the analgesic and antipyretic properties of acetaminophen is not established, but is thought to primarily involve central actions.14 OFIRMEV is the first and only IV formulation of acetaminophen available in the United States. OFIRMEV is indicated for

REPORT the management of mild to moderate pain, the management of moderate to severe pain with adjunctive opioid analgesics, and the reduction of fever. OFIRMEV is approved for use in patients at least 2 years of age.14

IV acetaminophen 1,000 mg (n=6) Oral acetaminophen 1,000 mg (n=6) Rectal acetaminophen 1,000 mg (n=6)

Clinical Pharmacology of OFIRMEV

4

3

2 Acetaminophen AUC0-6 (SD) ­ V}ÊUÊ /mL) IV: 24.9 (17.4) vs PO: 14.2 (52.1); P<0.0001 vs PR: 10.3 (24.6); P<0.0001

1

0 0

2

Time, h

4

6

Figure 2. Mean (SD) CSF acetaminophen concentration-time curves after IV, PO, and PR administration of 1,000 mg.

Pharmacokinetic study. Efficacy was not assessed.

AUC, area under the curve; CSF, cerebrospinal fluid; PO, oral; PR, rectal; SD, standard deviation Based on reference 15.

Op

Contributing Factors

ids o i

ised Gastric Fun ctio prom n Com Significant delay in gastric emptying

Su r

S

t

he

t re

es

Subsequent intestinal absorption of nutrients/ medication inhibited

ss

Pyloric narrowing or closure

An

Surgery, opioids, anesthesia, preoperative fasting, and postoperative stress can all work together in the period immediately following surgery to produce gastroparesis and delayed gastric emptying (Figure 3). These factors are important when choosing the appropriate formulation of acetaminophen in the perioperative setting as absorption of oral analgesics may be compromised in the immediate postoperative setting.18-21 Following surgery, compromised gastric function has been shown to diminish the absorption of oral acetaminophen. In a prospective pharmacokinetic study designed to assess absorption, Berger and colleagues demonstrated that opiate-related pyloric narrowing or closure leads to decreased plasma concentrations of acetaminophen given orally.19 Additionally, a study by Petring and colleagues confirmed that significant delays in gastric emptying occur with the administration of IV opioid analgesics. When used as a gastric absorption marker, postoperative plasma concentrations after acetaminophen given orally were significantly lower than

5

ry ge

Clinical Considerations Regarding Route Of Administration

Acetaminophen Concentration, mcg/mL

The pharmacokinetics and pharmacodynamics of IV acetaminophen have been well characterized (Figures 1 and 2).14,15 In a pharmacokinetic study conducted by Cadence Pharmaceuticals, Inc., IV acetaminophen was compared with oral acetaminophen.14 Compared with a 1-g dose of oral acetaminophen, 1 g of IV acetaminophen shows up to 70% higher maximum plasma concentration (C max ), with a median time to reach C max (T Tmax ) at 15 minutes (end of infusion).

Area under the concentration-time curve (AUC) is very similar for the same dose of IV acetaminophen and oral acetaminophen.14 The peak effect of 1 g acetaminophen occurs within 1 hour of administration and duration of effect is 4 to 6 hours.16 Additionally, there is no evidence of clinically significant drug accumulation with repeated dosing.17 In a second pharmacokinetic study by Singla and colleagues, the plasma and cerebrospinal fluid (CSF) pharmacokinetics of IV, oral, and rectal acetaminophen were compared. Six healthy male patients were included in a 3-way, crossover, single-center, single-dose design pharmacokinetic study. The IV route produced a 76% higher mean plasma Cmax (P=0.0004) than oral and a 256% higher Cmax (P<0.0001) than rectal administration of acetaminophen (Figure 1). The Tmax for the IV route was earlier (0.25 h) than that for the oral route (1 h, P=0.0018) or the rectal route (2.5 h, P=0.0025).15 In this study, the mean CSF AUC for IV acetaminophen over 6 hours was 75% higher than the oral AUC (P=0.0099) and 142% higher than the rectal AUC (P=0.0004). The mean CSF Cmax value for IV acetaminophen was 59.7% higher than that for oral (P<0.0001) and 86.8% higher than that for rectal administration (P<0.0001; Figure 2).15

Mean CSF Acetaminophen Concentrations 6

sia Fasting

Figure 3. Absorption of oral analgesics may be compromised in the perioperative setting.

Based on references 18-21.

3

REPORT preoperative values (P<0.001) in patients who received opioids after surgery.18

Analgesic Efficacy of OFIRMEV

Mean SPID24 (VAS, 100 mm)

0

As part of an extensive clinical data set consisting of numerous randomized controlled trials (RCTs), IV acetaminophen has demonstrated a significant analgesic benefit relating to pain relief or reduction in pain intensity, and has demonstrated analgesic efficacy in a variety of surgery types.

Two pivotal studies evaluated OFIRMEV in the treatment of acute postoperative pain after abdominal laparoscopic surgery (soft tissue pain) and major orthopedic surgery (bone and joint pain).

In abdominal laparoscopic surgery, Wininger and colleagues evaluated the analgesic efficacy of repeated doses of IV acetaminophen 1 g or IV placebo 100 mL at 6-hour intervals, or IV acetaminophen 650 mg or IV placebo 65 mL at 4-hour intervals, over 24 hours in 244 patients with moderate to severe postoperative pain following elective laparoscopic surgery (including cholecystectomy, hysterectomy, hernia repair, colonic resection, and prostatectomy). IV or oral opioid rescue medication was available to all patients. Efficacy was measured as the weighted sum of pain intensity differences over 24 hours (SPID24) based on 100-mm visual analog scale (VAS) for the IV acetaminophen 1 g versus combined placebo groups (primary end point); SPID24 based on VAS for the IV acetaminophen 650 mg versus combined placebo groups;

-45.2 -50

P=0.0068

-100

-150

-194.1 -200 OFIRMEV 1 g q6h + rescue (n=92) Placebo + rescue (n=108)

Figure 4. Sum of pain intensity differences over 24 hours after abdominal laparascopic surgery.

SPID24, sum of pain intensity differences over 24 hours; VAS, visual analog scale Based on reference 22.

50

OFIRMEV 1 g q6h + rescue (n=92)

P<0.0001

Placebo + rescue (n=42) Mean Pain Intensity (VAS, 100 mm)

P=0.012 P=0.024

40

P=NS 30

20

0.0 0.2 0.4 0.6 0.8 1.0

10

0

0-6

6-12

12-18

18-24

Time, h

Figure 5. Mean pain intensity scores at 6-hour intervals after abdominal laparascopic surgery.

VAS, visual analog scale; NS, not significant Based on references 17 and 22.

4

REPORT

OFIRMEV 1 g + PCA morphine (n=49) Placebo + PCA morphine (n=52)

1.8

P<0.05 at every time point

1.2

Pain Relief

pain relief; patientsâ&#x20AC;&#x2122; global evaluation of study treatment at 24 hours; time to first use of rescue medication; and total amount of rescue medication consumption over 24 hours.22 A significant reduction in SPID24 from baseline was seen with IV acetaminophen 1 g plus rescue when compared with placebo plus rescue (P<0.007; Figure 4). Time to meaningful pain relief after the first dose was significantly shorter in patients who received IV acetaminophen 1 g plus rescue compared to the matched placebo plus rescue group, with median values of 24.9 versus 53.9 minutes, respectively (P<0.003).22 Furthermore, an expanded analysis of these study data over 24 hours demonstrated that the mean pain intensity scores were significantly lower for the IV acetaminophen plus rescue group at each dosing interval through 18 hours (Figure 5).17,22 In major orthopedic surgery, Sinatra and colleagues evaluated the analgesic efficacy of repeated doses of IV acetaminophen 1 g versus placebo every 6 hours for 24 hours in 101 patients reporting moderate to severe pain following total hip or total knee replacement. Rescue IV patientcontrolled analgesia (PCA) morphine was available to all patients. Patients were started on study medication the morning of the first postoperative day to allow for anesthesia washout and to establish a baseline. Efficacy was measured as pain relief on a 5-point verbal scale over 6 hours (primary end point); pain intensity on a 100-mm VAS and a 4-point verbal scale over 24 hours; quantity of morphine consumed; time to first use of rescue medication; and patient satisfaction with pain management at 24 hours.16 In the 6-hour, single-dose evaluation period, IV acetaminophen 1 g plus PCA morphine demonstrated superior pain relief versus placebo plus PCA morphine from 15 minutes to 6 hours (Figure 6). In the repeated-dose evaluation period, SPID24 was significantly reduced in the IV acetaminophen group compared with the placebo group (P<0.01).23 There were no significant differences between IV acetaminophen and placebo groups regarding the incidence of AEs. Constipation, nausea, anemia, pruritus, and vomiting were the most frequently reported AEs in both groups.16 In major abdominal and pelvic surgery in patients requiring a planned admission to the intensive care unit (ICU), Memis and colleagues studied the efficacy of repeated doses of IV acetaminophen 1 g plus IV meperidine versus placebo plus IV meperidine. Patients were assessed for pain using both a behavioral pain scale (BPS) and a VAS. When BPS or VAS values were more than 4, IV meperidine 1 mg/kg was administered. Use of IV acetaminophen plus IV meperidine was associated with significantly lower pain scores as measured

by BPS and VAS over 24 hours (Figure 7).24 IV acetaminophen also has demonstrated rapid analgesic efficacy versus placebo in an emergency department (ED) setting. In patients presenting to the ED with renal colic, Bektas and colleagues found rapid reductions in pain intensity at 15 and 30 minutes after receiving 1 g of IV acetaminophen or 0.1 mg/kg of morphine versus placebo. IV fentanyl was available to patients with inadequate pain relief at 30 minutes. Statistically significant mean differences in pain intensity reductions compared with those for placebo were observed for IV acetaminophen (OR, 16; 95% CI, 5-27; P=0.005) and morphine

