Issuu

GeNerAlSurGeryNewS.com

April 2012 • Volume 39 • Number 4

The Independent Monthly Newspaper for the General Surgeon

opinion

An Optimistic Curmudgeon B y J on C. W hite , MD

ver the past two years I have written multiple editorials for General Surgery News cataloging the many challenges we have in health care today, including the obesity epidemic, the dysfunctional medical tort system, workforce shortages, the medical arms race and the unsustainable growth

we have experienced dramatic changes in our profession over the past century. of the health care industry. With each problem I have tried to outline potential solutions. I don’t know if any of my naive suggestions will be strategies that we ultimately adopt, but the important concept is that most problems have solutions. If we look back through the history of medicine in the United States, we will see that we have had a succession of problems, but they have always been solved. Often the solutions themselves engender new problems but, in time, see Optimistic page 30

Product Announcement

see page 11

CMS Rolls Out Changes for Ambulatory Surgical Centers Modest Pay Increases; New Data Reporting Requirements

Gloom and Doom Swirls Around Sepsis Research

B y C hristina F rangou

B y K ate o’r ourKe

ajor changes are under way in the Centers for Medicare & Medicaid Services (CMS) system of payments to ambulatory surgical centers (ASCs) and hospital outpatient departments. The CMS 2012 final rule increased payment rates to ASCs by 1.6% this year, and rates under the Outpatient Prospective Payment System rose by 1.9%. But, in a move that will prove more significant in the long term, CMS has adopted new quality measures for ASCs. The quality reporting system will be integrated over the next two years and will affect payments see ambulatOry surgery page 22

Innovative and Affordable Advances in Surgical Technology B y C hristina F rangou

world combined spent on these technologies. The overwhelming cost of surgical technology was the focus of an unusual panel session at last fall’s Clinical Congress of the American College of Surgeons (ACS). The session, titled “Extreme Affordability,” profiled surgeons

Houston—In the 1990s, two high-profile drugs for sepsis crashed and burned after promising early mortality data fizzled in later studies and the manufacturers had to halt the clinical trials. The mood among sepsis researchers was gloomy, and it now appears that the storm clouds are back—not only because of the withdrawal of drotrecogin alfa (activated; Xigris, Eli Lilly) from the market in October—but also due to more recent, disappointing results from other sepsis drug trials. These developments, outlined at the recent annual meeting of the Society of Critical Care Medicine (SCCM), have fueled the feeling that there are only gray clouds hovering over sepsis research. In fact, “we must be very anxious because the industry may no longer put its money in our field. They may just move away and go to other disciplines,” said JeanLouis Vincent, MD, PhD, head of the Department of Intensive Care at Erasme see glOOm and dOOm page 16

3-Part Series

san Francisco—Advances in surgical technology have been an undeniable boon for patients but, for budgets, not so much. The United States spent about $95 million on medical devices in 2011, roughly half of what the rest of the

REPORT IV Acetaminophen Improves Pain Management and Reduces Opioid Requirements in Surgical Patients: A Review of the Clinical Data and Case-based Presentations

see surgical innOvatiOn page 19

See insert at page 10

INSIDE In the News

Surgeons’ Lounge

Study hints at ‘prime time‘ Unreported clinical trial for surgeons: 35 to 50 data rampant, lead to years old . ......................... 4 research bias ............. 24

Experts discuss avoiding injury during laparoscopic cholecystectomy .............. 26

GSN editorial

GEnERAlSURGERynEwS.cOM / GEnERAl SURGERy nEwS / APRIl 2012

Automatic Piloting in Surgery Frederick L. Greene, MD Chairman, Department of General Surgery Carolinas Medical Center Charlotte, N.C.

ecently, I had dinner with a very good friend of mine who has been a commercial airline pilot for the past 30 years. He has flown for major airlines in the United States and now is a lead captain and instructor for a major international airline company. He also has been very involved recently in flight training and is quite versed in the use of simulators. I always enjoy having dinner with my friend and chatting about the resemblance of the airline industry and surgical practice, especially as it relates to our activities in the operating room. Recently, we discussed the similarities between cockpit checks and the time-outs that surgeons perform in the operating room in order to reduce misadventure and to assure that, like in the cockpit, everyone is taking a role in making certain that safety comes first. During this recent dinner, our conversation centered on a concept that was a little different. My friend told me about the attitudes and practices of young commercial pilots with whom he interacts. We talked about training in the era of having the most technologically advanced avionics and the effects of those technologies on decision making. We also talked about

the role of the automatic pilot in the whole sequence of take-off and landing. As a frequent flyer, I continue to be fascinated by the fact that most of the time, my plane is flown by a computer. He indicated to me that this reliance on automation is, in his opinion, becoming a real problem in that there is so much dependence by today’s young pilot on advanced technology that the potential role of the human factor is being diminished. As an example, he told me that when he flies as the lead pilot, he tends to turn off the automatic pilot well before the final approach. He likes to, in his words, “feel the plane.” He likes to have a more tactile sense as to how the plane is handling so he knows that he can make any necessary corrections, especially when there are significant weather issues. He has noticed that when he flies with younger pilots, they tend to keep on the automatic pilot almost to the moment when the plane touches the tarmac. While this in itself is not a safety issue, it has indicated to him—an instructor and a very seasoned pilot—that the dependence on automation and technology has become so engrained that the human factor, in many ways, is marginalized. The question today for him is whether the pilot is commanding the cockpit or the

Joseph J. Pietrafitta, MD Minneapolis, MN General Surgery, laparoscopy, colon and Rectal Surgery, laser Surgery

Los Angeles, CA General Surgery, laparoscopy, Surgical Education

Gary Hoffman, MD

Barry A. Salky, MD

Editorial Advisory Board

Los Angeles, CA colorectal Surgery

New York, NY laparoscopy

Maurice E. Arregui, MD

Namir Katkhouda, MD

Paul Alan Wetter, MD

Indianapolis, IN General Surgery, laparoscopy, Surgical Oncology, Ultrasound, Endoscopy

Kay Ball, RN, CNOR, FAAN

Los Angeles, CA laparoscopy

Miami, FL Ob/Gyn, laparoscopy

Youngstown, OH General Surgery, laparoscopy

Editorial Staff

Philip S. Barie, MD, MBA

Peter K. Kim, MD Bronx, NY Emergency General Surgery

Kevin Horty

New York, NY critical care/Trauma, Surgical Infection

L.D. Britt, MD, MPH

Raymond J. Lanzafame, MD

David Earle, MD

Rochester, NY General Surgery, laparoscopy, Surgical Oncology, laser Surgery, new Technology

Springfield, MA General Surgery, laparoscopy

James Forrest Calland, MD Philadelphia, PA General Surgery, Trauma Surgery

Edward Felix, MD

Fresno, CA General Surgery, laparoscopy

Robert J. Fitzgibbons Jr., MD Omaha, NE General Surgery, laparoscopy, Surgical Oncology

David R. Flum, MD, MPH Seattle, WA General Surgery, Outcomes Research

Michael Goldfarb, MD Long Branch, NJ laparoscopy, Telemedicine

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Gerald Marks, MD Wynnewood, PA colon and Rectal Surgery, colonoscopy

J. Barry McKernan, MD Marietta, GA laparoscopy

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© 2012 by McMahon Publishing, new york, ny 10036. All rights reserved. General Surgery News (ISSn 1099-4122) is published monthly by McMahon Publishing, 545 west 45th Street, new york, ny 10036. corp. Office, 83 Peaceable Street, Redding cT 00896. POSTMASTER: Please send address changes to General Surgery News, 545 w. 45th St., 8th Floor, new york, ny 10036.

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Today’s surgeon has become distanced from the use of basic surgical technology such as palpating tissue, suturing, knot tying and other basic concepts that were the foundation for surgical care in the past.

mission Statement It is the mission of General Surgery News to be an independent and reliable source of news and analysis about the current state of surgery. It strives to provide a venue for discussion and opinions, from all viewpoints, on the issues most important to surgeons.

Disclaimer Opinions and statements published in General Surgery News are those of the individual author or speaker and do not necessarily represent the views of the editorial advisory board, editorial staff or reporters.

All U.S. general surgeons, colorectal surgeons, vascular surgeons, surgical oncologists and trauma/critical care surgeons should receive General Surgery News free of charge. If you are changing your address or name, you must notify the AMA at (800) 262-3211 or the AOA (if appropriate) at (800) 621-1773 to continue receiving GSN. You need not be a member; however, they maintain the ultimate source of our mailing addresses. If you are not a general surgeon or other specialist listed above and would like to subscribe, please send a check payable to General Surgery News. Please allow 8-12 weeks for the first issue. Subscription — $70 per year (outside U.S.A. — $90). Single copies — $7 (outside U.S.A. — $10). Send checks and queries to: Circulation Coordinator, General Surgery News, 545 West 45th Street, 8th Floor, New York, NY 10036. Fax: (212) 664-1242.

INFECTIOUS DISEASE SPECIAL EDITION

In the News

GEnERAlSURGERynEwS.cOM / GEnERAl SURGERy nEwS / APRIl 2012

Clot-Busting Drug Use Signals Risk for Catheter Infections B y K ate o’r ourKe Houston—The use of tissue plasminogen activator (tPA) to unclog malfunctioning central venous catheters is associated with an increased risk that patients will develop a catheter-related bloodstream infection. The retrospective study, presented at the 2012 annual meeting of the Society of Critical Care Medicine (abstract

621), revealed a nearly threefold increase in risk for the infections in pediatric patients whose lines were dosed with tPA. “It is almost three times more likely for a central line to become infected if tPA has been used than when it has not been used,” said Mara Nitu, MD, associate professor and interim clinical section chief for pediatric critical care at Riley’s Hospital for Children at Indiana University Health, in Indianapolis,

who led the study. “The clot that prompts the need for tPA, not the tPA itself, is the true culprit. The medication use is just a signal; it should raise the concern level for higher likelihood of line infection.” Fibrin sheets and thrombi that are created when a clot forms provide attractive growth media for bacteria, she added. Studies in adults have linked the presence of a clot to an increased

risk for catheter-related blood infection, but research had not been conducted in pediatric populations. To fill this knowledge gap, Dr. Nitu and her colleagues reviewed quality and infection control records to identify the number of central venous catheters used in patients in the pediatric intensive care unit at their facility between July 2008 and December 2010. They also identified the prevalence of catheter-associated blood infections. After identifying 40 patients with the complication, they examined the medical records of these patients to determine if tPA was used five days before a positive culture. Electronic medical records from the phar1 macy revealed the total number of times tPA was ordered for a central line. Of the 3,289 central venous catheters used during the 2.5-year time Using suture to orient tissue specimens period, 12% required at least one dose is ambiguous, resulting in a 31% rate of of tPA. In the 40 patients who had an disagreement in margin interpretation. infection, 28% involved tPA during the Metal tags can block a full view five days before infection. Patients were 2.87 times as likely to develop a cathof the tissue. eter-related infection when tPA was used (95% confidence interval, 1.42-5.6; P=0.002). The average age of the cath® eter was not a statistically significant risk factor (16.1 days in tPA patients vs. 25.6; P=0.6). Surgeons use CorrectClips, sterile Nasia Safdar, MD, PhD, assistant radioͲgraphic clips, to orient excised tissue on professor in the Section of Infectious the image. CorrectClips attach securely, Diseases in the Department of Mediquickly and easily. They are minimally cine at the University of WisconsinMadison, said “the take-home message intrusive to the tissue and easily removed. is that thrombus formation should caution people to be vigilant for the risk for a [catheter-associated blood infection]. An occluded catheter that requires multiple doses of tPA should probably be removed.” Dr. Nitu said that when doctors realize they need to use tPA, they should be more aggressive in their planning www vectorsurgical.com to remove the line. “A central line that +1 (262) 798Ͳ7970 malfunctions and requires tPA should trigger the immediate planning of either replacing or removing the line,” she said. 1. Molina, M.A.; Snell, S.; Franceschi, D.; Jorda, M.; Gomez,C.; Moīat,F.; Powell, J.;

Eliminate a known source of error in cancer surgery.

CorrectClips

and Avisar, E. “Breast Specimen OrientaƟon,” Annals of Surgical Oncology 16 (2009): 285288.

Drs. Nitu and Safdar reported no relevant disclosures.

In the News

GEnERAlSURGERynEwS.cOM / GEnERAl SURGERy nEwS / APRIl 2012

Study Hints at ‘Prime Time’ for Surgeons: 35 to 50 Years Old B y V iCtoria s tern

urgeons between the ages of 35 and 50 may provide the safest care to patients undergoing thyroid surgery, according to a new study published online Jan. 11 in the British Medical Journal (2012;344:d8041). Overall, investigators found that surgeons within this 15-year age range had a lower risk for postoperative complications during thyroidectomies when compared with both their less and more experienced counterparts. “The take-home message of the study is that surgeons can’t necessarily expect to maintain their top performance without trying to improve every day,” said lead study investigator Antoine Duclos, MD, assistant professor of public health in the Department of Medical Information, Health Evaluation and Clinical Research at Lyon Academic Hospital in France. “Surgeons should want to assist in tracking their own outcomes over time to see whether they are performing well and how they can get better.”

a discussion about the possible drop in surgical performance over time. “Is there a decline in fine motor skills, worse judgment with advancing age, less of a grip on how to use new technology?” asked Amir A. Ghaferi, MD, MS, research fellow with the Michigan Surgical Collaborative for Outcomes Research and Evaluation group, in the Department of Surgery, University of Michigan Health Systems, Ann Arbor, who was not involved in the study. “I don’t think

anyone really knows why a surgeon’s performance may decline after a certain age. You can speculate until you’re blue in the face, but it’s hard to say anything definitively.” To help clarify whether years of surgical experience are associated with postoperative outcomes, Dr. Duclos and his colleagues prospectively collected outcomes data on 3,574 thyroid procedures completed by 28 surgeons between April 1, 2008 and Dec. 31, 2009, at high-volume

referral centers in five academic hospitals in France. The team used thyroid surgery as a benchmark because it is a highly reproducible and well-defined procedure that has not changed substantially in many years. The two major complications of thyroid surgery measured—recurrent laryngeal nerve palsy or hypoparathyroidism—were evaluated once 48 hours after surgery and again six months postsurgery. The researchers also see prime time page 34

In hernia repair

INNOVATING BY BEING IN TOUCH WITH YOUR NEEDS

‘I don’t think anyone really knows why a surgeon’s performance may decline after a certain age. you can speculate until you’re blue in the face, but it’s hard to say anything definitively.’ —Amir A. Ghaferi, MD, MS Previous studies have shown that surgeons generally reach their peak performance between the ages of 30 and 50 years and that physicians in practice for more years tend to possess less factual knowledge and are less likely to adhere to guidelines. In 2006, researchers looked respectively at mortality in approximately 461,000 patients undergoing one of eight surgical procedures between 1998 and 1999 and found that for pancreatectomy (adjusted odds ratio [OR], 1.67), coronary artery bypass grafting (OR, 1.17) and carotid endarterectomy, surgeons older than age 60 years, particularly those with low procedure volumes, had higher operative mortality rates than their younger counterparts (Ann Surg 2006;244:353-362). For the other five procedures, however, surgeon age was not an important predictor of patient mortality. Although the results showed a tenuous relationship between age and postoperative risk, the study helped spawn

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In the News

GEnERAlSURGERynEwS.cOM / GEnERAl SURGERy nEwS / APRIl 2012

Large Variability Found in Breast Surgeons’ Re-excision Rates Lack of Consensus on What Constitutes an ‘Optimal Margin’ B y C hristina F rangou

6.3% for 2 to 2.9 mm. The study demonstrates a lack of consensus among surgeons and radiation oncologists as to what constitutes an optimal negative margin width. Some clinicians believe that “no ink at margin” is sufficient, whereas others believe it should be 1 or even 2 mm at least. In an editorial accompanying the study, Monica Morrow, MD, chief of breast surgery at Memorial Sloan-Kettering Can-

The study authors point out that the effect of close but negative margins on local recurrence has not been conclusively determined and re-excision under these circumstances may or may not influence rates of recurrence.Other surgeons not affiliated with the study said it effectively documents a wide range of variability but does not address the reasons for the variation.

san Francisco—Breast surgeons in the United States have widely varied standards for performing re-excisions following breast-conservation surgery, according to a new study. Rates of re-excision ranged from 0% to 70% among breast ’A reasonable goal is to reduce some of the surgeons who participated in variation in re-excision rates, but the the study. It is unknown why such disparities exist or what subject is sufficiently complex that we will they mean for overall outcomes. “The long-term effect of this never eliminate all of it.’ —Hiram S. Cody III, MD variability is beyond the scope of our study, but it is feasible that out- cer Center, New York City, and Steven “Going forward, comes such as local recurrence and even J. Katz, MD, professor of internal medi- a reasonable goal is to overall survival could be affected by vari- cine, University of Michigan, Ann Arbor, reduce some of the variation in re-exciability in initial surgical care,” wrote said that the re-excision after breast-con- sion rates, but the subject is sufficientLaurence E. McCahill, MD, assistant serving surgery cannot be used as a qual- ly complex that we will never eliminate director, Richard J. Lacks Cancer Center ity measure. all of it,” said Hiram S. Cody III, MD, in Grand Rapids, Mich., and colleagues “Many factors drive the decision to attending surgeon at Memorial Sloan(JAMA 2012;307:467-475). perform margin re-excision, including Kettering Cancer Center and professor Dr. McCahill and colleagues per- clinical variables such as the method of of clinical surgery at Weill Cornell Medformed an observational study of breast pathological margin processing, quality of ical College in New York City. Surgeons surgery performed between 2003 and preoperative imaging, histological tumor have “probably been too focused on mar2008, at four large centers in the United type and patient age,” they said. gin width alone as an indication for reStates. The study included 2,206 patients The results should not be used to excision; I suspect this is the source of at with 2,220 invasive breast cancers. “direct patients to different surgeons least some of the variation in re-excision Analysis showed little consisten- based on having the ‘right rate,’” said Drs. rates,” he said. cy among surgeons and institutions with Morrow and Katz. “One size does not fit all and other regard to secondary breast cancer surgerPatients could end up without access to variables are at least as important as maries. Overall, 22.99% of women underwent lower-volume hospitals or lower-volume gin width: size of excision specimens, re-excisions. Of the re-excisions, 47.5% surgeons, or it could result in greater use extent of tumor near or at the margin, site were performed in patients with negative of mastectomy as surgeons restrict breast- of the positive margin, size of excision relmargins of less than 1 mm; 20.2% were conserving surgery to patients for whom ative to the breast, pathological risk facperformed for 1 to 1.9 mm margins and negative margins are easily achieved. tors for local recurrence, patient age and

comorbidities,” he said. Deanna Attai, MD, breast surgeon at the Center for Breast Care, Inc., Burbank, Calif., said there has never been a “good definition of what an acceptable margin is. “Part of the problem is that cancers are so variable in their presentation and it is also difficult to evaluate the entire margin. Although some studies demonstrate lower recurrence rates with larger margins, more is not necessarily better.” The American Society of Breast Surgeons (ASBS) does not have an official statement on acceptable margins. The quality measures from the ASBS focus on means of diagnosis and specimen orientation as quality measures. Dr. Attai, who is chair of the Communications Committee for ASBS, said there is some support for the development of margin guidelines based on a review of the literature. “I believe that this will be a project that the ASBS research committee will be evaluating,” Dr. Attai said. The study also showed that 14.1% of patients with positive margins did not undergo re-excision. “This finding is notable given that positive margins have been correlated with a long-term increased risk for local recurrence and are therefore almost uniformly excised,” the authors wrote. It is impossible to figure out from the data set why those women did not undergo re-excision. They had a mean age of 62 years and 92.8% were non-Hispanic white; the median invasive tumor size was 14.7 mm and 22% were node-positive.

Most C. difficile Infections Linked to Health Care Settings Researchers Call for More Collaborative Efforts To Promote Prevention B y g eorge o Choa

verall, 94% of Clostridium difficile infections (CDIs) are related to health care exposures, according to a recent report from researchers at the Centers for Disease Control and Prevention (CDC; MMWR Morb Mortal Wkly Rep 2012;61:157-162). Despite the known association between CDI and hospitals, the researchers found that 75% of these infections began among patients not currently hospitalized, including recently discharged patients, outpatients and nursing home residents. Fifty-two percent of CDIs treated in hospitals were present on admission. Some cases occurred in patients who were exposed to multiple health care settings, the investigators noted. For

example, 20% of hospital-onset CDIs occurred in recent residents of nursing homes. Also, 67% of infections that had their onset in nursing homes occurred in patients who were recently discharged from an acute care hospital. Also of note was a 20% decline over approximately 21 months in the pooled CDI rate among 71 hospitals that participated in CDI prevention programs in three states (Illinois, Massachusetts and New York). The prevention programs focused primarily on infection control, although the Massachusetts program included an antibiotic stewardship component as well. Infection control strategies included early reliable detection of cases, isolation of infected patients and enhanced environmental cleaning. Antibiotic stewardship comprised administering the correct antibiotic, at the right dosage, the right time and for the right duration. Data for the MMWR paper were generated using population-based surveillance from the CDC’s Emerging Infections Program in 2010, in which 10,342 CDIs

were identified. The researchers also used data from the CDC’s National Healthcare Safety Network, an Internet-based surveillance system, and from the three stateled prevention programs. According to the authors of the study, CDI incidence rates, mortality rates and medical care costs have reached historic highs, despite the fact that many of the infections can be prevented. They called for more to be done to prevent CDIs and suggested that infection control programs and antibiotic stewardship be extended to nonhospital settings. “State health departments and partner organizations have shown leadership in preventing CDIs in hospitals and can prevent more CDIs by extending their programs to cover other health care settings,” the authors concluded. “Clinicians and other health care providers, as well as inpatient and outpatient health care facilities, [and] state and federal public health officials … could benefit from increased collaboration in preventing CDIs.”

In the News

GeneralSurGerynewS.com / General SurGery newS / april 2012

‘Wait and See’ an Attractive Alternative in Some Rectal Cancers B y B rian D unleavy

“wait-and-see” policy after chemoradiotherapy appears to be a safe and feasible approach for some patients with rectal cancer. The study found that patients with rectal cancer who have achieved a clinical complete response after neoadjuvant chemoradiotherapy experience outcomes similar to those who undergo surgery

(J Clin Oncol 2011;29:4633-4640). Clinical complete response was determined based on findings from MRI, nodal evaluation and endoscopies with biopsy. Of the 21 patients treated with neoadjuvant chemoradiotherapy and no surgery, all but one remained alive without disease after a mean follow-up of 25 months (±19 months). One patient developed a small endoluminal local recurrence without nodal recurrence

after 22 months of follow-up. The patient eventually underwent transanal endoscopic microsurgery, which resulted in complete resection of the recurrence. A control group of 20 patients who achieved pathologic complete response after chemoradiotherapy and went on to have a total mesorectal excision (TME) had a mean follow-up of 35

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Chair

Stephen M. Cohen, MD, FACS, FASCRS Associate Clinical Professor, Department of Surgery Emory University School of Medicine Vice Chairman, Department of Surgery Southern Regional Medical Center Atlanta Colon and Rectal Surgery Atlanta, Georgia

Faculty

Daniel L. Miller, MD

Kanal A. Mansour Professor of Thoracic Surgery Emory University School of Medicine Chief, General Thoracic Surgery Surgical Director, Thoracic Oncology Program Winship Cancer Institute Atlanta, Georgia

Samuel Szomstein, MD, FACS Associate Director, The Bariatric and Metabolic Institute and Section of Minimally Invasive and Endoscopic Surgery Director, Bariatric Endoscopy Cleveland Clinic Florida Weston, Florida Associate Professor of Surgery Florida International University Miami, Florida Clinical Assistant Professor of Surgery Nova Southeastern University Fort Lauderdale, Florida

Sponsored by

Expiration Date: August 31, 2013

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 AKH Inc., Advancing Knowledge in Healthcare, and Applied Clinical Education. AKH Inc. is accredited by the ACCME to provide continuing medical education for physicians. AKH Inc. designates this enduring activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Goal

The goal of this activity is to educate general and colorectal surgeons on strategies for optimizing outcomes in complex hernia repair and abdominal wall reconstruction through choice of biologic mesh and proper surgical technique.

Learning Objectives

At the completion of this activity, participants should be better prepared to:

1 Classify the properties of biologic mesh available for addressing the challenges of complex hernia repair (eg, bovine pericardium, porcine intestine, porcine dermis, and human dermis) and their effects on tissue remodeling and revascularization.

2 Describe the importance of host response to the collagen scaffold and the balance between mesh degradation and new tissue infiltration with bovine pericardium-based mesh.

3 Identify appropriate surgical techniques to optimize the use of biologic mesh in abdominal wall reconstruction and complex hernia repair.

4 Review new treatment algorithms designed to provide best-practice measures and aid in handling surgical complications.

Supported by an educational grant from

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‘The risk for local or distant recurrence that could have been avoided with a standard resection must be balanced against the prospect of life with a permanent colostomy.’ —Manish A. Shah, MD months (±23 months). Two control patients died, one from metastatic disease (diagnosed after three years of follow-up) and the other from surgical complications associated with colostomy closure. None of the control patients experienced local recurrence. In the wait-and-see group, the cumulative probability for two-year diseasefree survival was 89%, and 100% for two-year overall survival. In the control group, these probabilities were 93% and 91%, respectively; the difference in survival rates was not significant. “A wait-and-see policy for clinical complete responses after chemoradiotherapy for rectal cancer with strict selection criteria and follow-up with up-to-date imaging techniques is feasible and safe,” concluded the investigators, from Maastricht University Medical Center, The Netherlands. “Outcome is at least comparable with that of patients with a pathologic complete response after surgery.” In an accompanying editorial (J Clin Oncol 2011;29:4604-4606), Joel E. Tepper, MD, and Bert H. O’Neil, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, wrote that “results have been impressive,” despite the limited length of follow-up. The editorial noted that the results were achieved with less toxicity and better short-term bowel function in the observed patients compared with those who underwent surgical resection. The authors added that these results support and enhance previous research, and raise the possibility that this approach could be generalized to a larger portion of the patient population. In the study, Monique Maas, MD, and colleagues noted that patients with clinical complete response showed a strong preference for the wait-andsee approach over resection, primarily because it offered the possibility of avoiding major surgery and a permanent colostomy. Manish A. Shah, MD, assistant see Wait page 10

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INDICATION RECOTHROM Thrombin, topical (Recombinant) is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical. IMPORTANT SAFETY INFORMATION Contraindications Â‡ Topical use only â€“ DO NOT INJECT directly into the circulatory system Â‡ Do not use for the treatment of massive or brisk arterial bleeding Â‡ Do not administer to patients with known hypersensitivity to RECOTHROM, any components of RECOTHROM or hamster proteins Warnings and Precautions Â‡ Potential risk of thrombosis if absorbed systemically Â‡ In patients with known hypersensitivity to snake proteins, there may be a potential for allergic reaction Adverse Reactions Â‡ 7KH VHULRXV DGYHUVH HYHQW WKDW RFFXUUHG LQ Â• Q RI SDWLHQWV H[SRVHG WR 5(&27+520 LQ FRPSOHWHG FOLQLFDO WULDOV ZDV DWULDO ÂžEULOODWLRQ 7KH PRVW FRPPRQ DGYHUVH HYHQWV UHSRUWHG LQ WKHVH WULDOV 1 ZHUH LQFLVLRQ VLWH SDLQ SURFHGXUDO SDLQ DQG QDXVHD $GYHUVH HYHQWV UHSRUWHG LQ WKHVH WULDOV were consistent with those commonly observed in surgical patients Please see Brief Summary of Full Prescribing Information on following page.