0.6

0.0 0 .25 .50 .75 1

2

3

4

5

6

Time, h

Figure 6. Mean pain relief scores after first dose in major orthopedic surgery.

PCA, patient-controlled analgesia Based on reference 16.

6

IV acetaminophen 1 g q6h + IV meperidine

5.68 5

4

Placebo + IV meperidine

P<0.01 3.70

3

P<0.01 2.64

2

2.40

1

0

BPS prior to extubation (n=20)

VAS after extubation (n=20)

Figure 7. Study in major abdominal and pelvic surgery.

BPS, behavioral pain scale; VAS, visual analog scale Based on reference 24.

5

REPORT

As part of a multimodal analgesic approach, the ASA guidelines recommend that preoperative initiation of analgesia for postoperative pain should be considered during patient preparation for perioperative pain management.10 The following study evaluated the effect of IV acetaminophen on postoperative pain when used preemptively (preoperatively or intraoperatively).

In a study of 90 patients undergoing total abdominal hysterectomy, Arici and colleagues evaluated the effect of IV acetaminophen 1 g given preoperatively (30 minutes before induction), IV acetaminophen 1 g given intraoperatively (at skin closure), or placebo. All patients had PCA morphine freely available as rescue. Results showed that postoperative pain intensity scores were significantly lower for both IV acetaminophen groups, preoperatively and intraoperatively, compared with placebo (P<0.05; Figure 8).26

placebo (Figures 9-11).16,24,26 In total hip and knee replacement, 1 g IV acetaminophen plus PCA morphine significantly reduced morphine consumption compared with placebo plus PCA morphine (â&#x20AC;&#x201C;46% over 6 h, P<0.01; â&#x20AC;&#x201C;33% over 24 h, P<0.01; Figure 9).

Median time to first rescue medication use was significantly longer with IV acetaminophen compared with placebo (3 h vs 0.8 h, P=0.0001).16 In major abdominal surgery, postoperative rescue meperidine consumption was reduced by 61% over 24 hours among patients receiving IV acetaminophen compared to placebo (Figure 10).24 Arici and colleagues found that IV acetaminophen plus standard of care demonstrated significantly less morphine consumption over 24 hours when compared to placebo plus standard of care (P<0.05; Figure 11). The data in this study suggest that when administered preoperatively, IV acetaminophen 1 g demonstrated a significantly greater reduction in morphine consumption compared to the same dose administered intraoperatively (P<0.05).26 Although IV acetaminophen has demonstrated the ability to reduce opioid consumption, the clinical significance of this has not been evaluated or demonstrated.

Reduced Opioid Consumption With OFIRMEV

Improved Patient Satisfaction With OFIRMEV

Reduced opioid consumption with IV acetaminophen has been demonstrated in a number of RCTs across a variety of surgical procedures with significant reductions compared with

Patient reports of satisfaction with pain management favor IV acetaminophen plus standard of care over placebo plus standard of care in a number of clinical trials and surgery types.

(OR, 14; 95% CI, 0.4-27; P=0.05); however, no difference was found between IV acetaminophen and morphine (OR, 2; 95% CI, â&#x20AC;&#x201C;13-16; P=0.74). This study was not designed as a headto-head, noninferiority trial.25

Preemptive Analgesic Efficacy of OFIRMEV

IV acetaminophen 1 g given 30 min before induction (n=28) IV acetaminophen 1 g before skin closure (n=27)

Mean Pain Intensity (VAS, 10 cm)

5.0

Placebo (n=27)

4.5

*P<0.05

4.0

*

3.5

*

3.0

*

2.5 2.0 1.5 1.0 0.5 0.0

1

2

4

Time, h

8

Figure 8. Mean pain intensity scores following total hysterectomy surgery.

VAS, visual analog scale Based on reference 26.

6

*

*

*

12

24

REPORT

IV acetaminophen 1 g q6h + IV meperidine (n=20) Placebo + IV meperidine (n=20) 200

198 Meperidine Consumption, mg

In the study by Wininger and colleagues, patients’ global evaluation of satisfaction with study treatment and satisfaction with AEs related to study treatment were reported at 24 hours. These results significantly favored IV acetaminophen plus rescue over the combined placebo plus rescue (all comparisons, P<0.001).22 Similar results were demonstrated in the study by Sinatra and colleagues; patients’ global evaluations of study treatment at 24 hours (repeated doses) were significantly more favorable among patients who received IV acetaminophen plus PCA morphine versus patients who received placebo plus PCA morphine. On a 4-point categorical scale, satisfaction scores of good to excellent reported at 24 hours were significantly higher in the IV acetaminophen plus PCA morphine arm over the placebo plus PCA morphine arm (40.8% vs 23.1%, P=0.004).17 A recent 2013 publication of a pooled analysis of patient satisfaction scores from 5 RCTs evaluated IV acetaminophen in the acute postoperative setting.27 The analysis included patient-level data from the 2 pivotal trials for OFIRMEV, as well as FDA registrational studies in the following surgery types: open abdominal gynecological surgery, vaginal hysterectomy, and hip arthroplasty. In each of these studies, patient satisfaction was measured using a 4-point categorical rating scale. The end points were excellent satisfaction (primary) and good d or excellent satisfaction at 24 hours after first administration of study drug.27

150

100

P<0.05 77 50

0

Figure 10. Meperidine consumption over 24 hours in major abdominal surgery.a Based on reference 24.

OFIRMEV 1 g + PCA morphine (n=49) Placebo + PCA morphine (n=52)

70

60

60

P<0.05

-33%

Morphine o p e Co Consumption, su pt o , mg g

50

ª

40

38.3

30

-46%

20 17.8

10

ª

40

P<0.05 30

20

0

0

Over 24 h P<0 <0.01 0

Figure 9. Morphine consumption after orthopedic surgery.a

a

50

10

9.7

Over 6 h P<0 <0.01 0

Morphine o p e Co Consumption, su pt o , mg g

57.4

Prior to induction (n=28)

Prior to closure (n=27)

Placebo (n=27)

Type of administration

PCA, patient-controlled analgesia

Figure 11. Morphine consumption over 24 hours in total abdominal hysterectomy.a

Based on reference 16.

Based on reference 26.

Note: Opioid consumption reduction is highly dependent on clinical trial design, and the clinical consequence of any amount of opiod consumption may not have been evaluated or demonstrated in any given trial.

7

REPORT

Table 1. Treatment-Emergent Adverse Events Occurring in at Least 3% of Adults Receiving OFIRMEV and at a Greater Frequency Than Placebo in Repeated-Dose Studiesa Treatment-Emergent Adverse Event

OFIRMEV

Placebo

(N=402) n (%)

(N=379) n (%)

Nausea

138 (34%)

119 (31%)

Vomiting

62 (15%)

42 (11%)

Pyrexiab

22 (5%)

52 (14%)

Headache

39 (10%)

33 (9%)

Insomnia

30 (7%)

21 (5%)

Based on reference 14. a

The differences between treatment groups were not statistically significant for any reported treatment-emergent adverse event.

b

Pyrexia adverse reaction frequency data are included in order to alert health care practitioners that the antipyretic effects of OFIRMEV may mask fever.