In the News

GEnERAlSURGERynEwS.cOM / GEnERAl SURGERy nEwS / APRIl 2012

Wait

Continued from page 7 professor of medicine, Weill Cornell Medical College, and director, Gastrointestinal Oncology Program, Division of Hematology and Medical Oncology, NewYork-Presbyterian/Weill Cornell, New York City, who was not involved in the study, noted that the question of the feasibility of a “wait-and-see” approach in patients who achieve a clinical complete response to preoperative chemoradiotherapy is an important one. “The appeal of not having a colostomy

provides adequate motivation for some patients with low rectal cancers to not have surgery following completion of chemoradiation for localized rectal cancer,” Dr. Shah said. “However, the risk for local or distant recurrence that could have been avoided with a standard resection must be balanced against the prospect of life with a permanent colostomy in these patients. The decision is no doubt difficult for many.” The article by Maas et al provides prospective data that may help guide this decision in some patients, he said. However, he noted an important caveat:

Immunogenicity The potential development of antibodies to RECOTHROM has been evaluated in multiple clinical trials. These pre-speciﬁed evaluations were performed in order to characterize the immunogenicity of RECOTHROM and the neutralizing potential of any detected antibodies. In completed clinical studies 5 of 552 (0.9%) patients exposed to RECOTHROM with both baseline and post-treatment antibody specimens available developed speciﬁc anti-RECOTHROM product antibodies. None of these antibodies were found to neutralize native human thrombin.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION RECOTHROM Thrombin, topical (Recombinant) ®

Rx Only The following is a brief summary of the full prescribing information for RECOTHROM Thrombin, topical (Recombinant). CONTRAINDICATIONS Do not inject directly into the circulatory system. Do not use for the treatment of massive or brisk arterial bleeding. Do not administer to patients with known hypersensitivity to RECOTHROM, any components of RECOTHROM, or hamster proteins. WARNINGS AND PRECAUTIONS Potential risk of thrombosis if absorbed systemically. In patients with known hypersensitivity to snake proteins, there may be a potential for allergic reaction. ADVERSE REACTIONS The serious adverse event that occurred in ≥ 1% (n=6/583) of patients exposed to RECOTHROM in completed clinical trials was atrial fibrillation. The most common adverse events in patients exposed to RECOTHROM in clinical trials (N=583) were incision site pain (51%), procedural pain (30%), and nausea (28%). Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug product cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical trials have been performed with RECOTHROM applied with absorbable gelatin sponge (Phase 2, Phase 3, and Phase 3b studies) and applied with a spray applicator (Phase 2 study). Adverse events reported in clinical trials were consistent with those commonly observed in surgical patients. Clinical Trials of RECOTHROM Used in Conjunction with Gelatin Sponge Among the 411 patients treated with study drug in the randomized, double-blind, Phase 3 study that compared RECOTHROM to bovine thrombin, both applied with gelatin sponge, in patients undergoing spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access, all but 2 patients (1 patient/treatment group) reported adverse events. Most events were moderate in severity and had a similar incidence in the RECOTHROM and bovine thrombin treatment groups. The most common adverse events were incision site pain (63% for both treatment groups), procedural pain (RECOTHROM 29%; bovine thrombin 34%), and nausea (RECOTHROM 28%; bovine thrombin 35%). Serious adverse events were reported by 18% of patients treated with RECOTHROM and 22% with bovine thrombin. Adverse events of interest were pre-specified, based on the thrombin mechanism of action, use of absorbable gelatin sponge, USP, historical reporting in association with cross-reacting antibodies to bovine thrombin product, and results from Phase 2 clinical trials of RECOTHROM applied with absorbable gelatin sponge. The incidences of these pre-specified adverse events were similar between treatment groups (see Table 1). Table 1. Events of Interest in the RECOTHROM Phase 3 Study AE Category* Patients with any event category Bleeding Cardiac Hypersensitivity Nausea + vomiting Other infection Post-operative wound infection Thromboembolic

RECOTHROM (N=205) n (%) 124 (60%) 27 (13%) 41 (20%) 30 (15%) 68 (33%) 26 (13%) 19 (9%) 12 (6%)

The two groups of patients “were dissimilar in an important way—namely, there was a clear difference in that 75% of the pathologic complete response cohort proceeded to surgery because they had suspicious radiographic findings of persistent disease.” Nonetheless, he said “the study did demonstrate that patients who did not undergo TME surgery following clinical complete response had superior bowel function—including less incontinence and fewer postoperative complications—than the cohort that proceeded with standard TME surgery.

Thrombin-JMI (N=206) n (%) 136 (66%) 24 (12%) 38 (18%) 37 (18%) 83 (40%) 31 (15%) 22 (11%) 10 (5%)

†

Adverse events were included in event categories based on a blinded review of the investigator verbatim and coded terms. † THROMBIN-JMI® Thrombin, Topical (Bovine). *

In an open-label, single-group Phase 3b study, 209 patients with documented or highly likely prior exposure to bovine thrombin within the previous 3 years were treated with RECOTHROM when undergoing surgeries (spinal or peripheral arterial bypass or arteriovenous graft formation for hemodialysis access). The most common adverse events were incision site pain (45%), procedural pain (39%), and nausea (27%). Similar to the Phase 3 study, serious adverse events were reported by 22% of patients treated with RECOTHROM. Clinical Trials of RECOTHROM Applied with Spray Applicator In an open-label, single-group, Phase 2 study in burn patients, 72 patients were treated with RECOTHROM applied with a spray applicator at the burn wound excision site prior to autologous skin grafting. This study included both adults (≥ 17 years of age, n=68) and pediatric patients ≤ 16 years of age (n=4). The most common adverse events in the adult and pediatric age groups included procedural pain (35%), pruritis (25%), and constipation (19%).

In the randomized, double-blind, Phase 3 study that compared RECOTHROM to bovine thrombin, both applied with gelatin sponge, in patients undergoing spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access, the development of specific anti-product antibodies was evaluated in both treatment groups. Blood samples were collected at baseline and at day 29 for 97% of the patients in both treatment groups. For patients randomized to RECOTHROM, the samples were analyzed by ELISA for antibodies to RECOTHROM, Chinese hamster ovary (CHO) host cell protein, and pro-thrombin activator (used in the conversion of single chain precursor to active RECOTHROM). For patients randomized to bovine thrombin, the samples were analyzed by ELISA for antibodies to bovine thrombin product. At baseline 1.5% of patients (n=3/198) in the RECOTHROM group had positive anti-product antibody titers compared with 5% of patients in the bovine thrombin group (n=10/200). Of the patients who had detectable anti-product antibodies at baseline, 0 of 3 in the RECOTHROM group and 8 of 10 in the bovine thrombin group exhibited ≥ 1.0 titer unit (≥ 10-fold) increases in antibody levels after study treatment. Treatment with RECOTHROM applied with absorbable gelatin sponge resulted in a statistically significantly lower incidence of specific anti-product antibody development. Three of 198 (1.5%; 95% CI, 0 to 4%) of the patients in the RECOTHROM arm developed specific anti-thrombin product antibodies (1 patient also developed anti-CHO host cell protein antibodies). No patients developed antibodies to pro-thrombin activator. Forty-three of 200 patients (22%; 95% CI, 16 to 28%) in the bovine thrombin arm developed specific antibodies to bovine thrombin product. None of the antibodies in the RECOTHROM group neutralized native human thrombin. Antibodies against bovine thrombin product were not tested for neutralization of native human thrombin. Because the study was not powered to detect a difference in clinical outcomes attributable to antibody formation, no conclusions can be drawn regarding the clinical significance of the difference in antibody formation based on the results of this study. In the open-label, single group, Phase 3b study in patients with a high likelihood of prior bovine thrombin exposure undergoing spinal, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access, 15.6% of patients (n=32/205) had anti-bovine thrombin product antibodies at baseline prior to treatment with RECOTHROM. Following treatment, none of the 200 evaluable patients (patients for whom specimens were available for antibody testing at baseline and post-RECOTHROM treatment) developed antibodies to RECOTHROM. In the randomized, double-blind, controlled Phase 2 studies of RECOTHROM compared to placebo (RECOTHROM excipients reconstituted with 0.9% sodium chloride, USP) applied in conjunction with absorbable gelatin sponge, which were performed across a range of surgical settings (spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access), the incidence of antibody development to RECOTHROM was 1.2% in the RECOTHROM group (n=1/83) compared to 2.4% (n=1/41) in the placebo group. In the open-label, single group Phase 2 study of RECOTHROM applied with the spray applicator to excised burn wounds, 1 patient developed antibodies following treatment (1.6%, n=1/62). The detection of antibody formation is highly dependent upon the sensitivity and specificity of the assay. The absolute immunogenicity rates reported here are difficult to compare with results from studies of other products due to differences in assay methodology, patient populations, and other underlying factors. To report SUSPECTED ADVERSE REACTIONS, contact ZymoGenetics, Inc. at 1-888-784-7662, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Drug interactions have not been formally studied. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with RECOTHROM. It is also not known whether RECOTHROM can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. RECOTHROM should be given to a pregnant woman only if clearly needed. Pediatric Use Of the 72 patients undergoing burn wound excision and grafting treated with RECOTHROM applied with the spray applicator in the open-label, single group, Phase 2 study, 4 were pediatric patients. All were age 12 to 16 years. The safety and effectiveness of RECOTHROM in all pediatric age groups have not been fully established. Geriatric Use Of the total number of patients in Phase 2 and Phase 3 clinical studies of RECOTHROM with absorbable gelatin sponge, 38% were 65 years old and over, while 16% were 75 years old and over. No substantive 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. For Full Prescribing Information, access www.RECOTHROM.com Manufactured for ZymoGenetics, Inc. RT022-06, January 2011

“Although the sample size is small, these data lay the foundation for a possible wait-and-see approach for patients who have a clinical complete response following standard chemoradiotherapy for localized rectal cancer.” Dr. Shah noted that the criteria for the selection of patients who might be eligible for such an approach were carefully prespecified in this study and involved highly specialized imaging, such as pelvic MRI enhanced with either miniature supermagnetic particles of iron oxide or gadofosveset trisodium, as well as diffusion-weighted MRI used to differentiate tumor from normal rectum. Therefore, an approach of watchful waiting would not be routinely advised—at least not yet, he concluded.

automatic

Continued from page 3 cockpit is controlling all of the important aspects of flying, which minimizes the decisions of the pilot. We certainly could make the same analogies in surgical practice today as our technology increases, especially using robotics, high-definition cameras, automatic stapling devices, energy sources and other modalities. The activities of surgeons have become inherently more remote from the patient just as the distance has lengthened between the pilot and his or her aircraft. Today’s surgeon has become distanced from the use of basic surgical technology such as palpating tissue, suturing, knot tying and other basic concepts that were the foundation for surgical care in the past. I guess one can take this analogy of automatism to its ultimate end, when the surgeon may not even be in the operating suite and may depend on others to place devices that will be manipulated from afar. This concept of automatic piloting in surgery could be detrimental in that it takes the human factor out of the equation. We cannot afford to wait until the plane is just a few feet off the tarmac to be ready to act in adversity. The introduction of new technology into our surgical world will continue, and hopefully it will enhance the operations that we perform and continue to minimize the secondary effects of pain, ileus and hernia formation. The surgeon of tomorrow, however, must continue to understand the anatomic and physiologic basics of what we do and not assume that the technology is a failsafe strategy. Just as my friend the pilot has noted, we need to take the controls as surgeons and to experience the effect of the wind and the weather in order to ensure that our technology will not lead us astray and let us down at the final moment of touchdown.

APRIL 2012

Brought to You by

REPORT IV Acetaminophen Improves Pain Management and Reduces Opioid Requirements in Surgical Patients: A Review of the Clinical Data and Case-based Presentations

cute pain is a common and suboptimally managed occurrence in the postoperative setting. In a survey of adults who had undergone surgical procedures in the United States, Warfield and colleagues noted that 77% reported pain after surgery, with 80% of affected individuals experiencing moderate to severe pain.1 Furthermore, postoperative pain is associated with various complications and poor

outcomes, including longer times to ambulation, longer hospital lengths of stay (LOS),2 higher rates of medical complications (eg, venous thromboembolic disease from reduced activity), and decreased patient satisfaction.3,4 Long-term complications also can arise from undertreated postoperative pain, including worse functional outcomes and a higher prevalence of chronic pain syndromes.2,4,5

Chair

Faculty

Eugene R. Viscusi, MD

Neil Singla, MD

Nasser Saad, PharmD

Associate Professor Director, Acute Pain Management Service Department of Anesthesiology Thomas Jefferson University Philadelphia, Pennsylvania

Founder and Chief Medical Officer Lotus Clinical Research Pasadena, California

Critical Care Pharmacy Manager Pharmacy Department New York Methodist Hospital Brooklyn, New York

Anthony Gonzalez, MD 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

Supported by

Jeffrey Stepanian, PA-C Senior Physician Assistant Orthopedics Evergreen Orthopedic Clinic Kirkland, Washington

REPORT

Table 1. Mean Pharmacokinetic Data After First Dose in Healthy Adults Parameter

OFIRMEV 1g (n=34)

Cmax

28.4 mcg/mL

Oral acetaminophen 1g (n=33) 15.1 mcg/mL

Tmax

0.28 h

0.72 h

t1/2

2.39 h

2.66 h

Area under the curve

47.0 mcg • h/mL

42.4 mcg • h/mL

Hepatic firstpass exposure

in postoperative patients. A review of the pharmacokinetics and pharmacodynamics will be followed by a discussion of data from clinical studies and case-based presentations.

IV Acetaminophen: Pharmacokinetics and Pharmacodynamics Although acetaminophen (paracetamol or N-acetyl[APAP]) produces a central analgesic effect, its precise mechanism(s) remain unknown. Postulated targets include cyclooxygenase isoenzymes, endogenous opioid or serotoninergic bulbospina pathways, and/or cannabinoid/ vanilloid tone.17 More recently, evidence suggests that acetaminophen is a TRPV-1 agonist that mediates response to pain.18 It also has an antipyretic effect, which may be mediated by inhibition of prostaglandin formation that otherwise acts to increase the temperature “set point” within the hypothalamus.19 This agent is available in oral and rectal formulations in the United States and also has been available as an IV formulation in Europe since 2002 and in the United States since 2010. One important advantage of acetaminophen over other analgesic agents used for the treatment of postoperative pain is its safety and tolerability profile.20 In contrast to opioids, acetaminophen does not produce sedation, respiratory depression, or ileus and constipation, nor is it associated with a risk for substance abuse or misuse.16 Nonsteroidal antiinflammatory drugs (NSAIDs) also are commonly used in the postoperative setting, but can compromise renal function and increase the risk for cardiovascular events.21 Furthermore, the adverse effects of NSAIDs on mucosal integrity and platelet function are associated with an increased risk for bleeding, a complication that can be particularly problematic in the postoperative setting.22 The pharmacokinetics and pharmacodynamics of IV acetaminophen have been well characterized (Table 1).16 IV infusion of acetaminophen results in a rapid elevation in plasma concentrations and higher peak levels compared with P-aminophenol

Acetaminophen Concentration, mcg/mL

Although monotherapy with opioids has been the mainstay of treatment for postoperative pain, these agents are associated with various adverse events (AEs)—nausea and vomiting, constipation, and ileus—that can occur even at low doses of opioids and can result in significant discomfort and longer hospital LOS.6 Some of the more severe AEs include respiratory depression and sedation, both of which increase the risk for respiratory failure, aspiration, decreased mobility, and falls.6,7 Thus, opioid monotherapy is not an adequate or appropriate strategy to improve pain management in postoperative patients. Over the past decade, multimodal analgesia has gained recognition for being an effective strategy in managing postoperative pain.8-10 Using different classes of analgesics each with different pathways and receptors, multimodal analgesia optimizes analgesic efficacy using lower doses of each of the respective agents, thus limiting the risk for dose-related AEs.10 Clinicians find this approach beneficial, particularly when using regimens that allow lower doses of opioids. Consequently, multimodal analgesia can improve recovery after surgery and ensure rehabilitation and transfer to the outpatient setting, while reducing overall costs.11,12 Agents with potency for modulating one or more discrete mechanisms of pain transmission and that have a good safety profile are favorable for multimodal analgesia.4 Additionally, analgesics that can be given intravenously can enhance bioavailability and earlier onset of analgesic effect in the immediate postoperative period, as surgical patients may experience postoperative nausea and vomiting or because the enteral route may not be an option based on the procedure.13 In fact, both parenteral opioids and major surgery have been shown to cause profound delays in gastric absorption, which have implications regarding optimal route of drug delivery during the perioperative period.14,15 IV acetaminophen (OFIRMEV™) can be integrated into a multimodal approach to optimize pain management effectively. In November 2010, the FDA approved the use of IV acetaminophen for the management of mild to moderate pain, the management of moderate to severe pain with adjunctive opioid analgesics, and the reduction of fever.16 The following material will discuss the use of IV acetaminophen as a component of multimodal analgesia

Mean Plasma Values

IV acetaminophen 1,000 mg ( n=6 ) Oral acetaminophen 1,000 mg (n=6) Rectal acetaminophen 1,000 mg 2 (n=6)

0 0

Yes

Time, h

Cmax, peak concentration; t½, half-life; Tmax, maximum plasma concentration

Figure 1. Acetaminophen plasma concentration over time.