The analysis concluded that implementing a multimodal analgesic regimen that includes IV acetaminophen results in significantly greater patient satisfaction. Patients who received IV acetaminophen were more than twice as likely as those who received placebo to report excellentt satisfaction with study treatment (32.3% vs 15.9%, respectively; P<0.001).27

Clinical Safety of OFIRMEV The safety of IV acetaminophen has been established by a clinical trial data set comprised of 1,020 adult patients, including 37.3% (n=380) who received 5 or more doses, and 17% (n=173) who received more than 10 doses. Most adult patients, 86.9% (n=886), were treated with IV acetaminophen 1 g every 6 hours. A total of 13.1% (n=134) received IV acetaminophen 650 mg every 4 hours. The most common treatment-emergent AEs (TEAEs) occurring in at least 3% of adult patients treated with IV acetaminophen and at a greater frequency than placebo in repeated-dose studies were nausea, vomiting, headache, and insomnia (Table 1).14 Health care practitioners should be aware that the antipyretic effects of IV acetaminophen may mask fever in patients treated for postsurgical pain.

OFIRMEV contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the recommended maximum daily limits, and often involve more than one acetaminophen-containing product.

Safety data from a pooled analysis of 5 repeated-dose, placebo-controlled clinical studies involving adults demonstrate that when dosed appropriately, the incidence of liver function enzyme elevations was comparable to that seen with placebo (Table 2).17

8

Recommended Dosing of OFIRMEV OFIRMEV is administered as a 15-minute infusion and may be given as a single or repeated dose for the treatment of acute pain or fever. For adults and adolescents weighing 50 kg or more, the recommended dosage is 1,000 mg every 6 hours or 650 mg every 4 hours, with a maximum single dose of 1,000 mg, a minimum dosing interval of 4 hours, and a maximum daily dose of acetaminophen not to exceed 4,000 mg in 24 hours (Table 3).14 Take care when prescribing, preparing, and administering OFIRMEV Injection to avoid dosing errors that could result in accidental overdose and death. In particular, ensure that the dose in milligrams and milliliters is not confused, the dosing is based on weight for patients under 50 kg, infusion pumps are properly programmed, and the total daily dose of acetaminophen from all sources does not exceed maximum daily limits.

Dosing for children at least 2 years of age and adolescents and adults weighing less than 50 kg is listed in Table 3. For doses less than 1,000 mg, the appropriate dose must be withdrawn from the vial and placed into a separate container (eg, glass bottle, plastic IV container, or syringe) before administration. Once the vacuum seal of the OFIRMEV glass vial has been penetrated, or the contents have been transferred to another container, the dose must be administered within 6 hours.14

Conclusion Although there have been many developments and an increased emphasis on pain management over the past 2 decades, relatively little has changed with regard to the incidence of postsurgical pain or of patientsâ&#x20AC;&#x2122; perception of their pain management.5 Postoperative pain continues to be inadequately controlled. Because of this, opioid monotherapy should

REPORT

Table 2. Peak ALT/AST Value Post-Baseline for Patients in 5 Pooled, Repeated-Dose, Placebo-Controlled Studies in Adultsa OFIRMEV

Placebo

(N=402) n (%)

(N=379) n (%)

ALT >3x ULN

4 (1.1%)

6 (1.7%)

>5x ULN

1 (0.3%)

2 (0.6%)

AST >3x ULN

4 (1.0%)

4 (1.1%)

>5x ULN

2 (0.5%)

3 (0.8%)

ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal Based on reference 17. a

Acetaminophen is contraindicated in patients with severe hepatic impairment or severe active liver disease and should be used with caution in patients with hepatic impairment or active liver disease.

Table 3. Recommended Dosing of OFIRMEV Age Group

Dose Given Every 4 h

Dose Given Every 6 h

Maximum Single Dose

Maximum Total Daily Dose of Acetaminophen By All Routes

Adults and adolescents (≥13 y) weighing ≥50 kg

650 mg

1,000 mg

1,000 mg

4,000 mg in 24 h

Adults and adolescents (≥13 y) weighing <50 kg and Children (2-12 y)

12.5 mg/kg

15 mg/kg

15 mg/kg (up to 750 mg)

75 mg/kg in 24 h (up to 3,750 mg)

Based on reference 14.

no longer be viewed as an adequate strategy for postoperative pain management.5,9 Multimodal analgesia represents a shifting paradigm in perioperative pain management and has garnered the support of numerous professional organizations, including the ASA, ASPMN, AHRQ, and The Joint Commission.9,10,12,13 The ASA guidelines recommend that, unless contraindicated, acetaminophen, COXIBs, or NSAIDs be considered as part of a multimodal analgesic regimen.10 Surgery, opioids, anesthesia, preoperative fasting, and postoperative stress can all work together in the immediate postoperative period to produce a profound gastroparesis and delayed gastric emptying. These factors should be taken into consideration when determining the appropriate route of analgesic administration.

IV acetaminophen is well suited for use in a multimodal analgesic regimen, with unique properties including rapid onset, established safety profile, and reduction in pain and fever.

Include OFIRMEV as a foundational agent when establishing and implementing a multimodal analgesic regimen on standing orders in general surgery. Initiate analgesia with OFIRMEV preoperatively with the aim of improving pain relief and significantly reducing opioid use.

OFIRMEV is the first and only agent in the class of IV nonopioid, non-NSAID analgesics approved in the United States. As a foundational agent within a perioperative multimodal analgesic regimen, OFIRMEV improves pain relief, reduces opioid consumption, and increases patient satisfaction with pain treatment in the perioperative setting.

9

REPORT

Case Study 1 A healthy 70-year-old male found to have a large cecal polyp in a previous colonoscopy.a Sonia Ramamoorthy, MD, FACS, FASCRS he polyp was removed and the pathology report was consistent with a villous adenoma. The patient returned for a follow-up colonoscopy in 2013; he was found to have a recurrent 3-cm polyp in the same location. The polyp was partially removed and pathology showed a villous adenoma with high-grade dysplasia. It was recommended that he undergo right hemicolectomy. The patient was seen in a surgery clinic and it was determined that he would benefit from a laparoscopicassisted right hemicolectomy.

As part of the institution’s enhanced bowel recovery protocol, the patient was counseled about early ambulation, limiting narcotic intake, alternative pain medications, and he was given preoperative gabapentin (300 mg). The patient also underwent preoperative transversus abdominis plane block with 20 mL of bupivacaine one-fourth strength with epinephrine. The patient underwent an uneventful laparoscopic-assisted right hemicolectomy, and per protocol, 1 g of OFIRMEV was administered before skin closure. The patient was given one-fourth strength bupivacaine hydrochloride injection into the wound. The surgery was approximately 2 hours in duration. The anastomosis was performed extracorporeally and the extraction site was 4 cm periumbilically.

Postoperatively, he was given 15 mg IV ketorolac every

T

6 hours and 1 g of OFIRMEV every 6 hours, not to exceed 4 doses in a 24-hour period. He was continued on gabapentin 300 mg every 8 hours. IV morphine sulfate 2 mg was available as needed every 2 hours for severe breakthrough pain. On the day of surgery, he was ambulating in the halls and reported pain scores of 0 to 2 (VAS). He was started on clear liquids. The patient reported an uneventful night, and on POD 1, he passed flatus in the morning. He continued to ambulate throughout the day. His medications were continued and his pain scores remained at 0. By the evening of POD 1, the patient’s diet was advanced and plans were made for discharge the following day. The patient was discharged POD 2 following a bowel movement. He requested only oral ibuprofen and oral acetaminophen on discharge for pain. The patient’s total morphine intake during hospitalization was 2 mg given immediately postoperatively in the postanesthesia care unit.

The patient was seen in clinic POD 14 for a follow-up visit.

His wounds had healed adequately and he reported minimal pain since discharge that was adequately treated with oral acetaminophen. His activities were normal except for the surgical restrictions, and his final pathology report was consistent with villous adenoma with high-grade dysplasia.

Case Study 2 A 34-year-old female presents with a long history of morbid obesity.a Anthony Gonzalez, MD he patient has failed multiple medical attempts at weight loss, including diet, exercise, pharmacologic therapy, and holistic measures. She presented to the bariatric surgeon for evaluation for weight loss surgery, specifically sleeve gastrectomy.

On evaluation by the bariatric surgeon, she was found to have a past medical history of obstructive sleep apnea, treated with a continuous positive airway pressure mask during sleep, and fibrocystic breast disease. Her social history consisted of rare tobacco use and social alcohol consumption.

Her weight at the time of the office visit was 135 kg and her height was 66 inches; this calculated to a BMI of 48 kg/m2.

After discussing the diagnosis of morbid obesity and its medical, social, and psychological implications with the patient, the options for weight loss surgery were reviewed. The patient was offered 3 bariatric procedure options: adjustable gastric band, gastric sleeve, and gastric bypass. After careful discussion, both the patient and the surgeon agreed that the best bariatric procedure would be a robotic sleeve gastrectomy, along with a robotic hiatal hernia repair and upper endoscopy.

Before the procedure, the patient was given deep vein thrombosis prophylaxis, antibiotics, and 1 g of OFIRMEV. Via 4 laparoscopic incisions 5 to 12 mm in size, a robotic sleeve gastrectomy was created over a 36 French bougie. The staple

T

a

10

line was oversewn. The hiatal hernia was repaired with nonabsorbable sutures. The upper endoscopy was completed at the end of the procedure. The duration of the procedure was 1 hour and 23 minutes.

The patient was transferred to the recovery room and postoperative orders were completed. They included 1 g of OFIRMEV every 6 hours, 30 mg of ketorolac every 8 hours, and 0.5 to 1.0 mg of hydromorphone every 3 hours as needed by the patient. The initial pain assessment score in the recovery room was a 7/10 (based on a 10-point VAS). The patient received 2 mg of IV hydromorphone during the night after surgery. Later that night the patient received her second dose of OFIRMEV (1 g); the pain score 32 minutes after that dose was 4/10.

On postoperative day (POD) 1, the patient received her third dose of 1 g of OFIRMEV and the pain score was measured 30 minutes later and found to be 0/10. The last dose of OFIRMEV was given later that first postoperative day, as was 30 mg of ketorolac; the pain score 30 minutes after administration was 4/10. A total of 2 mg of IV hydromorphone was given to the patient on POD 1.

The patient ambulated 50 yards on the surgical day and more than 200 yards on PODs 1 and 2. She was discharged on POD 2.

Note: These case studies are intended only to provide health care professionals with examples of the use of OFIRMEV (acetaminophen) injection in the treatment of the specified patients. The outcomes described may not be representative of, and may differ significantly from, outcomes that may be obtained in treating other patients. These case studies are not intended to provide specific treatment advice, recommendations, or opinions, and should not replace a clinician’s judgment with respect to the treatment of any particular patient.

REPORT Important Safety Information WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY Take care when prescribing, preparing, and administering OFIRMEV injection to avoid dosing errors which could result in accidental overdose and death.

OFIRMEV contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the recommended maximum daily limits, and often involve more than one acetaminophen-containing product.

OFIRMEV is contraindicated in patients with severe hepatic impairment, severe active liver disease or with known hypersensitivity to acetaminophen or to any of the excipients in the formulation.

Acetaminophen should be used with caution in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia, or severe renal impairment.

Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), StevensJohnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.

Discontinue OFIRMEV immediately if symptoms associated with allergy or hypersensitivity occur, or at the first appearance of skin rash. Do not use in patients with acetaminophen allergy.

The most common adverse reactions in patients treated with OFIRMEV were nausea, vomiting, headache, and insomnia in adult patients and nausea, vomiting, constipation, pruritus, agitation, and atelectasis in pediatric patients.

The antipyretic effects of OFIRMEV may mask fever in patients treated with postsurgical pain.

OFIRMEV is approved for use in patients â&#x2030;Ľ2 years of age.

Do not exceed the recommended maximum daily dose of OFIRMEV. OFIRMEV should be administered only as a 15-minute infusion.

11

REPORT References 1. Warfield CA, Kahn CH. Acute pain management. Programs in U.S. hospitals and experiences and attitudes among U.S. adults. Anesthesiology.

1995;83(5):1090-1094.

15. Singla NK, Parulan C, Samson R, et al. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen. Pain Pract. 2012;12(7):523-532.

2. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003;97(2):534-540.

16. Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, PayenChampenois C. Efficacy and safety of single and repeated administration of 1 gram intravenous acetaminophen injection (paracetamol) for pain management after major orthopedic surgery. Anesthesiology. 2005;102(4):822-831.

3. The Joint Commission. Facts about pain management. http://www.jointcommission.org/assets/1/18/pain_management.pdf.

Accessed March 4, 2014.

17. Data on file. Cadence Pharmaceuticals, Inc.

4. HCAHPS Fact Sheet. http://www.hcahpsonline.org/files/HCAHPS%20 Fact%20Sheet%20May%202012.pdf. Accessed March 13, 2014.

18. Petring OU, Dawson PJ, Blake DW, et al. Normal postoperative gastric emptying after orthopaedic surgery with spinal anaesthesia and i.m. ketorolac as the first postoperative analgesic. Br J Anaesth. 1995;74(3):257-260.

5. Gan TJ, Habib AS, White W, Miller T. Postoperative pain continues to be undermanaged. Abstract presented at: 11th Annual Pain Medicine Meeting on November 15-18, 2012 at Miami, FL. Abstract A63.

19. Berger MM, Berger-Gryllaki M, Wiesel PH, et al. Intestinal absorption in patients after cardiac surgery. Crit Care Med. 2000;28(7):2217-2223.

20. Behm B, Stollman N. Postoperative ileus: etiologies and interventions.

Clin Gastroenterol Hepatol. 2003;1(2):71-80.

7. Data from hospital research database maintained by Premier Healthcare Alliance.

21. Petring OU, Blake DW. Gastric emptying in adults: an overview related to anaesthesia. Anaesth Intensive Care. 1993;21(6):774-781.

8. Pizzi LT, Toner R, Foley K, et al. Relationship between potential opioid-related adverse effects and hospital length of stay in patients receiving opioids after orthopedic surgery. Pharmaco. 2012;32(6):502-514.

22. Wininger SJ, Miller H, Minkowitz HS, et al. A randomized, double-blind, placebo-controlled, multicenter, repeat-dose study of two intravenous acetaminophen dosing regimens for the treatment of pain after abdominal laparoscopic surgery. Clin Ther. 2010;32(14):2348-2369.

10. American Society of Anesthesiologists. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management.

Anesthesiology. 2012;116(2):248-273.

11. Kehlet H, Dahl JS. The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg. 1993;77(5):1048-1056.

12. Jarzyna D, Jungquist CR, Pasero C, et al. American Society for Pain Management Nursing guidelines on monitoring for opioid-induced sedation and respiratory depression. Pain Manag Nurs. 2011;12(3):118-145.

13. Hughes RG, ed. Patient Safety and Quality: An Evidence-Based Handbook for Nurses. Rockville, MD: Agency for Healthcare Research and Quality; 2008.

14. Prescribing Information for OFIRMEV® (acetaminophen) injection. San Diego, CA: Cadence Pharmaceuticals, Inc., 2013.

23. Sinatra RS, Jahr JS, Reynolds L, et al. Intravenous acetaminophen for pain after major orthopedic surgery: an expanded analysis. Pain Pract.

2012;12(5):357-365.

24. Memis D, Inal MT, Kavalci G, Sezer A, Sut N. Intravenous paracetamol reduced the use of opioids, extubation time, and opioid-related adverse effects after major surgery in intensive care unit. J Crit Care. 2010;25(3): 458-462.

25. Bektas F, Eken C, Karadeniz O, Goksu E, Cubuk M, Cete Y. Intravenous paracetamol or morphine for the treatment of renal colic: a randomized, placebo-controlled trial. Ann Emerg Med. 2009;54(4):568-574.

26. Arici S, Gurbet A, Türker G, et al. Preemptive analgesic effects of intravenous paracetamol in total abdominal hysterectomy. Agri. 2009;21(2):54-61.

27. Apfel CC, Souza K, Portillo J, Dalal P, Bergese SD. Patient satisfaction with intravenous acetaminophen: a pooled analysis of five randomized, placebo-controlled studies in the acute postoperative setting. J Healthc Qual. [published online ahead of print January 16, 2014]. doi:10.1111/jhq.12062.

Disclosures: Dr. Gonzalez reported that he has served on the speaker’s bureau for Cadence Pharmaceuticals, Inc. and has served as a proctor and speaker for Ethicon Endo-Surgery, Inc. and Intuitive Surgical, Inc. Dr. Ramamoorthy reported that she serves as a consultant for Cadence Pharmaceuticals, Inc., Edwards Lifesciences, and Ethicon Endo-Surgery, Inc. Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Cadence Pharmaceuticals, Inc., 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.

Copyright © 2014 Cadence Pharmaceuticals, Inc. and McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

12

OFV13780214

9. The Joint Commission Sentinel Event Alert. Safe use of opioids in the hospital. Issue 49. http://www.jointcommission.org/assets/1/18/SEA_49_opioids_8_2_12__ nal.pdf. Accessed on March 4, 2014.

SR1413

6. Sinatra R. Causes and consequences of inadequate management of acute pain. Pain Med. 2010;11(12):1859-1871.

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use OFIRMEV® safely and effectively. See full prescribing information for OFIRMEV. OFIRMEV (acetaminophen) Injection Initial U.S. Approval: 1951

WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY See full prescribing information for complete boxed warning Take care when prescribing, preparing, and administering OFIRMEV Injection to avoid dosing errors which could result in accidental overdose and death.

OFIRMEV contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the recommended maximum daily limits, and often involve more than one acetaminophen-containing product (see WARNINGS).