Based on reference 16.

Based on reference 23.

REPORT

Clinical Studies of IV Acetaminophen Two pivotal trials investigated the use of IV acetaminophen for the treatment of postoperative pain. In the first study, 101 patients with moderate to severe pain following orthopedic surgery were given either 1 g IV acetaminophen or placebo

at 6-hour intervals for 24 hours.24 Supplemental IV patientcontrolled analgesia (IV-PCA) morphine was available to all patients if needed. IV acetaminophen was significantly better than placebo in terms of pain relief from 15 minutes to 6 hours postoperatively, median time to morphine rescue (IV acetaminophen: 3 hours; placebo: 0.8 hours), and morphine consumption over 24 hours (38.3 vs 57. 4 mg for placebo; 33% decrease in morphine consumption with IV acetaminophen) (Figure 3).24 An expanded analysis of these study data was recently published and demonstrated that the sum of pain intensity differences over 24 hours (SPID24) using a 0- to 100-mm visual analog scale (VAS) was significantly improved with IV acetaminophen when compared with placebo.36 Rescue medication consumption, requests, and actual administration were all lower in the IV acetaminophen group when compared with placebo for each 6-hour dosing interval.36 The other pivotal trial of IV acetaminophen was a double-blind, placebo-controlled, parallel-group study in which 244 patients with moderate to severe pain after abdominal laparoscopic surgery were randomized to receive either IV acetaminophen (1,000 mg every 6 hours or 650 mg every 4 hours) or IV placebo (100 mL every 6 hours or 65 mL every 4 hours) over 24 hours.37 Results showed that the primary end point, SPID24, was statistically more favorable than placebo (-194.1 vs -45.2 mm; P<0.007),37 and the time to meaningful pain relief was significantly shorter in patients receiving IV acetaminophen 1,000 mg compared with placebo (24.9 vs 53.9 minutes, P<0.003).37 Furthermore, IV acetaminophen was associated with a longer median time to first rescue medication, a lower proportion of patients requiring rescue medications, and significantly better

IV acetaminophen 1,000 mg (n=6) Oral acetaminophen 1,000 mg (n=6) Rectal acetaminophen 1,000 mg 2 (n=6)

Acetaminophen Concentration, mcg/mL

oral acetaminophen (Figure 1),23 sustained pharmacokinetic differences from oral acetaminophen over repeated doses, with a clinical analgesic effect that occurs within 5 to 15 minutes of administration.24 The clinical analgesic effect peaks within 1 hour and lasts for approximately 4 to 6 hours.16 These characteristics are favorable when compared with either oral or rectal formulations of acetaminophen. Specifically, the mean peak concentration after infusion of IV acetaminophen is approximately 70% higher than the mean peak concentration observed at an equivalent oral dose.16 Additionally, the higher peak concentration with IV acetaminophen remains far below the concentration considered the threshold for potential hepatotoxicity (150 mcg/mL at 4 hours post-administration).25-27 The median time to reach maximum plasma concentration (Tmax) for IV acetaminophen, is 15 minutes (at the end of infusion), whereas the Tmax for oral or rectal routes of administration is 45 to 75 minutes (depending on the formulation) or 3 to 4 hours, respectively.28,29 Pharmacokinetic parameter estimates for IV acetaminophen are similar in children, adolescents, and adults, when normalized for body weight.16 IV acetaminophen is not approved for patients under the age of 2.16 Acetaminophen readily penetrates the blood–brain barrier, and its analgesic and antipyretic effects correlate well with cerebrospinal fluid (CSF) levels.23,25,30 In fact, the rapid CSF penetration, combined with the earlier and higher peak concentration observed with IV acetaminophen, may be responsible for its more rapid onset of action and peak efficacy compared with oral or rectal acetaminophen (Figure 2).23,25,31 Regardless of route of administration, acetaminophen is metabolized by the liver via 3 primary pathways: glucuronidation (85%), sulfation, and oxidation.25,32 The latter pathway metabolizes acetaminophen into the hepatotoxic compound, N-acetylP-benzoquinone imine, which is subsequently metabolized to non-hepatotoxic compounds by glutathione.33 Thus, hepatotoxicity may occur in the setting of elevated hepatic levels of acetaminophen that overcome hepatic glutathione stores.25 This mechanism of hepatotoxicity becomes especially relevant when considering that absorption of drugs via the enteral route may result in locally high drug levels in the portohepatic circulation (ie, “first-pass” effect).25 By contrast, IV infusion of drugs results in rapid elevations of plasma levels while avoiding this first-pass effect. Indeed, first-pass pharmacokinetic models have shown that the IV route of administration reduced initial hepatic acetaminophen exposure by approximately 2-fold when compared with the oral route.25,34 In adults weighing more than 50 kg, a maximum dose of 4 g per day, in repeated doses, has been shown to be safe and well tolerated.16 The American Society of Anesthesiologists (ASA) Task Force on Acute Pain Management has endorsed the use of acetaminophen as a component of multimodal analgesia for the purposes of reducing reliance on opioids.35 The availability of this agent as an IV formulation furthers the ability to deliver acetaminophen in the postoperative setting. The ASA guidelines specifically advocate the use of nonopioid analgesics administered as first-line agents around the clock and for opioids to be used as adjunctive agents.35

Mean Cerebrospinal Fluid Values

Acetaminophen AUC 0-6 (SD) ( mcg • h/mL) IV: 24.9 (17.4) vs PO: 14.2 (52.1); P<0.0001 vs PR: 10.3 (24.6); P<0.0001

0 0

Time, h

Figure 2. Mean (SD) CSF acetaminophen concentration-time curves after IV, PO, and PR administration of 1,000 mg (N=6). AUC, area under the curve; CSF, cerebrospinal fluid; PO, oral; PR, rectal; SD, standard deviation Based on reference 23.

REPORT patient satisfaction with pain control when compared with placebo.37 Although both IV acetaminophen regimens, 1,000 mg every 6 hours or 650 mg every 4 hours, are efficacious, only the 1,000-mg dose produced a statistically significant difference in time to meaningful pain relief and total pain relief over the first dosing interval compared with placebo.37 IV acetaminophen also has been studied in other surgical populations. For example, Cakan and colleagues performed a prospective, double-blind, randomized placebo-controlled study of IV acetaminophen (1 g every 6 hours for 24 hours) in 40 patients undergoing lumbar laminectomy and discectomy.38 Pain scores at rest and on movement at multiple time points (12, 18, and 24 hours) were significantly lower with IV acetaminophen than with placebo.38 Furthermore, patients receiving IV acetaminophen had greater satisfaction with pain control (“excellent” rating: 45% vs 5%, P<0.05), lower morphine consumption at all evaluation times, and a decreased incidence of vomiting (P<0.05).38 The efficacy and safety of IV acetaminophen versus placebo has been investigated in patients following major abdominal and pelvic surgery requiring a planned admission to the intensive care unit (ICU). Memis and colleagues studied the efficacy of IV acetaminophen (1 g every 6 hours for 24 hours) or placebo (100 mL saline every 6 hours for 24 hours).39 Use of IV acetaminophen was associated with significantly lower pain scores and lower postoperative opioid consumption (61% reduction, P<0.05) and lower nausea and vomiting (P<0.05) and sedation scores (P<0.05) when compared with placebo. Patients were sent to the ICU still intubated, and those receiving IV acetaminophen demonstrated a shorter time to extubation compared with placebo (64.3 vs 204.5 minutes; P<0.05).39 In addition to these studies, IV acetaminophen has been

OFIRMEV 1 g + PCA morphine (n=49) Placebo + PCA morphine (n=52)

-33%

Morphine Consumption, mg



-46%

Conclusion



10 17.8 mg

9.7 mg

Over 6 h P<0.01

57.4 mg

38.3 mg

Over 24 h P<0.01

Figure 3. Morphine consumption following orthopedic surgery. PCA, patient-controlled analgesia Based on reference 24.

shown to exert similar benefits in the postoperative setting in adults undergoing a variety of other types of surgical procedures, including open abdominal, gynecologic, cardiac surgery, and thyroidectomy.40 Several studies have shown that these postoperative benefits also occurred in pediatric patients undergoing hernia repair, tonsillectomy, strabismus surgery, or dental procedures.41-44 Another benefit associated with the use of IV acetaminophen in the postoperative setting is its antipyretic properties. Peacock and colleagues reported that IV acetaminophen was as effective as oral acetaminophen in reducing fever.45 The significance of this effect is underscored by the fact that fever can adversely affect the patient’s metabolism and cardiovascular system, especially during the “temperature spike” phase with its shivering-induced increase in metabolic rate, norepinephrinemediated peripheral vasoconstriction, and increased arterial blood pressure.46 Additionally, antipyretic therapy may enhance patient comfort in the postoperative setting and could potentially reduce the risk for fever-associated delirium in the elderly or febrile seizures in the pediatric population.47,48 However, the role of postoperative fever or the use of antipyretics as independent predictors of outcomes has not been definitively studied in the postoperative setting. IV acetaminophen may be preferable for some surgical patients because, unlike other analgesics, it does not affect mental status, rates of bleeding, respiratory drive, gastric mucosal integrity, or renal function.21 However, acetaminophen doses in excess of 4 g daily have been associated with hepatic injury, and therapeutic doses have been associated with injury in patients who are at an increased risk for hepatotoxicity (eg, the elderly, alcoholics, and those who have preexisting liver disease or who are severely malnourished)16 ; thus, clinicians are encouraged to follow the recommended doses based on the patient’s weight and the appropriate time intervals when administering repeat doses (Table 2).16 Clinicians should be cautious to ensure that patients are not receiving more than one form of acetaminophen at a given time as overdoses have been associated with accidental administration of multiple drugs containing acetaminophen. In a study of 213 patients, the safety of IV acetaminophen was compared with standard of care, with results showing a numerically lower proportion of patients with elevated liver function tests in the IV acetaminophen group.49 Furthermore, in a meta-analysis of 36 studies involving the use of IV acetaminophen in the postoperative setting, there was no statistical difference in the rates of AEs, including liver function abnormalities, when comparing IV acetaminophen with placebo.50

Postoperative pain is a common problem with serious implications in terms of patient outcomes and health care costs. Opioid monotherapy is inadequate for postoperative pain management, and opioids and NSAIDs are associated with various common AEs that limit their overall utility. IV acetaminophen has properties well suited for use within a multimodal analgesia paradigm, including delivery by a nonoral route, fast onset, proven safety, and reduction in pain and fever as demonstrated by multiple clinical studies. When used as a component of multimodal analgesia, IV acetaminophen also can improve outcomes by reducing the amount of opioids required for pain control in the postoperative setting among a wide variety of surgical patients.

REPORT Table 2 . Recommended Dosing of IV Acetaminophen Age Group

Dose Given Every 4 h

Dose Given Every 6 h

Maximum Single Dose

Maximum Total Daily Dose of Acetaminophen (Any Route)

Adults and adolescents (≥13 y) weighing ≥50 kg

650 mg

1,000 mg

4,000 mg in 24 h

Adults and adolescents (≥13 y) weighing <50 kg

12.5 mg

15 mg/kg

15 mg/kg (up to 750 mg)

75 mg/kg in 24 h (up to 3,750 mg)

Children (2-12 y)

12.5 mg

15 mg/kg

75 mg/kg

Based on reference 16.

Case Study 1 A 47-year-old woman undergoing an anterior-posterior cervical spine procedure. Eugene R. Viscusi, MD

he patient had a 2-month history of severe, burning neck pain radiating to her arms and numbness and weakness of the upper extremities. Magnetic resonance imaging confirmed discogenic cord impingement at C 4-5-6 levels. She had had moderate control of her pain with oxycodone 10 mg every 4 hours over the past month. Otherwise, she was generally healthy. She required a general anesthetic with electrodiagnostic monitoring of her spinal cord and hence needed total IV anesthetic. The surgeon cautioned that NSAIDs would be contraindicated because of concerns for bone healing. A multimodal perioperative analgesic approach was planned. Because she used 40 to 60 mg of oxycodone per day, she was considered opioid-tolerant and special care would be taken to meet her opioid requirements and avoid opioid withdrawal. Approximately 1 hour before induction, 1 g IV acetaminophen was administered. Her surgery concluded in approximately 5 hours. Upon arrival to the postanesthesia care unit (PACU), she was awake, responsive, and complaining of pain. Because more than 4 hours had elapsed since her last dose of IV acetaminophen, 1 g was administered and her pain improved. IV-PCA with hydromorphone was initiated in the PACU. Because she was opioid-tolerant, the patientadministered dose was set at 0.3 mg with a 6-minute lock-out. Supplemental nursing doses were 0.6 mg as needed every 2 hours. IV acetaminophen was continued for 24 hours, 1 g every 6 hours to a maximum of 4 g every 24 hours. Oral pregabalin

150 mg was continued twice daily throughout the inpatient stay. Throughout the remainder of her operative day, she was able to titrate to comfort with supplemental IV-PCA. At 24 hours following surgery, the patient was awake, alert, comfortable, and had advanced to solid food. She described her pain as “aching now but the burning was much less than before surgery.” She said she was able to maintain reasonable comfort with her PCA but noticed improvement when IV acetaminophen was administered. She said the IV acetaminophen did not make her sleepy. She used approximately 20 mg of hydromorphone via IV-PCA over 24 hours. Oral conversion was requested with intent to discharge by postoperative day (POD) 3. She was placed on oxycodone extended release (ER) 20 mg twice daily, oxycodone immediate release (IR) 10 mg as needed every 4 to 6 hours, and IV acetaminophen was continued for an additional 24 hours. She remained comfortable throughout the next day. On POD 3, she was discharged home on oxycodone ER 20 mg, oxycodone IR 10 mg every 4 hours as needed, pregabalin 75 mg twice daily, and oral acetaminophen 975 mg (ie, 325 g x 3) every 6 hours with follow-up in 2 weeks. At 2 weeks, her pain was much improved and she was using her oxycodone IR 10 mg only 2 to 3 times per day. At this point, oxycodone ER and pregabalin were discontinued. She was maintained on oxycodone IR 10 mg every 4 to 6 hours as needed and acetaminophen 650 mg every 4 to 6 hours as needed.