RECENT MAJOR CHANGES Boxed Warning Dosage and Administration General Dosing Information (2.1) Recommended Dosage: Adults and Adolescents (2.2) Recommended Dosage: Children (2.3) Warnings and Precautions Hepatic Injury (5.1) Serious Skin Reactions (5.2) Risk of Medication Errors (5.3)

10/2013 10/2013 10/2013 10/2013 10/2013 10/2013 10/2013

INDICATIONS AND USAGE OFIRMEV (acetaminophen) injection is indicated for the

Management of mild to moderate pain (1)

Management of moderate to severe pain with adjunctive opioid analgesics (1)

Reduction of fever (1) DOSAGE AND ADMINISTRATION OFIRMEV may be given as a single or repeated dose. (2.1) OFIRMEV should be administered only as a 15-minute intravenous infusion. (2.4) Adults and Adolescents Weighing 50 kg and Over:

1000 mg every 6 hours or 650 mg every 4 hours to a maximum of 4000 mg per day. Minimum dosing interval of 4 hours. (2.2) Adults and Adolescents Weighing Under 50 kg:

15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours to a maximum of 75 mg/kg per day. Minimum dosing interval of 4 hours. (2.2) Children:

Children 2 to 12 years of age: 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours to a maximum of 75 mg/kg per day. Minimum dosing interval of 4 hours. (2.3)

DOSAGE FORMS AND STRENGTHS Injection for intravenous infusion.

Each 100 mL glass vial contains 1000 mg acetaminophen (10 mg/mL). (3)

CONTRAINDICATIONS Acetaminophen is contraindicated:

In patients with known hypersensitivity to acetaminophen

FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: RISK OF MEDICATION ERRORS AND HEPATOTOXICITY 1.

INDICATIONS AND USAGE 2.

DOSAGE AND ADMINISTRATION 2.1 General Dosing Information 2.2 Recommended Dosage: Adults and Adolescents 2.3 Recommended Dosage: Children 2.4 Instructions for Intravenous Administration 3.

DOSAGE FORMS AND STRENGTHS 4.

CONTRAINDICATIONS 5.

WARNINGS AND PRECAUTIONS 5.1 Hepatic Injury 5.2 Serious Skin Reactions 5.3 Risk of Medication Errors 5.4 Allergy and Hypersensitivity 6.

ADVERSE REACTIONS 6.1 Clinical Trial Experience 7.

DRUG INTERACTIONS 7.1 Effects of other Substances on Acetaminophen 7.2 Anticoagulants 8.

USE IN SPECIFIC POPULATIONS

or to any of the excipients in the IV formulation. (4) In patients with severe hepatic impairment or severe active liver disease. (4) WARNINGS AND PRECAUTIONS Administration of acetaminophen in doses higher than recommended (by all routes of administration and from all acetaminophen-containing products including combination products) may result in hepatic injury, including the risk of liver failure and death. (5.1) Do not exceed the maximum recommended daily dose of acetaminophen (by all routes of administration and all acetaminophen-containing products including combination products). (5.1) Take care when prescribing, preparing, and administering OFIRMEV injection to avoid dosing errors which could result in accidental overdose and death. (5.3) Use caution when administering acetaminophen in patients with the following conditions: hepatic impairment or active hepatic disease, in cases of alcoholism, chronic malnutrition, severe hypovolemia, or severe renal LPSDLUPHQW FUHDWLQLQH FOHDUDQFH P/ PLQ

'LVFRQWLQXH 2),50(9 LPPHGLDWHO\ DW WKH ¿UVW appearance of skin rash and if symptoms associated with allergy or hypersensitivity occur. Do not use in patients with acetaminophen allergy. (5.2, 5.4)

ADVERSE REACTIONS The most common adverse reactions in patients treated with OFIRMEV were nausea, vomiting, headache, and insomnia in adult patients and nausea, vomiting, constipation, pruritus, agitation, and atelectasis in pediatric patients. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Cadence Pharmaceuticals Inc. at 1-877-647-2239 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch f g .

DRUG INTERACTIONS Substances that induce or regulate hepatic cytochrome enzyme CYP2E1 may alter the metabolism of acetaminophen and increase its hepatotoxic potential. (7.1) Chronic oral acetaminophen use at a dose of 4000 mg/day has been shown to cause an increase in international normalized ratio (INR) in some patients who have been stabilized on sodium warfarin as an anticoagulant. (7.2) USE IN SPECIFIC POPULATIONS Pregnancy: Category C. There are no studies of intravenous acetaminophen in pregnant women. Use only if clearly needed. (8.1) Nursing Mothers: Caution should be exercised when administered to a nursing woman. (8.3) Pediatric Use: The effectiveness of OFIRMEV for the treatment of acute pain and fever has not been studied in pediatric patients less than 2 years of age. The safety and effectiveness of OFIRMEV in pediatric patients older than 2 years is supported by evidence from adequate and well controlled studies in adults with additional safety and pharmacokinetic data for this age group. (8.4) Geriatric Use: No overall differences in safety or effectiveness were observed between geriatric and younger subjects. (8.5) Hepatic Impairment: OFIRMEV is contraindicated in patients with severe hepatic impairment or severe active liver disease and should be used with caution in patients with hepatic impairment or active liver disease. (4, 5.1, 8.6) Renal Impairment: In cases of severe renal impairment, longer dosing intervals and a reduced total daily dose of acetaminophen may be warranted. (5.1, 8.7) Revised: 10/2013

8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Patients with Hepatic Impairment 8.7 Patients with Renal Impairment 10. OVERDOSAGE 11. DESCRIPTION 12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14. CLINICAL STUDIES 14.1 Adult Acute Pain 14.2 Adult Fever 14.3 Pediatric Acute Pain and Fever 16. HOW SUPPLIED/STORAGE AND HANDLING *Sections or subsections omitted from the full prescribing inforr mation are not listed.

FULL PRESCRIBING INFORMATION WARNING: Risk of Medication Errors and Hepatotoxicity Take care when prescribing, preparing, and administering OFIRMEV Injection to avoid dosing errors which could result in accidental overdose and death. In particular, be careful to ensure that: the dose in milligrams (mg) and milliliters (mL) is not confused; the dosing is based on weight for patients under 50 kg; infusion pumps are properly programmed; and the total daily dose of acetaminophen from all sources does not exceed maximum daily limits.

OFIRMEV contains acetaminophen.

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed the maximum daily limits, and often involve more than one acetaminophen-containing product (see WARNINGS).

1 INDICATIONS AND USAGE OFIRMEV® (acetaminophen) injection is indicated for the management of mild to moderate pain the management of moderate to severe pain with adjunctive opioid analgesics the reduction of fever.

2 DOSAGE AND ADMINISTRATION 2.1 General Dosing Information OFIRMEV may be given as a single or repeated dose for the treatment of acute pain or fever. No dose adjustment is required when converting between oral acetaminophen and OFIRMEV dosing in adults and adolescents who weigh 50 kg and above. Calculated maximum daily dose of acetaminophen is based on all routes of administration (i.e., intravenous, oral, and rectal) and all products containing acetaminophen.

Exceeding the maximum mg/kg daily dose of acetaminophen as described in Tables 1 and 2 may result in hepatic injury, including the risk of liver failure and death. To avoid the risk of overdose, ensure that the total amount of acetaminophen from all routes and from all sources does not exceed the maximum recommended dose.

2.2 Recommended Dosage: Adults and Adolescents Adults and adolescents weighing 50 kg and over: the recommended dosage of OFIRMEV is 1000 mg every 6 hours or 650 mg every 4 hours, with a maximum single dose of OFIRMEV of 1000 mg, a minimum dosing interval of 4 hours, and a maximum daily dose of acetaminophen of 4000 mg per day (includes all routes of administration and all acetaminophen-containing products including combination products).

Adults and adolescents weighing under 50 kg: the recommended dosage of OFIRMEV is 15 mg/ kg every 6 hours or 12.5 mg/kg every 4 hours, with a maximum single dose of OFIRMEV of 15 mg/ kg, a minimum dosing interval of 4 hours, and a maximum daily dose of acetaminophen of 75 mg/ kg per day (includes all routes of administration and all acetaminophen-containing products including combination products).

4 CONTRAINDICATIONS

Table 1: Dosing for Adults and Adolescents Age group

Dose given Dose given every 6 hours every 4 hours

Maximum single dose

Maximum total daily dose of acetaminophen (by all routes)

Adults and adolescents (13 years and older) weighing Â&#x2022; NJ

650 mg

1000 mg

4000 mg in 24 hours

Adults and adolescents (13 years and older) weighing NJ

12.5 mg/kg 15 mg/kg

1000 mg

15 mg/kg 75 mg/kg in (up to 750 mg) 24 hours (up to 3750 mg)

2.3 Recommended Dosage: Children Children 2 to 12 years of age: the recommended dosage of OFIRMEV is 15 mg/kg every 6 hours or 12.5 mg/kg every 4 hours, with a maximum single dose of OFIRMEV of 15 mg/kg, a minimum dosing interval of 4 hours, and a maximum daily dose of acetaminophen of 75 mg/kg per day.