Case Study 2 A 60-year-old woman undergoing total left knee revision. Jeffrey Stepanian, PA-C

he patient presented with a history of uncomplicated left knee total joint arthroplasty 2 years prior and an 18-month complaint of severe pain in her left knee causing significant mobility issues and requiring a walker. X-rays showed a loose tibial component, with no signs of infection. She was diagnosed

with aseptic loosening and a total left knee revision was planned. At the time of surgery, she had been taking oral oxycodone/ acetaminophen as her primary analgesic for the past 8 months, normally a total of 30 mg oxycodone and 2 g acetaminophen per day. Despite this, she complained of persisent, constant,

REPORT and severe pain at an 8 on a 10-point pain intensity scale. No other significant comorbidities were noted. The patient underwent a left total knee revision under general anesthesia. A regional nerve block was not performed. Prior to the skin incision at 7:30 AM, 1,000 mg IV acetaminophen was administered simultaneously with 2 g of cefazolin. Following the surgery, which lasted 181 minutes, the patient was taken to the PACU in stable condition. A Polar Care cryotherapy bladder was applied to the patient’s left knee. While in the PACU, the patient complained of pain at a level of 6 to 9/10. A bolus of 100 mcg IV fentanyl was administered, but failed to be effective. The patient was then administered boluses of 0.2 mg IV hydromorphone, and she required 4 doses while in the PACU still with a pain intensity reading of 7. The patient arrived on the orthopedic floor at 12:05 PM still complaining of significant pain. At 12:40 PM, 0.5 mg IV hydromorphone was administered with a pain intensity rating of 6/10. Almost 2 hours later, the patient was administered 15 mg IV ketoralac with no change in pain intensity. At 2:25 PM, the patient received a second dose of 1,000 mg IV acetaminophen, and at 4:45 PM, she received 10 mg oxycodone IR. The pain intensity rating was now 5/10. The patient received a second dose of 10 mg oxycodone IR at 9:15 PM, at which time the pain intensity rating was still 5/10. Cryotherapy and rehabilitation using a continuous motion machine were continued every 4 hours. IV acetaminophen was continued at a dose of 1,000 mg every 6 hours At the start of POD 1, the patient’s pain intensity rating was 5/10. The patient felt that her pain was controlled better

with IV acetaminophen than with oxycodone. She was given one last dose of IV acetaminophen at 7:15 AM, resulting in a pain intensity rating of 3/10. Cryotherapy and rehabilitation continued as before. The patient was able to ambulate 150 feet using a front-wheeled walker and ascend and descend a flight of stairs. With adequate pain control and good mobility, the patient was discharged home at 1:30 PM with oxycodone to use as needed. At her postoperative visit a week later, she confirmed that she never needed to use the oxycodone following discharge. She no longer required the walker and was using a cane for ambulation. This case describes a total knee revision where the patient was opioid-tolerant, and where the IV acetaminophen contributed to good-quality analgesia and allowed for discharge on POD 1. In addition, this facility has instituted a multimodal pre-op and post-op pain protocol for primary total knee arthroplasties that consists of a preoperative joint injection of 20 cc 2% lidocaine with epinephrine, a postoperative joint injection of 60 cc 0.25% bupivacaine with 2 mg of morphine sulfate, 15 to 30 mg IV ketorolac for 4 doses (unless medically contraindicated), continuous passive motion machine, cryotherapy, and IV/oral opiates. IV acetaminophen has now been added to the protocol commencing at time of induction and continuing every 6 hours for 24 hours. The addition of IV acetaminophen has resulted in an average hospital LOS of 1.7 days for primary total knee arthroplasties, a reduction of 0.6 days compared with the previous pain protocol.

Case Study 3 A 49-year-old woman undergoing a robotic laparoscopic sleeve gastrectomy. Anthony Gonzalez, MD

he patient had a history of diabetes, hyperlipidemia, hypertension, back pain, shortness of breath with exertion, gastroesophageal reflux disease, diabetic neuropathy, chronic foot infections, and was morbidly obese with a body mass index (BMI) of 46 kg/m2 (height: 64 inches, weight: 120 kg). She also had a past surgical history of a perforated bowel with history of exploratory laparotomy. She had failed multiple medical attempts for weight loss as prescribed by her primary care physician. These failed attempts included a grapefruit diet; low-carb diets; restricted caloric diets in combination with exercise, hypnosis, and acupuncture; and use of diet pills such as phentermine and orlistat. She sought consultation for weight loss surgery for morbid obesity and comorbid medical problems. After a complete surgical and psychological evaluation, the patient was offered 3 procedures for consideration: adjustable gastric banding, sleeve gastrectomy, and gastric bypass. Based on her age, BMI, and comorbid medical issues, the sleeve gastrectomy was deemed the best option. After a long discussion and obtaining consent, she agreed to proceed with the bariatric procedure. The patient underwent a robotic laparoscopic sleeve gastrectomy uneventfully. This procedure involved the creation of 5 small (5-mm) incisions and had an operative time of nearly

1 hour. In addition to preoperative antibiotic and prophylaxis for deep vein thrombosis, she was given a preoperative dose of 1 g IV acetaminophen. She was maintained without anything to eat or drink for the first 24 hours following surgery. Postoperatively, she was prescribed IV acetaminophen 1 g every 6 hours around the clock for mild to moderate pain. She was given hydromorphone 1 to 2 mg every 3 hours as needed for severe or breakthrough pain. During the first 24 hours after surgery, the patient did not require any opioids for pain relief. She only received IV acetaminophen during the first 24 hours. Upon questioning by the nursing staff, she stated that the pain was well relieved and did not require additional medication. On POD 1, now able to eat and drink, the patient was offered acetaminophen/hydrocodone elixir. She tolerated clear liquids, but did not ask for any pain medication. The patient was discharged on POD 2 with a prescription for acetaminophen/hydrocodone elixir. At her follow-up office visit, the patient was doing well and reported no need to use the prescribed medication for pain relief. She reported excellent pain control and was “very satisfied” with the care at the hospital. She noted that the overall experience of undergoing and recovering from this surgery was much better than her previous surgical experience.

Note: The case studies presented are composite and are not intended to identify specific patients.

REPORT

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35. American Society of Anesthesiologists. Practice Guidelines for acute pain management in the perioperative setting: an updated report by the ASA Task Force on acute pain management. Anesthesiology. 2012;116(2): 248-273.

19. Graham GG, Scott KF. Mechanism of action of paracetemol. Am J Ther. 2005;12(1):46-55. 20. Joshi GP. Multimodal analgesia techniques and postoperative rehabilitation. Anesthesiol Clin North Am. 2005;23(1):185-202. 21. Graham GG, Graham RI, Day RO. Comparative analgesia, cardiovascular and renal effects celecoxib, rofecoxib, and acetaminophen (paracetemol). Curr Pharm Des. 2002;8(12):1063-1075. 22. Leese PT, Hubbard RC, Karim A, Isakson PC, Yu SS, Geis GS. Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: a randomized, controlled trial. J Clin Pharmacol. 2000;40(2): 124-132. 23. Singla NK, Parulan C, Samson R, et al. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral or rectal acetaminophen. Proceedings and Abstracts of the 10th Annual American Society of Regional Anesthesia and Pain Medicine Pain Medicine Meeting and Workshops. New Orleans, Louisiana; November 17-20, 2011. 24. 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. 25. Jahr JS, Lee VK. Intravenous acetaminophen. Anesthesiol Clin. 2010;28(4): 619-645. 26. Gregoire N, Hovsepian L, Gualano V, Evene E, Dufour G, Gendron A. Safety and pharmacokinetics of paracetamol following intravenous administration of 5 g during the first 24 h with a 2-g starting dose. Clin Pharmacol Ther. 2007;81(3):401-405. 27. Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. Clinical Toxicology. 2002;40(1):3-20. 28. Moller PL, Sindet-Pedersen S, Petersen CT, Juhl GI, Dillenschneider A, Skoglund LA. Onset of acetaminophen analgesia: comparison of oral intravenous routes after third molar surgery. Br J Anaesth. 2005;94(5): 642-648. 29. Birmingham PK, Tobin MJ, Henthorn TK, et al. Twenty-four-hour pharmacokinetics of rectal acetaminophen in children: an old drug with new recommendations. Anesthesiology. 1997;87:244-252. 30. Jensen LL, Handberg G, Brosen K, Schmedes A, Ording H. Paracetamol concentrations in plasma and cerebrospinal fluid. Eur J Anaesthesiol. 2004; 21(suppl 32):193. Abstract A-785. 31. Pan CP. Breitmeyer JB, Royal MA. IV acetaminophen PK/PD correlation following total hip arthroplasty. Nature. 2010;87(suppl 1):S63. Abstract PIII-75. 32. Gelotte CK, Auiler JF, Lynch JM, Temple AR, Slattery JT. Disposition of acetaminophen at 4, 6, and 8 g/day for 3 days in healthy young adults. Clin Pharmacol Ther. 2007;81(6):840-848. 33. Manyike PT, Kharasch ED, Kalhourn TF, Slattery JT. Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther. 2000;67(3):275-282.

36. Sinatra RS, Jahr JS, Reynolds L, et al. Intravenous Acetaminophen for pain after major orthopedic surgery: an expanded analysis. Pain Pract. 2011 Oct 19. [Epub ahead of print] 37. 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. 38. Cakan T, Inan N, Culhaoglu S, Bakkal K, BaĹ&#x;ar H. Intravenous paracetamol improves the quality of postoperative analgesia but does not decrease narcotic requirements. J Neurosurg Anesthesiol. 2008;20(3):169-173. 39. 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. 40. Macario A, Royal MA. A literature review of randomized clinical trials of intravenous acetaminophen (paracetamol) for acute postoperative pain. Pain Pract. 2011;11(3):290-296. 41. Alhashemi JA, Daghistani MF. Effects of intraoperative i.v. acetaminophen vs i.m. meperidine on post-tonsillectomy pain in children. Br J Anaesth. 96(6): 790-795. 42. Murat I, Baujard C, Foussat C, et al. Tolerance and analgesic efficacy of a new i.v. paracetamol solution in children after inguinal hernia repair. Paediatr Anaesth. 2005;15(8):663-670. 43. Cok OY, Eker HE, Pelit A, et al. The effect of paracetamol on postoperative nausea and vomiting during the first 24h after strabismus surgery: a prospective, randomised, double-blind study. Eur J Anaesthesiol. 2011;28(12):836-841. 44. Alhashemi JA, Daghistani MF. Effect of intraoperative intravenous acetaminophen vs. intramuscular meperidine on pain and discharge time after paediatric dental restoration. Eur J Anaesthesiol. 2007;24(2):128-133. 45. Peacock WF, Breitmeyer JB, Pan C, Smith WB, Royal MA. A randomized study of the efficacy and safety of intravenous acetaminophen compared to oral acetaminophen for the treatment of fever. Acad Emerg Med. 2011;18(4): 360-366. 46. Nakamura K. Central circuitries for body temperature regulation and fever. Am J Physiol Regul Integr Comp Physiol. 2011;301(5):R1207-R1228. 47. Isaacs SN, Axelrod PI, Lorber B. Antipyretic orders in a university hospital. Am J Med. 1990;88(1):31-35. 48. Plaisance KI, Mackowiak PA. Antipyretic therapy: physiologic rationale, diagnostic implications, and clinical consequences. Arch Intern Med. 2000;160(4):449-456. 49. Candiotti KA, Bergese SD, Viscusi ER, Singla SK, Royal MA, Singla NK. Safety of multiple-dose intravenous acetaminophen in adult inpatients. Pain Med. 2010;11(12):1841-1848. 50. Tzortzopoulou A, McNicol ED, Cepeda MS, Francia MB, Farhat T, Schumann R. Single dose intravenous propacetamol or intravenous paracetamol for postoperative pain. Cochrane Database Syst Rev. 2011;(10):CD007126.

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, 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 ÂŠ 2012, 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.

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In the News

GEnERAlSURGERynEwS.cOM / GEnERAl SURGERy nEwS / APRIl 2012

Experts Discuss Endoscopic Repair of Colonic Perforations B y M oniCa J. s Mith new York—The time may have arrived when endoscopists can, and should, treat perforations in some patients who would have been referred to surgery, according to G.S. Raju, MD, professor in the Department of Gastroenterology, Hepatology and Nutrition at the University of Texas MD Anderson Cancer Center, Houston, who spoke at the annual course of the New York Society for Gastrointestinal Endoscopy, held in December. “You could actually manage these patients by endoscopy,” Dr. Raju told meeting attendees, summarizing his review of the topic that was published in the December issue of Gastrointestinal Endoscopy (2011;74:1380-1388). “Over the past couple of decades, we have learned to control bleeding, and it is now extremely rare for a patient to go to surgery to control that complication,” Dr. Raju said. “But we have not done the same thing for perforations. So in this past decade, we are making progress to treat that complication.” Colonoscopy-related perforations generally result from mechanical or thermal injury during polypectomy. They are relatively rare—depending on the type of resection used to remove polyps, the risk for perforation can vary from 0.1% to 5%, with endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) carrying the highest risk. When perforations do occur, they result in an air leak within seconds. If the leak is not recognized and repaired quickly, the injury can result in tension pneumoperitoneum. After time, fluid will leak and lead to peritonitis and sepsis. Traditionally, upon recognizing that a perforation has occurred, an endoscopist would refer the patient to a surgeon, who would likely take the patient to the operating room. The patient would undergo general anesthesia, a laparotomy or thoracotomy, and dissection to identify the perforation, followed by repair of the perforation and a fairly extensive recovery. “This approach has a significant morbidity and mortality, which could be avoided if we take a different route of endoscopy closure,” Dr. Raju explained. “That perforation is going to be small, and we can close it with clips so that the patient doesn’t need surgery. That’s a paradigm shift from surgical to nonsurgical management.”

moving Toward Nonsurgical management Only a decade ago, surgery was the only option for patients who suffered perforation—the tools and techniques had not yet been developed to allow endoscopists to manage perforations on the spot. “We started [laboratory animal research] to answer the questions: Could perforations be closed? If so, could we create a leakproof sealing? How far could we push ourselves in terms of the size of the polyp perforation we could close, and how does it compare with surgery?” Dr. Raju said. Dr. Raju and his team found that indeed they could apply a leakproof seal on perforations, and that these

repairs, along with sidestepping all the risks associated with major surgery, also resulted in fewer adhesions than surgery. “We know now how to close a perforation that is linear and a perforation that is horizontal,” he said. Of course, prevention is the most important factor in managing perforations. Preventative measures include ensuring thorough bowel preparation, maintaining a dry field and proper colonoscope technique. Examination of any resection site is essential to identify any perforation that might have occurred and to gauge the next step. “One-third of perforations can be diagnosed at the time of the procedure, and this gives us an opportunity to close a perforation,” Dr. Raju said. It is also important to identify those patients who will develop post-polypectomy syndrome or a perforation after the procedure, and to recognize which patients will benefit from prophylactic closure of a defect. Delayed perforations usually occur within the first day or two, and up to two weeks after the procedure. After two weeks, the patient is in the clear. “If we want to catch all the perforations that happen in endoscopy, we should set up a system whereby you contact the patients within 14 days after the procedure,” Dr. Raju said.