Table 2: Dosing for Children Age group

Dose given Dose given every 6 hours every 4 hours

Children 2 to 12 years of age

12.5 mg/kg 15 mg/kg

Maximum single dose

Maximum total daily dose of acetaminophen (by all routes)

15 mg/kg 75 mg/kg in (up to 750 mg) 24 hours (up to 3750 mg)

2.4 Instructions for Intravenous Administration For adult and adolescent patients weighing Â&#x2022; NJ UHTXLULQJ PJ GRVHV RI 2),50(9 administer the dose by inserting a vented intravenous set through the septum of the 100 mL vial. OFIRMEV may be administered without further dilution.

Examine the vial contents before dose preparation or administering. DO NOT USE if particulate matter or discoloration is observed. Administer the contents of the vial intravenously over 15-minutes. Use aseptic technique when preparing OFIRMEV for intravenous infusion. Do not add other medications to the OFIRMEV vial or infusion device.

For doses less than 1000 mg, the appropriate dose must be withdrawn from the vial and placed into a separate container prior to administration.

Using aseptic technique, withdraw the appropriate dose (650 mg or weight-based) from an intact sealed OFIRMEV vial and place the measured dose in a separate empty, sterile container (e.g. glass bottle, plastic intravenous container, or syringe) for intravenous infusion to avoid the inadvertent delivery and administration of the total volume of the commercially available container. The entire 100 mL vial of OFIRMEV is not intended for use in patients weighing less than 50 kg. OFIRMEV is a single-use vial and the unused portion must be discarded.

Place small volume pediatric doses up to 60 mL in volume in a syringe and administer over 15 minutes using a syringe pump.

Monitor the end of the infusion in order to prevent the possibility of an air embolism, especially in cases where the OFIRMEV infusion is the primary infusion.

Once the vacuum seal of the glass vial has been penetrated, or the contents transferred to another container, administer the dose of OFIRMEV within 6 hours.

Do not add other medications to the OFIRMEV solution.

Diazepam and chlorpromazine hydrochloride are physically incompatible with OFIRMEV, therefore do not administer simultaneously.

3 DOSAGE FORMS AND STRENGTHS OFIRMEV is a sterile, clear, colorless, non pyrogenic, preservative free, isotonic formulation of acetaminophen intended for intravenous infusion. Each 100 mL glass vial contains 1000 mg acetaminophen (10 mg/mL).

Acetaminophen is contraindicated: Â&#x2021; in patients with known hypersensitivity to acetaminophen or to any of the excipients in the intravenous formulation. Â&#x2021; in patients with severe hepatic impairment or severe active liver disease [see WARNINGS AND PRECAUTIONS (5.1)].

5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Injury Administration of acetaminophen in doses higher than recommended may result in hepatic injury, including the risk of liver failure and death [see OVERDOSAGE (10)]. Do not exceed the maximum recommended daily dose of acetaminophen [see DOSAGE AND ADMINISTRATION (2)].

The maximum recommended daily dose of acetaminophen includes all routes of acetaminophen administration and all acetaminophen-containing products administered, including combination products.

Use caution when administering acetaminophen in patients with the following conditions: hepatic impairment or active hepatic disease, alcoholism, chronic malnutrition, severe hypovolemia (e.g., due to dehydration or blood loss), or severe renal LPSDLUPHQW FUHDWLQLQH FOHDUDQFH Â&#x201D; P/ PLQ >see USE IN SPECIFIC POPULATIONS (8.6, 8.7)].

5.2 Serious Skin Reactions Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Patients should be informed about the signs of serious skin reactions, and use of the drug VKRXOG EH GLVFRQWLQXHG DW WKH ÂżUVW DSSHDUDQFH RI VNLQ rash or any other sign of hypersensitivity.

5.3 Risk of Medication Errors Take care when prescribing, preparing, and administering OFIRMEV (acetaminophen) Injection in order to avoid dosing errors which could result in accidental overdose and death. In particular, be careful to ensure that: Â&#x2021; the dose in milligrams (mg) and milliliters (mL) is not confused; Â&#x2021; the dosing is based on weight for patients under 50 kg; Â&#x2021; infusion pumps are properly programmed; and Â&#x2021; the total daily dose of acetaminophen from all sources does not exceed maximum daily limits [see DOSAGE AND ADMINISTRATION (2)].

5.4 Allergy and Hypersensitivity There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, and pruritus. There were infrequent reports of life-threatening anaphylaxis requiring emergent medical attention. Discontinue OFIRMEV immediately if symptoms associated with allergy or hypersensitivity occur. Do not use OFIRMEV in patients with acetaminophen allergy.

cannot be directly compared to rates in other clinical WULDOV DQG PD\ QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG LQ practice.

Adult Population p A total of 1020 adult patients have received OFIRMEV in clinical trials, including 37.3% (n=380) who received 5 or more doses, and 17.0% (n=173) who received more than 10 doses. Most patients were treated with OFIRMEV 1000 mg every 6 hours. A total of 13.1% (n=134) received OFIRMEV 650 mg every 4 hours.

All adverse reactions that occurred in adult patients treated with either OFIRMEV or placebo in repeated dose, placebo-controlled clinical trials at an incidence Â&#x2022; DQG DW D JUHDWHU IUHTXHQF\ WKDQ SODFHER DUH listed in Table 3. The most common adverse events LQ DGXOW SDWLHQWV WUHDWHG ZLWK 2),50(9 LQFLGHQFH Â&#x2022; 5% and greater than placebo) were nausea, vomiting, headache, and insomnia.

Table 3. Treatment-Emergent Adverse Reactions Occurring Â&#x2022; % in OFIRMEV-treated Patients and at a greater frequency than Placebo in Placebo-Controlled, Repeated Dose Studies System Organ Class â&#x20AC;&#x201C; Preferred Term

Gastrointestinal Disorders Nausea Vomiting General Disorders and Administration Site Conditions Pyrexia* Nervous System Disorders Headache Psychiatric Disorders Insomnia

OFIRMEV (N=402) n (%)

Placebo (N=379) n (%)

138 (34) 62 (15)

119 (31) 42 (11)

22 (5)

52 (14)

39 (10)

33 (9)

30 (7)

21 (5)

* Pyrexia adverse reaction frequency data is included in order to alert healthcare practitioners that the antipyretic effects of OFIRMEV may mask fever.

Other Adverse Reactions Observed During g Clinical Studies of OFIRMEV in Adults The following additional treatment-emergent adverse reactions were reported by adult subjects treated with OFIRMEV in all clinical trials (n=1020) that occurred with an incidence of at least 1% and at a frequency greater than placebo (n=525).

Blood and lymphatic y p system y disorders: anemia General disorders and administration site conditions: fatigue, infusion site pain, edema peripheral Investigations g : aspartate aminotransferase increased, breath sounds abnormal Metabolism and nutrition disorders: hypokalemia Musculoskeletal and connective tissue disorders: muscle spasms, trismus Psychiatric y disorders: anxiety Respiratory, p y, thoracic and mediastinal disorders: dyspnea Vascular disorders: hypertension, hypotension Pediatric p population p A total of 355 pediatric patients (47 neonates, 64 infants, 171 children, and 73 adolescents) have received OFIRMEV in active-controlled (n=250) and open-label clinical trials (n=225), including 59.7% (n=212) who received 5 or more doses and 43.1% (n=153) who received more than 10 doses.

Pediatric patients received OFIRMEV doses up to 15 mg/kg on an every 4 hours, every 6 hours, or every 8 hours schedule. The maximum exposure was 7.7, 6.4, 6.8, and 7.1 days in neonates, infants, children, and adolescents, respectively.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Â&#x2021; Hepatic Injury [[see WARNINGS AND PRECAUTIONS (5.1)] Â&#x2021; Serious Skin Reactions [see WARNINGS AND PRECAUTIONS (5.2)] Â&#x2021; Allergy and Hypersensitivity [see WARNINGS AND PRECAUTIONS (5.4)]

7KH PRVW FRPPRQ DGYHUVH HYHQWV LQFLGHQFH Â&#x2022; 5%) in pediatric patients treated with OFIRMEV were nausea, vomiting, constipation, pruritus, agitation, and atelectasis.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

Other Adverse Reactions Observed During g Clinical Studies of OFIRMEV in Pediatrics The following additional treatment-emergent

adverse reactions were reported by pediatric subjects treated with OFIRMEV (n=355) that occurred with an incidence of at least 1%.

Blood and lymphatic y p system y disorders: anemia Cardiac disorders: tachycardia Gastrointestinal disorders: abdominal pain, diarrhea General disorders and administration site conditions: injection site pain, edema peripheral, pyrexia Investigations g : hepatic enzyme increase Metabolism and nutrition disorders: hypoalbuminemia, hypokalemia, hypomagnesemia, hypophosphatemia, hypervolemia Musculoskeletal and connective tissue disorders: muscle spasm, pain in extremity Nervous system y disorders: headache Psychiatric y disorders: insomnia Renal and urinary y disorders: oliguria Respiratory, p y, thoracic and mediastinal disorders: pulmonary edema, hypoxia, pleural effusion, stridor, wheezing Skin and subcutaneous tissue disorders: periorbital edema, rash Vascular disorders: hypertension, hypotension 7 DRUG INTERACTIONS 7.1 Effects of other Substances on Acetaminophen Substances that induce or regulate hepatic cytochrome enzyme CYP2E1 may alter the metabolism of acetaminophen and increase its hepatotoxic potential. The clinical consequences of these effects have not been established. Effects of ethanol are complex, because excessive alcohol usage can induce hepatic cytochromes, but ethanol also acts as a competitive inhibitor of the metabolism of acetaminophen.

7.2 Anticoagulants Chronic oral acetaminophen use at a dose of 4000 mg/day has been shown to cause an increase in international normalized ratio (INR) in some patients who have been stabilized on sodium warfarin as an anticoagulant. As no studies have been performed evaluating the short-term use of OFIRMEV in patients on oral anticoagulants, more frequent assessment of INR may be appropriate in such circumstances.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. There are no studies of intravenous acetaminophen in pregnant women; however, epidemiological data on oral acetaminophen use in pregnant women show no increased risk of major congenital malformations.

Animal reproduction studies have not been conducted with IV acetaminophen, and it is not known whether OFIRMEV can cause fetal harm when administered to a pregnant woman. OFIRMEV should be given to a pregnant woman only if clearly needed.

The results from a large population-based prospective cohort, including data from 26,424 women with live born singletons who were H[SRVHG WR RUDO DFHWDPLQRSKHQ GXULQJ WKH ÂżUVW trimester, indicate no increased risk for congenital malformations, compared to a control group of unexposed children. The rate of congenital malformations (4.3%) was similar to the rate in the general population. A population-based, casecontrol study from the National Birth Defects Prevention Study showed that 11,610 children with SUHQDWDO H[SRVXUH WR DFHWDPLQRSKHQ GXULQJ WKH ÂżUVW trimester had no increased risk of major birth defects compared to 4,500 children in the control group.

Other epidemiological data showed similar results.

While animal reproduction studies have not been conducted with intravenous acetaminophen, studies in pregnant rats that received oral acetaminophen during organogenesis at doses up to 0.85 times the maximum human daily dose (MHDD = 4 grams/day,

based on a body surface area comparison) showed evidence of fetotoxicity (reduced fetal weight and length) and a dose-related increase in bone variations UHGXFHG RVVLÂżFDWLRQ DQG UXGLPHQWDU\ ULE FKDQJHV

Offspring had no evidence of external, visceral, or skeletal malformations. When pregnant rats received oral acetaminophen throughout gestation at doses of 1.2-times the MHDD (based on a body surface area comparison), areas of necrosis occurred in both the liver and kidney of pregnant rats and fetuses. These effects did not occur in animals that received oral acetaminophen at doses 0.3-times the MHDD, based on a body surface area comparison.

In a continuous breeding study, pregnant mice received 0.25, 0.5, or 1.0% acetaminophen via the diet (357, 715, or 1430 mg/kg/day). These doses are approximately 0.43, 0.87, and 1.7 times the MHDD, respectively, based on a body surface area comparison. A dose-related reduction in body ZHLJKWV RI IRXUWK DQG ÂżIWK OLWWHU RIIVSULQJ RI WKH treated mating pair occurred during lactation and post-weaning at all doses. Animals in the high dose group had a reduced number of litters per mating pair, male offspring with an increased percentage of abnormal sperm, and reduced birth weights in the next generation pups.

8.2 Labor and Delivery There are no adequate and well-controlled studies with OFIRMEV during labor and delivery; therefore, it should be used in such settings only after a careful EHQHÂżW ULVN DVVHVVPHQW 8.3 Nursing Mothers While studies with OFIRMEV have not been conducted, acetaminophen is secreted in human milk in small quantities after oral administration.

Based on data from more than 15 nursing mothers, the calculated infant daily dose of acetaminophen is approximately 1 â&#x20AC;&#x201C; 2% of the maternal dose. There is one well-documented report of a rash in a breastfed infant that resolved when the mother stopped acetaminophen use and recurred when she resumed acetaminophen use. Caution should be exercised when OFIRMEV is administered to a nursing woman.

8.4 Pediatric Use The safety and effectiveness of OFIRMEV for the treatment of acute pain and fever in pediatric patients ages 2 years and older is supported by evidence from adequate and well-controlled studies of OFIRMEV in adults. Additional safety and pharmacokinetic data were collected in 355 patients across the full pediatric DJH VWUDWD IURP SUHPDWXUH QHRQDWHV Â&#x2022; ZHHNV SRVW menstrual age) to adolescents. The effectiveness of OFIRMEV for the treatment of acute pain and fever has not been studied in pediatric patients < 2 years of age. [see DOSAGE AND ADMINISTRATION - Recommended Dosage: Children (2.3) and PHARMACOKINETICS (12.3)].

8.5 Geriatric Use Of the total number of subjects in clinical studies of OFIRMEV, 15% were age 65 and over, while 5% percent were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and RWKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂżHG differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Patients with Hepatic Impairment Acetaminophen is contraindicated in patients with severe hepatic impairment or severe active liver disease and should be used with caution in patients with hepatic impairment or active liver disease [see WARNINGS AND PRECAUTIONS (5.1), CLINICAL PHARMACOLOGY (12)]. A reduced total daily dose of acetaminophen may be warranted.

8.7 Patients with Renal Impairment

In cases of severe renal impairment (creatinine FOHDUDQFH Â&#x201D; P/ PLQ ORQJHU GRVLQJ LQWHUYDOV DQG a reduced total daily dose of acetaminophen may be warranted.

10 OVERDOSAGE Signs g and Symptoms y p In acute acetaminophen overdosage, dosedependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and thrombocytopenia may also occur. Plasma acetaminophen levels > 300 mcg/mL at 4 hours after oral ingestion were associated with hepatic damage in 90% of patients; minimal hepatic damage is anticipated if plasma levels at 4 hours are < 150 mcg/mL or < 37.5 mcg/mL at 12 hours after ingestion. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion.

Treatment If an acetaminophen overdose is suspected, obtain a serum acetaminophen assay as soon as possible, but no sooner than 4 hours following oral ingestion. Obtain liver function studies initially and repeat at 24-hour intervals. Administer the antidote N-acetylcysteine (NAC) as early as possible.

As a guide to treatment of acute ingestion, the acetaminophen level can be plotted against time since oral ingestion on a nomogram (RumackMatthew). The lower toxic line on the nomogram is equivalent to 150 mcg/mL at 4 hours and 37.5 mcg/ mL at 12 hours. If serum level is above the lower line, administer the entire course of NAC treatment.

Withhold NAC therapy if the acetaminophen level is below the lower line.

For additional information, call a poison control center at 1-800-222-1222.

11 DESCRIPTION Acetaminophen is a non-salicylate antipyretic and non-opioid analgesic agent. Its chemical name is N-acetyl-p-aminophenol. Acetaminophen has a molecular weight of 151.16. Its structural formula is:

OFIRMEV injection is a sterile, clear, colorless, non pyrogenic, isotonic formulation of acetaminophen intended for intravenous infusion. It has a pH of approximately 5.5 and an osmolality of approximately 290 mOsm/kg. Each 100 mL contains 1000 mg acetaminophen, USP, 3850 mg mannitol, USP, 25 mg cysteine hydrochloride, monohydrate, USP, 10.4 mg dibasic sodium phosphate, USP. pH is adjusted with hydrochloric acid and/or sodium hydroxide.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The precise mechanism of the analgesic and antipyretic properties of acetaminophen is not established but is thought to primarily involve central actions.

12.2 Pharmacodynamics Acetaminophen has been shown to have analgesic and antipyretic activities in animal and human studies.