A Surgeon’s Perspective George Chang, MD, MS, associate professor of surgical oncology and associate medical director of the Colorectal Center at MD Anderson Cancer Center, commended Dr. Raju and his colleagues for their work in the endoscopic management of perforations. “We’ve long identified that patients with small perforations who are clinically asymptomatic and identified with minimal pneumoperitoneum or pneumatosis after endoscopic procedures often can be managed without an operation. Obviously, the goal of treating patients is to treat them in as minimally invasive a way as possible, but without compromising safety, and that’s the key,” said Dr. Chang, who is director of clinical operations in the Minimally Invasive and New Technologies in Oncologic Surgery Program, at MD Anderson. “I would recommend engaging surgical consultation earlier rather than later,” he noted. “Patients will need to be very closely monitored to ensure that a more significant complication has not occurred.” Close monitoring is also important in the event that the endoscopic repair fails, despite initially appearing to have worked. “The closure may be attempted and may appear to be technically successful, but the patient could have a clinical deterioration,” Dr. Chang explained. “You cannot do this [repair] and then forget about the patient.” Another point Dr. Chang stressed is that an endoscopist faced with a complex polyp should take careful stock of his or her own skills in EMR or ESD before attempting to remove the lesion. “In the heat of the battle, it can sometimes be difficult to make some of those decisions. This is clearly an advanced technique that only appropriately trained endoscopists should attempt. We must remember to first, do no harm.” Dr. Chang added that the endoscopic management of

perforations is not for everyone: “not for every patient, not for every polyp and not for every endoscopist.”

Training opportunities Considering the rarity of colonoscopy-related perforations and the challenges of endoscopic management, some may wonder what would motivate an endoscopist to learn these techniques. “I think, like anything else, this takes time for people to get used to,” Dr. Raju said. “You don’t lose anything if you try to close it; if you can’t, the patient needs to go to surgery. It’s not much different from using a biopsy forceps—it’s a bit of a technical detail. The way I look at this is that you need to learn the technique of clip closure so that you can push yourself to do additional things you would not have otherwise undertaken.” In other words, endoscopists who learn to close perforations may be able to apply that knowledge to other challenges in endoscopy. “Learning the techniques to close a perforation will equip you to do a little more, to take the extra steps to remove the large, flat lesions that would traditionally have been sent to surgery,” he said, noting that he and his colleagues found this to be true for themselves as they gained confidence in managing perforations endoscopically. As with learning any new skill or technique, it does take time and practice to manage perforations with throughthe-scope or, less commonly, over-the-scope clips. Furthermore, gaining experience may be difficult considering the relative rarity of perforations. Dr. Raju suggests starting small, such as managing routine defects after polyp removal, to gain skill and confidence with using endoscopic clips. “When we remove polyps, we often create defects, which are not through and through. You can try to close those defects [with a clip] and gain experience that way,” he suggested. “If you have a deep defect, you could reinforce the wall and prevent a delayed perforation. This is something you can work on in your practice.” Drs. Raju and Chang reported no relevant conflicts of interest.

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opinion

GEnERAlSURGERynEwS.cOM / GEnERAl SURGERy nEwS / APRIl 2012

An Evolution in the Management of Colonoscopic Perforations One Surgeon’s Experience B y g ary h. h oFFMan , MD

ndoscopic management using through-the-scope clips is a proven tool for both preventing a perforation after polypectomy and for treating a recognized perforation (see “Endoscopic Management of Colonic Perforation,” page 11). However, a more common clinical situation is the presentation and recognition of the perforation in the recovery room or after the patient has been discharged. At this point, the patient is in severe pain. The abdominal exam, a mainstay of physical diagnosis, is of no value as the abdomen is distended and tense, rendering the exam useless in following the patient’s clinical course. Operative intervention is commonly the next step. I would suggest an additional approach in the management of many of these patients with an endoscopic perforation: immediate, ultrasound-guided abdominal paracentesis, followed by vigilant, nonoperative observation. The patient will be relatively pain-free after the paracentesis, allowing the surgeon to better use the abdominal exam as a guide to continuing close observation or proceeding to the operating room. To follow this course, the surgeon must possess surgical fortitude, vigilance and the flexibility to change course should the clinical findings warrant a change.

Painful experiences In my experience with more than 13,000 colonoscopies performed over 28 years, four of my patients have experienced perforations, a rate of 0.03%. National rates for colonoscopic perforations range from 0.1% to 0.3%. All four perforations occurred in patients who had undergone a complete colon preparation prior to the colonoscopy. All perforations were recognized in the recovery room. All of the procedures had been performed without difficulty and without a concomitant polypectomy. None of these patients had a large, gaping, scopeinduced colotomy. The first patient underwent an immediate laparotomy. Upon opening the abdomen, there was a rush of free air, but a site of perforation or other abnormality was not found. No other intervention was undertaken and the patient did well. I began to re-evaluate the treatment approach to an endoscopic perforation. I wondered if the cause of the patient’s abdominal pain was secondary to the abdominal free air with peritoneal

distention, or due to either a leak of colonic contents or the actual colotomy itself. Was an immediate laparotomy really necessary? An endoscopic perforation might be analogous to a self-sealing, diverticular perforation. In many pain-free patients with a diverticular perforation and an unprepared or “dirty” bowel, treatment is often expectant and nonoperative. I came to believe that it might be possible to avoid operative intervention in patients with post-colonoscopy perforations. I postulated that the intense postperforation abdominal pain was a result of abdominal distention and peritoneal membrane distention from the intraabdominal free air and not from the perforation itself or from the leak of any colonic contents.

what if I could monitor a pain-free patient with an iatrogenic perforation? would I better be able to follow the patient’s clinical course without being adversely influenced by a tense, painful abdomen? The Nonoperative Approach Begins The next two patients whose perforations were diagnosed in the recovery room had extensive diverticulosis with thin, fragile diverticular walls. I suspected that the insufflation of air, or the movement of the scope through the colon had caused the perforation. I immediately hospitalized these two patients, ordered nothing by mouth and prescribed antibiotics and liberal amounts of pain medication. I opted then for close observation without immediate surgical intervention. I watched these two patients closely, knowing that I could handle the problem if there was a turn for the worse. Initially, I evaluated them three times each day in the hospital and awaited signs of normal flatus production, signaling the return of bowel function. I was fully prepared to operate with even the smallest worrisome physical finding or with worsening laboratory data. Both patients did well, with resolution of abdominal pain in four to six days. The abdominal bloating lasted longer but eventually resolved. I took heart that I had been correct in my treatment logic and in my patient care.

The Nonoperative Approach evolves The decision to operate often is driven by the sight of a patient who is in

intense abdominal pain. Urgent operative intervention for a perforated viscus is the most common method of treatment. This is one of the first lessons learned during residency. However, most surgeons do not perform a high volume of colonoscopies and therefore do not have a wide breadth of experience in this specific area. When you are a hammer, everything looks like a nail. Surgeons are often hammers. However, not all patients are nails and not all postcolonoscopy perforations require surgical intervention. What if I could monitor a pain-free patient with an iatrogenic perforation? Would I better be able to follow the patient’s clinical course without being adversely influenced by a tense, painful abdomen? This situation would be similar to that of observing a patient who has a perforated, self-sealing colonic diverticulum and minimal abdominal pain. Perhaps not all nails would require immediate hammering.

ultrasound, Paracentesis and close observation When I encountered my fourth patient with a post-colonoscopy perforation, I asked the radiologist to remove all of the intra-abdominal free air using ultrasound guidance. With this accomplished, my patient simply sat in the hospital, pain-free and bored. After the return of bowel function, the patient was started on a clear liquid diet, which was accompanied by mild cramping that quickly resolved. The patient was discharged home four days later on a progressive diet. Rather than using the distended and tender abdomen as reason to operate, I had been able to monitor a pain-free patient and use any new onset of pain as a marker for a worsening situation, possibly requiring surgical intervention. This did not happen and no other intervention was necessary.

A Question for you To Ponder Although I have a new perspective on the evaluation and treatment of postcolonoscopy perforations, I hope never to need to use this knowledge or experience. A nonoperative treatment protocol requires extreme vigilance and diligence with frequent examinations of the patient, the vital signs and labs as well as in-depth training in the care of abdominal emergencies. I knew that I could successfully handle the problem no matter the clinical course, and I could always turn quickly to the scalpel if anything were to change. I was willing to shoulder the load of watchful waiting,

I asked the radiologist to remove all of the intra-abdominal free air using ultrasound guidance. with this accomplished, my patient simply sat in the hospital pain-free and bored. while gaining some new gray hairs in the process. A surgeon is often the final treating physician or consultant responsible for a decision to operate or not. In the end, the surgeon must decide if he or she has the experience, the skills and the surgical fortitude to follow a patient who traditionally, and most commonly, is taken to the operating room immediately. The surgeon will experience considerable anxiety while pursuing this nonoperative path. Obviously, the anxiety will lessen with an improving clinical course, but the wait can be trying for the surgeon. A comfortable, pain-free patient will allow the surgeon some increased measure of objectivity, so that the patient can be followed, and the symptom of pain can be used more objectively as a signpost, rather than an indication for immediate operative intervention. Finally, a fifth patient underwent a rather large cecal polypectomy, at which time I placed three prophylactic through-the-scope clips for added protection against a perforation. The patient called the day after the procedure, complaining of right lower quadrant pain. A computed tomography scan showed two small extraluminal air bubbles. The pain resolved almost immediately with hospitalization, bed rest, intravenous fluids and antibiotics. The patient was discharged home. Through-the-scope clips have become a major adjunct in our armamentarium and the authors are to be commended for their analysis of the endoscopic management of colonic perforations. But, as always and in any situation, experience, planning and preparedness are our best tools. —Dr. Hoffman is an attending surgeon, in the Divisions of Colorectal Surgery and General Surgery, and an instructor in the Colon and Rectal Surgical Fellowship at Cedars-Sinai Medical Center, Los Angeles. He is a senior member of Los Angeles Colon and Rectal Surgical Associates (www.lacolon.com).

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In the News gloom

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GEnERAlSURGERynEwS.cOM / GEnERAl SURGERy nEwS / APRIl 2012

doom

withdrawn, this drug was the only available pharmaceutical specifically designed to treat sepsis. PROWESS-SHOCK was launched in 2008 at the request of the European Medicines Agency (EMA). In 2007, the EMA said the positive PROWESS results had not been reproduced in other studies and encouraged Eli Lilly to conduct a randomized placebo-controlled study in patients with severe sepsis and documented organ failure to confirm that the drug’s benefits outweighed the risks, the most serious being bleeding. PROWESS-SHOCK included 1,696

University Hospital, in Brussels, Belgium. In the beginning, the prospects for drotrecogin alfa were promising. The drug was approved in 2001 based on results from the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial, which demonstrated a 6% improvement in 28-day mortality for patients with severe sepsis who received the drug (30.8% vs. 24.7%; P=0.05). Until it was

patients with severe sepsis and septic shock (Table). The patient population was “a subset with a strong efficacy signal in PROWESS,” said B. Taylor Thompson, MD, professor of medicine at Massachusetts General Hospital and Harvard Medical School, in Boston, who presented the data at SCCM. The 28-day mortality in patients receiving drotrecogin alfa (n=846) was 26.4% compared with 24.2% in the placebo arm (n=834), which was not a statistically significant difference (P=0.31). Mortality was not improved in the subset of patients with severe protein C deficiency. No increase in serious

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‘I understand [Xigris] is a difficult and expensive compound to produce, and so unless there is some orphan status, it would probably not be a good business [decision to resume production].’ —Judith A. Jacobi, PharmD bleeding events during infusion was identified. Compared with the patients in the original PROWESS study, patients in PROWESS-SHOCK had fewer primary sites of infection in the lung (44% vs. 54%) and abdomen (3% vs. 20%), whereas more patients in PROWESS-SHOCK experienced organ failure and received mechanical ventilation (82% vs. 75%). But, regardless of differences, said Dr. Thompson, the PROWESS-SHOCK population was one in which the drug would have been expected to work. Dr. Thompson said subgroup analyses would be published in an upcoming journal article, but “we found no benefit in any of the prespecified subgroups.”

Anatomy of a Failed Trial At the SCCM meeting, Dr. Vincent offered a number of possible explanations for the trial’s failure. Perhaps, he said, the original PROWESS was positive by chance and the drug never worked. Perhaps the mortality rate, which has fallen in recent years due to better care, makes detecting a difference more difficult. Perhaps PROWESS-SHOCK suffered from the drug being available on the market for the best candidates, and the randomized patients were not good candidates for the drug. “I would vote for the third option, but nobody knows,” said Dr. Vincent. According to Dr. Thompson, the mortality rate in the placebo arm of PROWESS-SHOCK (24%) was lower than projected (32%). This is consistent with other recent randomized trials. In a study evaluating the small molecule TAK-242, the 24.2% mortality rate identified in the placebo arm was lower than the expected 40% (Crit Care Med 2010;38:1685-1694). The nine-year observational ARISE (Australasian Resuscitation in Sepsis Evaluation) study identified a 21% mortality rate for patients with sepsis. “If the attributable mortality from sepsis has been reduced, much larger sample sizes will be needed to detect potential beneficial effects of new therapies. That is just simple math,” said Dr. Thompson. “If the lower attributable mortality from sepsis is due to early and more effective care, then the severity and/or consequences of aberrant innate immune activation, and thus the

In the News

GEnERAlSURGERynEwS.cOM / GEnERAl SURGERy nEwS / APRIl 2012

Table. ProweSS-SHocK Patient Inclusion criteria Meet at least two of the four systemic inflammatory response syndrome criteria Clear evidence of infection Received IV fluid resuscitation of ≥30 mL/kg administered 4 h before or after initiation of vasopressor therapy Continuous requirement of at least one of four vasopressors for at least 4 h

or not] to continue to sell this agent is a business decision by Lilly. I understand it is a difficult and expensive compound to produce, so unless there is some orphan status, it would probably not be a good business [decision to resume production]. If they continue to make it available on an emergency basis, I am sure there would be opportunities to use it in selected patients.” According to a representative for Lilly, the company is not pursuing any further avenues for the drug.

conflicting results Not all the news presented on

drotrecogin at SCCM was bad. Two small studies showed positive results for the drug in bone marrow transplant patients, a group that was excluded from PROWESS because of their increased risk for bleeding (abstracts 369 and 705). In a third study, researchers used the Co-operative Antimicrobial Therapy of Septic Shock database to investigate retrospectively the real-world effectiveness of drotrecogin alfa (abstract 39). The database includes consecutive patients older than age 18 years who were admitted to 29 academic and community intensive care units between 1997 and 2007. “It is essentially

a pseudo-randomization method,” said Emily Rimmer, MD, hematologist from the University of Manitoba, in Winnipeg, Canada, who presented the study. The final study cohort included 310 patients who received drotrecogin and 630 patients who did not. The researchers identified a 7% absolute reduction in 30-day mortality associated with the use of drotrecogin (34.5% vs. 41.5%; P=0.05). Subgroup analyses identified a significant reduction in mortality in patients in the lowest APACHE II quartile (9.5% vs. 22%; P=0.04) and consistent but see glOOm and dOOm page 18