Single doses of OFIRMEV up to 3000 mg and repeated doses of 1000 mg every 6 hours for 48 hours KDYH QRW EHHQ VKRZQ WR FDXVH D VLJQLÂżFDQW HIIHFW RQ platelet aggregation. Acetaminophen does not have any immediate or delayed effects on small-vessel hemostasis. Clinical studies of both healthy subjects DQG SDWLHQWV ZLWK KHPRSKLOLD VKRZHG QR VLJQLÂżFDQW changes in bleeding time after receiving multiple

Table 4: OFIRMEV Pharmacokinetic Parameters Mean (SD) Subpopulations AUC (Îźg Ă&#x2014; h/mL)

Cmax (Îźg/mL)

T½ (h)

CL (L/h/kg)

Vss (L/kg)

Neonates

62 (11)

25 (4)

7.0 (2.7)

0.12 (0.04)

1.1 (0.2)

Infants

57 (54)

29 (24)

4.2 (2.9)

0.29 (0.15)

1.1 (0.3)

Children

38 (8)

29 (7)

3.0 (1.5)

0.34 (0.10)

1.2 (0.3)

Adolescents

41 (7)

31 (9)

2.9 (0.7)

0.29 (0.08)

1.1 (0.3)

Adults

43 (11)

28 (21)

2.4 (0.6)

0.27 (0.08)

0.8 (0.2)

The pharmacokinetic exposure of OFIRMEV observed in children and adolescents is similar to adults, but higher in neonates and infants. Dosing simulations from pharmacokinetic data in infants and neonates suggest that dose reductions of 33% in infants 1 month to < 2 years of age, and 50% in neonates up to 28 days, with a minimum dosing interval of 6 hours, will produce a pharmacokinetic exposure similar to that observed in children age 2 years and older.

At therapeutic levels, binding of acetaminophen to plasma proteins is low (ranging from 10% to 25%).

Acetaminophen appears to be widely distributed throughout most body tissues except fat.

Metabolism and Excretion Acetaminophen is primarily metabolized in WKH OLYHU E\ ÂżUVW RUGHU NLQHWLFV DQG LQYROYHV WKUHH principal separate pathways: Conjugation with glucuronide, conjugation with sulfate, and oxidation via the cytochrome P450 enzyme pathway, primarily CYP2E1, to form a reactive intermediate metabolite (N-acetyl-p-benzoquinone imine or NAPQI). With therapeutic doses, NAPQI undergoes rapid conjugation with glutathione and is then further metabolized to form cysteine and mercapturic acid conjugates.

Acetaminophen metabolites are mainly excreted in the urine. Less than 5% is excreted in the urine as unconjugated (free) acetaminophen and more than 90% of the administered dose is excreted within 24 hours.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis g Long-term studies in mice and rats have been completed by the National Toxicology Program to evaluate the carcinogenic potential of acetaminophen.

In 2-year feeding studies, F344/N rats and B6C3F1 mice were fed a diet containing acetaminophen up to 6000 ppm. Female rats demonstrated equivocal evidence of carcinogenic activity based on increased incidences of mononuclear cell leukemia at 0.8 times the maximum human daily dose (MHDD) of 4 grams/day, based on a body surface area comparison. In contrast, there was no evidence of carcinogenic activity in male rats (0.7 times) or mice (1.2-1.4 times the MHDD, based on a body surface area comparison).

Mutagenesis g Acetaminophen was not mutagenic in the bacterial reverse mutation assay (Ames test).

In contrast, acetaminophen tested positive in the in vitro mouse lymphoma assay and the in vitro chromosomal aberration assay using human lymphocytes. In the published literature, acetaminophen has been reported to be clastogenic when administered a dose of 1500 mg/kg/day to the rat model (3.6-times the MHDD, based on a body surface area comparison). In contrast, no clastogenicity was noted at a dose of 750 mg/kg/day (1.8-times the MHDD, based on a body surface area comparison), suggesting a threshold effect.

Impairment p of fertility y In studies conducted by the National Toxicology Program, fertility assessments have been completed in Swiss mice via a continuous breeding study.

There were no effects on fertility parameters in mice consuming up to 1.7 times the MHDD of acetaminophen, based on a body surface area comparison. Although there was no effect on sperm motility or sperm density in the epididymis, WKHUH ZDV D VLJQLÂżFDQW LQFUHDVH LQ WKH SHUFHQWDJH RI abnormal sperm in mice consuming 1.7 times the MHDD (based on a body surface area comparison) and there was a reduction in the number of mating SDLUV SURGXFLQJ D ÂżIWK OLWWHU DW WKLV GRVH VXJJHVWLQJ the potential for cumulative toxicity with chronic administration of acetaminophen near the upper limit of daily dosing.

Published studies in rodents report that oral acetaminophen treatment of male animals at doses that are 1.2 times the MHDD and greater (based on a body surface area comparison) result in decreased testicular weights, reduced spermatogenesis, reduced fertility, and reduced implantation sites in females given the same doses. These effects appear to increase with the duration of treatment. The clinical VLJQLÂżFDQFH RI WKHVH ÂżQGLQJV LV QRW NQRZQ 14 CLINICAL STUDIES 14.1 Adult Acute Pain 7KH HIÂżFDF\ RI 2),50(9 LQ WKH WUHDWPHQW RI acute pain in adults was evaluated in two randomized, double-blind, placebo-controlled clinical trials in patients with postoperative pain.

Pain Study 1 HYDOXDWHG WKH DQDOJHVLF HIÂżFDF\ RI repeated doses of OFIRMEV l000 mg vs. placebo every 6 hours for 24 hours in 101 patients with moderate to severe pain following total hip or knee replacement. OFIRMEV was statistically superior to placebo for reduction in pain intensity over 24 hours. There was an attendant decrease in opioid FRQVXPSWLRQ WKH FOLQLFDO EHQHÂżW RI ZKLFK ZDV QRW demonstrated.

Pain Study 2 evaluated the analgesic HIÂżFDF\ RI UHSHDWHG GRVHV RI 2),50(9 1000 mg every 6 hours or 650 mg every 4 hours for 24 hours versus placebo in the treatment of 244 patients with moderate to severe postoperative

pain after abdominal laparoscopic surgery. Patients receiving OFIRMEV experienced a statistically VLJQLÂżFDQW JUHDWHU UHGXFWLRQ LQ SDLQ LQWHQVLW\ RYHU 24 hours compared to placebo.

14.2 Adult Fever 7KH HIÂżFDF\ RI 2),50(9 PJ LQ WKH treatment of adult fever was evaluated in one randomized, double-blind, placebo-controlled clinical trial. The study was a 6-hour, single-dose, endotoxin-induced fever study in 60 healthy adult PDOHV $ VWDWLVWLFDOO\ VLJQLÂżFDQW DQWLS\UHWLF HIIHFW of OFIRMEV was demonstrated through 6 hours in comparison to placebo. The mean temperature over time is shown in Figure 1.

Mean Temperature (qC)

doses of oral acetaminophen.

12.3 Pharmacokinetics Distribution The pharmacokinetics of OFIRMEV have been studied in patients and healthy subjects from premature neonates up to adults 60 years old. The SKDUPDFRNLQHWLF SURÂżOH RI 2),50(9 KDV EHHQ demonstrated to be dose proportional in adults following administration of single doses of 500, 650, and 1000 mg.

The maximum concentration (Cmax) occurs at the end of the 15 minute intravenous infusion of OFIRMEV. Compared to the same dose of oral acetaminophen, the Cmax following administration of OFIRMEV is up to 70% higher, while overall exposure (area under the concentration time curve [AUC]) is very similar.

Pharmacokinetic parameters of OFIRMEV (AUC, Cmax, terminal elimination half-life [T½], systemic clearance [CL], and volume of distribution at steady state [Vss]) following administration of a single intravenous dose of 15 mg/kg for the pediatric population and 1000 mg in adults are summarized in Table 4.

IV acetaminophen Placebo

40.0 39.5 39.0 38.5 38.0

0

1

2

3

4

5

6

Time Post Dose (Hours)

Figure 1: Mean Temperature (°C) Over Time

14.3 Pediatric Acute Pain and Fever OFIRMEV was studied in 355 pediatric patients in two active-controlled and three open-label safety and pharmacokinetic trials [see PEDIATRIC USE (8.4)].

16 HOW SUPPLIED/STORAGE AND HANDLING OFIRMEV is supplied in a 100 mL glass vial containing 1000 mg acetaminophen (10 mg/mL).

Carton of 24 vials, NDC 43825-102-01 OFIRMEV should be stored at 20 °C to 25 °C (68 °F to 77 °F) [See USP Controlled Room Temperature].

For single use only. The product should be used within 6 hours after opening. Do not refrigerate or freeze.

OFIRMEV (acetaminophen) injection Manufactured for: Cadence Pharmaceuticals, Inc. San Diego, CA 92130 Revised 10/2013 Š 2013 Cadence Pharmaceuticals, Inc. All rights reserved.

OFIRMEVÂŽ and CADENCEÂŽ are trademarks of Cadence Pharmaceuticals, Inc. U.S. PATENT NUMBERS: 6,028,222; 6,992,218 OFV12821013