Hypoperfusion (renal, acidosis, hepatic) Drotrecogin initiated within 24 h of shock onset

therapeutic target, will be reduced.” Dr. Thompson presented data from 11 registries showing a benefit in mortality for the use of drotrecogin, including a U.S. registry of 1,576 patients (mortality, 47% vs. 41%) and a French registry of 1,049 patients (68% vs. 47%). Questioning whether a responsive subset of patients could have been included in the registries that were excluded in the PROWESS-SHOCK trial, he said it is possible that registries of usual-care practices include under-resuscitated patients with greater degrees of inflammation and/ or organ/endothelial injury than what was seen in PROWESS-SHOCK. “If there is some subset out there that responds to this drug, you would think that we would have a few of [these patients] in PROWESS-SHOCK.” According to Dr. Thompson, severe sepsis and septic shock phenotypes are unreliable surrogate markers for aberrant or excessive innate immune/coagulation system activation. “We need to better understand innate immune suppression,” he said. “We need enrichment strategies like the cancer community—biomarkers and genetics—to find the responsive subsets. But I think the severe sepsis phenotype is obsolete.” Judith Jacobi, PharmD, a critical care pharmacist at Indiana University Health Methodist Hospital, Indianapolis, and outgoing president of the SCCM, said the results of PROWESS-SHOCK are “very disappointing.” She added that she will miss the drug the most when treating patients who have sepsis-induced coagulopathy. “The mechanism of action of the activated protein C is geared toward that underlying problem of sepsis coagulopathy.” When Dr. Thompson was queried as to whether patients with sepsis coagulopathy were included in the trial, he responded “only unless severe thrombocytopenia was also present.” Dr. Jacobi said, “I suspect that the decision [whether

Less pain. Less opioids. OFIRMEV® provides significant pain relief*1 • OFIRMEV 1 g (Q6h) + patient-controlled analgesia (PCA) morphine demonstrated significant pain relief vs placebo + PCA morphine (P<0.05 over 6 h)1 • OFIRMEV 1 g (Q6h) + PCA morphine showed greater reduction in pain intensity over 24 h (SPID24)† compared to placebo + PCA morphine (P<0.001)2

OFIRMEV reduces opioid consumption*1 • OFIRMEV 1 g (Q6h) + PCA morphine significantly reduced morphine consumption vs placebo + PCA morphine (–46% over 6 h, P<0.01; –33% over 24 h, P<0.01)1 • The clinical benefit of reduced opioid consumption was not demonstrated

Schedule OFIRMEV Q6h for the first 24 h • Continue OFIRMEV or transition to PO analgesia based on patient assessment

Indication OFIRMEV 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 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. Do not exceed the maximum recommended daily dose of acetaminophen. Administration of acetaminophen by any route in doses higher than recommended may result in hepatic injury, including the risk of severe hepatotoxicity and death.

OFIRMEV should be administered only as a 15-minute intravenous infusion. Discontinue OFIRMEV immediately if symptoms associated with allergy or hypersensitivity occur. 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. OFIRMEV is approved for use in patients ≥2 years of age. The antipyretic effects of OFIRMEV may mask fever in patients treated for postsurgical pain. 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.com. Please see Brief Summary of Prescribing Information on adjacent page or full Prescribing Information at OFIRMEV.com.

*Randomized, double-blind, placebo-controlled, single- and repeated-dose 24-h study (n=101). Patients received OFIRMEV 1 g + PCA morphine or placebo + PCA morphine the morning following total hip or knee replacement surgery. Primary endpoint: pain relief measured on a 5-point verbal scale over 6 h. Morphine rescue was administered as needed. †SPID24=sum of pain intensity differences, based on VAS score, from baseline, at 0 to 24 h.

References: 1. Sinatra RS, Jahr JS, Reynolds LW, Viscusi ER, Groudine SB, Payen-Champenois 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;102:822-831. 2. Data on file. Cadence Pharmaceuticals, Inc.

OFIRMEV and the OFIRMEV dot design are trademarks of Cadence Pharmaceuticals, Inc.

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In the News gloom

and

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nonsignificant reductions in mortality among all remaining quartiles. “The results of our study are at odds with the recent PROWESS-SHOCK study, and we believe that our data may help to provide some insight into possible reasons for these discrepant results,” said Dr. Rimmer. “Our study suggests that the mortality rate of patients with septic shock is decreasing over time. This may be related to improvements in the supportive care of these patients.”

GEnERAlSURGERynEwS.cOM / GEnERAl SURGERy nEwS / APRIl 2012

The bad news from PROWESSSHOCK is compounded by disappointing results from studies assessing other agents. Herwig Gerlach, MD, PhD, director of the Department of Anesthesiology, Critical Care and Pain Management at the Vivantes Klinkikum Neukoelln Hospital in Berlin, discussed a number of negative prospective trials and meta-analyses that evaluated immunoglobulin use in sepsis. For this reason, the 2012 Surviving Sepsis Campaign guidelines suggest that IV immunoglobulin G not be used in adult patients with severe sepsis/septic shock. The investigational agent talactoferrin

(Agennix) is the most recent drug to take a nosedive. Researchers were excited when a randomized Phase II trial involving 190 patients with severe sepsis showed that talactoferrin reduced 28-day all-cause mortality (26.6% vs. 14.6%; P=0.04). On Feb. 2, however, Agennix announced that the promising results did not pan out in the Phase III OASIS (Oral Talactoferrin in Severe Sepsis) trial. Preliminary data from the 930-patient trial showed 28-day mortality was higher in the talactoferrin arm than in the placebo arm. At the SCCM meeting, Steven

LaRosa, MD, director of the Division of Infectious Disease and associate professor of medicine at Texas A&M Health Science Center College of Medicine, in Temple, presented data from the ACCESS trial that evaluated the tolllike receptor 4 (TLR4) inhibitor eritoran tetrasodium. This Phase III randomized, double-blind trial compared eritoran with placebo in patients with severe sepsis. The international, multicenter trial, which analyzed data from almost 2,000 patients, found that eritoran did not improve the primary end point of all-cause mortality at day 28 or the secondary end point of mortality at one year. “There is no separation in the curves,” said Dr. LaRosa. No benefit could be identified in any subgroups. “We are left with endotoxin being thought to be a key mediator of sepsis pathology and a drug that, at least in vitro, appears to block TLR4 signaling quite well, and yet, we have a very stone-cold negative result.” According to Dr. LaRosa, large sepsis trials are challenging for a myriad of reasons including patient heterogeneity, different practice patterns and sepsis involving a variety of pathogens and infection sites. “It is hard to think that a single agent is going to behave the same in all the patients,” said Dr. LaRosa. He pointed out, however, that in the case of eritoran, they might have just picked the wrong agent or a multi-targeted attack is required. Another possible explanation is that once septic shock has begun, it is too late to intervene with a TLR4 inhibitor. According to Dr. Vincent, biomarker analysis and genomic research are the future of sepsis clinical trials. A study published in December concluded that similarities in gene expression patterns between different injuries reveal a fundamental human response to severe inflammatory stress, with genomic signatures surprisingly far more common than different (J Exp Med 2011;208:2581-2590). Dr. Thompson said that if Phase II trials with strong signals for efficacy do not predict results in Phase III trials, then all of the efficacy risk is carried over to Phase III trials. Although this is not attractive to industry, neither is the fact that positive results from a Phase III trial may not predict the success of a second Phase III trial, as in the case of PROWESS-SHOCK. Ongoing clinical trials are evaluating AZD9773 (AstraZeneca), an antibody against tumor necrosis factor, and endotoxin removal by hemoperfusion (Spectral Diagnostics). Dr. Thompson disclosed relationships with AstraZeneca, Hemodec and Lilly. Dr. LaRosa disclosed receiving investigator grants from Eisai. Dr. Vincent disclosed serving on the advisory board of 39 companies and receiving study grants from 34.

Optimizing the Selection and Use Of Topical Hemostats This monograph is based on a symposium held in Boston on November 12, 2011.

Participate online at topical-hemostats.com Release Date: April 1, 2012 Statement of Need Intraoperative hemostasis is an important clinical goal; excessive bleeding is associated with prolonged procedures, extended hospitalization, and serious complications. Low clinician awareness has been observed around the availability, selection, and use of the array of topical hemostats. Educational and knowledge gaps also are acknowledged by pharmacists with regard to the use of topical hemostats, as these products may enter hospitals via central supply rather than pharmacy ordering. Topical hemostats have diverse clinical and pharmacoeconomic profiles, and a number of direct and non-medication costs (eg, storage, preparation, product waste, potential for uncommon but serious side effects) must be considered with their use.

Program Goal To educate clinicians on the selection and use of topical hemostats in the hospital setting.

Learning Objectives After completing this activity, participants should be better able to: 1 Appraise the clinical and economic effects of excessive intraoperative or postoperative bleeding and common preoperative strategies for minimizing bleeding events. 2 Describe key clinical factors that influence the selection and use of topical hemostats as adjuncts for achieving surgical hemostasis. 3 Delineate clinical characteristics and pharmacoeconomic (direct and non-medication costs) considerations by which topical hemostats should be evaluated, acquired, and used in hospitals. 4 Develop a plan for reconciling cautionary guidance and clinical best practices with regard to the selection and use of the full range of topical hemostats.

Target Audience This activity is designed to meet the educational needs of physicians, pharmacists, nurses, and other health care professionals.

Accreditation Statements Physician: 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 AKH Inc., Advancing Knowledge in Healthcare, and Applied Clinical Education. AKH Inc. is accredited by the ACCME to provide continuing medical education for physicians. AKH Inc. designates this enduring activity for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Sponsored by

Expiration Date: April 1, 2013 Pharmacist: AKH Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. AKH Inc. approves this application-based activity for 2.0 contact hours (0.2 CEUs). UAN 00779999-12-013-H04-P. Initial release date: April 1, 2012. Nurse: AKH Inc. is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s COA.

AKH Inc. designates this educational activity for 2 contact hours (0.2 CEUs). Accreditation applies solely to educational activities and does not imply approval or endorsement of any commercial product by the ANCC-COA.

Conflict of Interest Statement

It is the policy of AKH Inc. to ensure independence, balance, objectivity, scientific rigor, and integrity in all of its continuing education activities. The faculty must disclose to the participants any significant relationships with commercial interests whose products or devices may be mentioned in the activity or with the commercial supporter of this continuing education activity. Identified conflicts of interest are resolved by AKH prior to accreditation of the activity and may include any of or combination of the following: attestation to non-commercial content; notification of independent and certified CME/CE expectations; referral to National Faculty Initiative training; restriction of topic area or content; restriction to discussion of science only; amendment of content to eliminate discussion of device or technique; use of other faculty for discussion of recommendations; independent review against criteria ensuring evidence support recommendation; moderator review; and peer review. AKH/Applied clinical Educatin (ACE) planners and reviewers have no relevant financial relationships to disclose.

Financial Disclosures

Dr. Baker: Consultant to Accredo Health Group, Inc. (advisory board), Medco Health Solutions (Pharmacy & Therapeutics Committee) Dr. Boucher: Speakers’ bureau for ZymoGenetics Dr. Doria: Nothing to disclose

Mary Culpepper (medical writer): Nothing to disclose

Disclosure of Unlabeled Use

This educational activity may contain discussion of some agents that have been studied but are not FDAapproved for use as hemostatics. Refer to official prescribing information for all products for discussion of approved indications, contraindications, and warnings.

Estimated Time of Completion: 120 minutes. Method of Participation

There are no fees for participating in and receiving credit for this activity. Read the objectives and monograph, complete the post-test and evaluation, and mail

Supported by an educational grant from A Bristol-Myers Squibb Company

Chair

Cataldo Doria, MD, PhD, FACS Nicoletti Family Professor of Transplant Surgery Director, Division of Transplantation Co-Director, Jefferson Kimmel Cancer Center - Liver Tumor Center Thomas Jefferson University Hospital Philadelphia, Pennsylvania

Faculty

Danial E. Baker, PharmD Professor of Pharmacotherapy Associate Dean for Clinical Programs Director, Drug Information Center College of Pharmacy Washington State University Spokane, Washington

Bradley A. Boucher, PharmD, FCCP, FCCM Professor, Vice-Chair for Institutional Programs Department of Clinical Pharmacy Associate Professor Department of Neurosurgery University of Tennessee Health Science Center Memphis, Tennessee

Medical Writer

Mary Culpepper to: AKH Inc., PO Box 2187, Orange Park, FL 320670534; or fax to (904) 683-3803. Statements of participation will be mailed/emailed approximately 6 to 8 weeks after receipt of mailed or faxed submissions. Online participation is available at topical-hemostats.com. A score of at least 70% is required for successful completion, and one retake is allowed. The corrected answer sheet will be provided. Credit is available through April 1, 2013. If you have questions about this CME/CE activity, please contact AKH Inc. at service@akhealthcare.com

Disclaimer

This course is designed solely to provide the health care professional with information to assist in his or her practice and professional development and is not a diagnostic tool to replace professional advice or treatment. The course serves as a general guide to the health care professional, and therefore cannot be considered as giving legal, nursing, medical, or other professional advice in specific cases. AKH Inc., ACE, and the faculty specifically disclaim responsibility for any adverse consequences resulting directly or indirectly from information in the course, for undetected error, or through readers’ misunderstanding of the content.

Copyright © 2012 AKH Inc. and ACE. No part of this syllabus may be used or reproduced in any manner whatsoever without written permission except in the case of brief quotations included in articles or reviews.

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Introduction Despite advances in surgical techniques and operative hemostasis management, excessive bleeding remains a major surgical complication that contributes to poor clinical outcomes.1 Excessive blood loss has been reported in 3% to 14% of cardiovascular surgeries,2-5 and re-exploration for microvascular bleeding after cardiac surgery is an important source of morbidity and mortality.6 In one study, mortality rates increased from 8% in patients who lost less than 500 mL of blood during surgery to 42.9% for those who lost more than 2,000 mL.1,7 In addition to its clinical consequences, excessive perioperative bleeding leads to increased economic costs related to extended procedure times, transfusion of blood products, prolonged hospital length of stay (LOS), intensive care unit stay, and significant use of clinical and staff resources.1,8,9 Across surgery types, bleedingrelated complications or transfusions extended incremental LOS by 6 days in a recent retrospective analysis.8 A key responsibility of the surgeon is to reduce blood loss via hemostasis (ie, arrest bleeding).10 This requires maintenance of a fine balance between bleeding and clotting risks,11 a challenge that is intensified by the increasing use of potent antithrombotic drugs.12 These risks extend beyond surgery; although the hemostatic pendulum swings toward bleeding intraoperatively, it moves toward clotting immediately postoperatively and back toward bleeding in recovery.11 Surgeons must anticipate and manage bleeding. Adjuncts to intraoperative hemostasis such as hemostats, sealants, and adhesives represent an increasingly important approach to controlling perioperative bleeding, particularly for minimally invasive operations in which bleeding may not be amenable to conventional methods of hemostasis (ie, suture, ligature, cautery). Optimal selection and use of these agents requires surgical team members—surgeons, anesthesiologists, hematologists, pharmacists, and nurses—to understand the available materials and products Table 1. Interventions To Minimize Bleeding1 Preoperative

Administer erythropoiesis-stimulating agents Conduct autologous blood donation Consider individualized risk–benefit ratio for proceeding with surgery Discontinue medications • Anticoagulants • NSAIDs • Antiplatelet drugs (clopidogrel, prasugrel) • Herbals (ginseng, gingko biloba) Establish evidence-based institution-wide guidelines for lower RBC transfusion thresholds Minimize blood sampling

Intraoperative Postoperative

Correct coagulopathy, hypothermia, acidosis Correct hypocalcemia Administer systemic (ε-aminocaproic acid, tranexamic acid), topical hemostatic agents Transfuse blood products, avoid hemodilution Use blood recovery systems (“cell savers”)

Surgical

Use minimally invasive techniques (endoscopic, laparoscopic, robotic) Apply direct pressure Use mechanical devices • Endostaplers • Hemoclips • Intracorporeal devices Use suture ligation (larger vessels), electrocautery (smaller vessels)

NSAID, nonsteroidal anti-inflammitory drug; RBC, red blood cell

in order to arrest bleeding intraoperatively and minimize risk for adverse events (AEs) postoperatively. Among adjunct products are topical thrombins, which have been used successfully as hemostats since the 1940s and currently are used in more than 1 million US surgeries annually.10,13 However, bovinederived topical thrombin preparations occasionally have been associated with hemostatic abnormalities ranging from asymptomatic to mild or severe bleeding or thrombosis, which rarely have been fatal.14 Believed to be uncommon, immune-mediated coagulopathies (IMCs) result from the development of antibodies that cross-react with human coagulation factors and disrupt inherent clotting mechanisms. Topical thrombins of 3 biologic origins are available, with 2 introduced since 2007. Clinical concerns associated with each are appropriate for review, given their prevalence as standalone hemostats and in combination with other adjuncts to surgical hemostasis.

Minimizing Perioperative Bleeding Strategies for reducing excessive bleeding are multimodal and can be initiated before, during, and after surgery (Table 1).1,15 Among others, medications that irreversibly inhibit the P2Y12 platelet receptor should be discontinued16; the potentially lethal triad of coagulopathy, hypothermia, and acidosis should be corrected17,18; and minimally invasive techniques used. When conventional methods are inadequate to control mild to moderate bleeding, or for bleeding that may not be amenable to those approaches (eg, diffuse raw surface bleeding, friable tissue, bone bleeding), topical hemostats represent a reasonable adjunct approach. They are not substitutes for meticulous surgical technique, and their effectiveness depends on appropriate selection and application. Despite the improved safety of the blood supply, the importance of limiting transfusion is recognized (sidebar, Rationale for Restrictive Transfusion Strategies).19-25

Coagulation and Hemostasis Coagulation is a physiologic defense mechanism that maintains circulatory integrity and limits blood loss after a vascular insult.10,11,26 The generation of thrombin from its precursor, prothrombin, is the central event of coagulation—a process that is central to physiologic hemostasis, implicated in thrombosis,27 and dependent on a complex sequence of self-activating biochemical reactions among circulating coagulation factors.1 Traditionally, hemostasis has been described as a cascade of enzymatic reactions occurring on cell surfaces containing exposed tissue factor and phospholipids resulting in the formation of thrombin (IIa), a serine protease. The process of coagulation itself is one of vasoconstriction, platelet plug formation, cross-linking of fibrin, and fibrinolysis (ie, clot dissolution).10 Thrombin controls the final step of the coagulation cascade by catalyzing the conversion of soluble fibrinogen to fibrin to form the basis of a blood clot11; inducing cross-linking of the fibrin clot through factor XIII activation; and activating platelets—ultimately forming a stable, cross-linked, fibrin-platelet clot.1 In addition, coagulation activity is amplified via platelet-mediated thrombin generation (ie, thrombin bursts) and activation of factors V, VIII, and XI.2,10,11,28 Thrombin, which also binds to specific receptors, enhancing platelet aggregation, is a multifaceted biological mediator with both procoagulant and anticoagulant functions, among others.11,29 In surgery, thrombin products are used as biologically active hemostats to convert fibrinogen to fibrin at the site of active bleeding.30

Why wait? Access this program and post-test at topical-hemostats.com

Rationale for Restrictive Transfusion Strategies

s a result of screening improvements, the safety of the US blood supply has increased dramatically; rates of transfusion-transmitted HIV and hepatitis C and B viruses are 1 in 2,135,000; 1 in 1,935,000, and 1 in 205,000 transfusions, respectively.19 The majority of transfusion-related morbidity and mortality now is caused by noninfectious complications, such as transfusion-associated acute lung injury (TRALI), transfusionassociated circulatory overload (TACO), and hemolytic transfusion reactions (associated with ABO or non-ABO alloantibodies) resulting from incorrect blood component transfusion (ie, mistransfusion).19-21 Blood transfusions also have been associated with dose-responsive increases in multiorgan failure in trauma patients22 and increased mortality in critically ill patients.23 Although the blood supply is the safest it has ever been,20,21 there is a growing appreciation that unnecessary transfusions are not prudent in view of the potential harm from a variety of serious complications24 and that the safest transfusion is no transfusion.19 In the coagulation cascade, circulating prothrombin is converted to active thrombin by activated factors X and V.13 The conventional model (Figure 1) 1 is represented as 2 somewhat independent pathways (ie, extrinsic, intrinsic) that converge at the point in which factor V is situated; thrombin generation can be disrupted profoundly by any substance or event that inhibits factor V.1,28 Because some components of physiologic hemostasis were not represented fully by the cascade, a cell-based model has been developed. In these models, coagulation properties are localized to specific cell surfaces, and thrombin plays central roles in 3 overlapping phases: initiation, amplification (ie, activation of factors V and XI, cleavage of factor XIII); and propagation that ultimately results in clot formation.31

Intrinsic pathway

In the absence of randomized controlled trials (RCTs) demonstrating improved outcomes after red blood cell (RBC) transfusion, investigators have sought to determine the threshold at which the benefits outweigh the risks. 19 For adult trauma and critical care patients, evidence-based recommendations developed by a joint task force of the Eastern Association for Surgery of Trauma and the American College of Critical Care Medicine of the Society of Critical Care Medicine suggest transfusion at hemoglobin [Hb] levels lower than 7 g/dL.25 This group cautions, however, that Hb level should not be the sole determinant or “trigger” for transfusion. A task force of the Society of Thoracic Surgeons (STS) and the Society of Cardiovascular Anesthesiologists (SCA) also recommends transfusion as a reasonable strategy when Hb is less than 7 g/dL in patients undergoing thoracic surgery, in which multimodal interventions to preserve RBC volume offer the best chance of maintaining hemostasis.16 The cascade model has proven useful in characterizing pathways that refl ect the processes measured in the clinical coagulation laboratory.28 When possible, patients should be riskstratified preoperatively for bleeding or thrombosis,11 with careful attention given to history of previous bleeding and use of medications that affect that clotting (Table 2). Based on levels of concern, screening laboratory tests of coagulation (eg, activated partial thromboplastin time [aPTT], prothrombin time [PT]) may be ordered.11 Surgical teams also can use point-of-care tests for the measurement of activated clotting time (ACT), aPTT, and PT to guide anticoagulation therapy intraoperatively11; one such test, thromboelastography, evaluates a broad spectrum of the coagulation cascade.32

Extrinsic pathway

Common pathway

F ac tor Va

Prothrombin

T hrombin F ac tor XIIIa

Soluble fibrinogen

Loose fibrin clot

Stable fibrin matrix (Blood clot)

Figure 1. Simplified coagulation cascade.1

Bleeding in the Surgical Patient

duration of extracorporeal circulation). Spinal orthopedic surgeries may be associated with major and prolonged bleeding as well, a consequence of long surgery duration, muscle dissection, bone excision, and disruption of internal vertebral vessels.31 Other surgical procedures with high bleeding risks include joint orthopedic surgery (eg, hip or knee arthroplasty), hysterectomy, vascular grafting, colorectal surgery, and craniotomy.31 Different surgery types have different effects on the coagulation system, necessitating individualized treatment strategies.11 The volume of intraoperative blood loss varies widely by procedure and institution and may be affected by the type and delivery of anesthesia and degree of hypotension. Severe bleeding often is defined as greater than 2 L of blood loss within the first 24 hours postoperatively,9 representing approximately 40% of circulating blood volume in an adult of average size. Although overall mortality in elective and urgent surgery is very low (0.1%),33 it can be much higher in specific subcategories, reaching 20% in elective vascular surgery with severe bleeding34 and 40% in cases of major organ damage (eg, liver rupture).33

Bleeding is expected in most surgical procedures and may be anticipated in some that are considered nonsurgical (eg, percutaneous coronary intervention).33 Multiple factors may account for blood loss in procedures with particularly high bleeding risks, such as cardiopulmonary bypass (CPB), and joint or spine orthopedic surgery; a constellation or series of events or “multiple hits” may be responsible, in conjunction with isolated or multiple hemostatic defects. 26 For example, surgery induces a hyperadrenergic state, causing the release of tissue plasminogen activator (TPA) and consumption of coagulation factors, platelets, and physiologic anticoagulants secondary to bleeding and hemodilution.11 In cardiac and liver surgeries, approximately 75% to 90% of bleeding is caused by local surgical interruption or vessel interruption, with 10% to 25% resulting from acquired or congenital coagulopathy.33 CPB with extracorporeal circulation disrupts hemostasis in several ways: hemodilution, activation of tissue factor and fibrinolysis, consumption of thrombin and plasmin, the release of other inflammatory-mediated factors, and consumption of clotting factors.1,31 Also contributing to bleeding in CPB are patient factors (eg, advanced age, emergency surgery, long

Spectrum of Agents To Aid Hemostasis Functional characteristics, mechanisms, and materials are important considerations in the selection of an adjunct to hemostasis, as are patient factors, surgery type, and the characteristics of the bleeding encountered. Three main groups of agents are FDAapproved to aid in topical hemostasis. Sealants polymerize, activate, and form a mechanical barrier to leakage, with or without the presence of blood. They can prevent the leakage of blood (ie, vascular sealing) as well as nonclotting fluids (eg, dural sealing to prevent cerebrospinal fluid loss).30 Adhesives fully polymerize, activate, and join tissues and are used externally in combination with deep dermal sutures to facilitate skin closure. They function without need for an intact clotting mechanism; some cyanoacrylate-based adhesives act as barriers against bacteria l penetration as well.30,35 Topical hemostats, which promote blood clot formation directly, are among the most widely used intraoperative bleeding interventions. Because of their effectiveness and ease of use, topical hemostats often are surgeons’ first choices for controlling bleeding. Also, although direct acquisition costs vary by hospital, topical hemostats are relatively inexpensive compared with sealants and adhesives. Some are more difficult than others to store, prepare, and use, and these considerations may have clinical and pharmacoeconomic

Table 2. Prepoperative Hemostatic Evaluation11 Risk Level

History/Physical

Tests

Level 1

Negative history, physical examination Minor procedure

None required

Level 2

Negative history, physical examination Major procedure

aPTT, platelet count

Level 3

Suspicious history Procedure with high risk for bleeding

aPTT, platelet count, PT, BT

Level 4

History strongly suggestive of major hemostatic defect

BT after aspirin to rule out vWD; specific assays for factors VIII and IX; thrombin time

aPTT, activated partial thromboplastin time; BT, bleeding time; PT, prothrombin time; vWD, von Willebrand disease Reprinted with permission.

Table 3. Topical Hemostats30

Use

Ease of Preparation, Use

Cost

Examples

Mechanical

Minimal bleeding

Relatively easy

Relatively inexpensive

Gelatin Collagen Oxidized regenerated cellulose Polysaccharide spheres

Active

Localized, diffuse bleeding

Relatively easy

More expensive than mechanical; less expensive than flowable, fibrin sealant

Topical thrombins of 3 biologic origins • Bovine • Pooled human plasma • Recombinant

Flowable

Localized bleeding

Relatively easy

More expensive than mechanical, active

Gelatin granules + thrombin

Fibrin sealant

Localized, diffuse bleeding

Relatively more complex

More expensive than mechanical, active, flowable

Fibrinogen + thrombin

Why wait? Access this program and post-test at topical-hemostats.com implications affecting which are purchased by a hospital. Topical hemostats are subcategorized as mechanical, active, flowable, and fibrin sealants (fibrin sealant is unique in that it has separate FDA approvals as a hemostat, sealant, and adhesive) (Table 3).30 Table 4. Mechanical Agents36-48

Mechanical hemostats (Table 4)36-48 promote clotting by acting as a barrier to blood flow and creating a scaffolding on which clotting can occur.16,30 They can be used immediately out of the package, are applied to a bleeding site using direct pressure, and are most useful Clinical Considerations

Risks, Precautions

Porcine gelatin • Gelfoam absorbable gelatina sponge,36 compressed sponge,37 powder38 • Surgifoam absorbable gelatinb sponge,40 powder40

Sponge and powder Store at RT Immediately available for use Not resterilizable Use alone or + saline/topical thrombin When possible, remove after hemostasis

Bovine collagen • Avitene Ultrafoam collagen sponge,41 flour,41 sheets41 • Helistat,42 Helitene43 • Instat,44 Instat MCH44

Single or multiple sheets Store at RT Immediately available for use Not resterilizable Use dry (not + thrombin) Remove excess When possible, remove after hemostasis

Oxidized regenerated cellulose • Surgicel,45 Surgicel Fibrillar,45 Surgicel Nu-Knit,45 Surgicel Snow45

Sheets, flours, sponges Store at RT Immediately available for use Not resterilizable Use dry (not + saline/thrombin) Remove excess

Polysaccharide spheres • Arista AH46 • Hemostase MPH47 • Vitasure48

Powder in bellows applicator Avoid extreme temperatures (<–40ºF and >140ºF) Immediately available for use Not resterilizable Remove excess

Swelling; infection (relatively safe)

RT, room temperature a A kit (Gelfoam Plus)39 also is available: porcine gelatin sponge + 125 IU/mL lyophilized human pooled thrombin; does not require refrigeration. b A kit also is available: Surgifoam absorbable gelatin powder for use with thrombin or saline.

Table 5. Active Hemostats (Topical Thrombin)14,49,50 Biologic Origin

How Supplied

Storage

Risks, Precautions

Bovine • Thrombin-JMI14

Powder for solution • 5,000-IU vial + 5-mL diluent; 20,000-IU vial + 20-mL diluent • 20,000-IU vial + spray pump, actuator (pump spray kit) • 5,000- or 20,000-IU vial + 5- or 20-mL diluent, spray tip, syringe (syringe spray kit) • 5,000-IU vial + 5-mL diluent, nasal drug delivery device, syringe (epistaxis kit)

2°C-25°C unopened 2°C-8°C for ≤24 h after reconstitution RT for ≤8 h after reconstitution

Black box warning Do not inject Do not use for massive or brisk arterial bleeding Antibody formation, hemostatic abnormalities Hypersensitivity to material of bovine origin

Human • Evithrom49

Frozen solution • 2-, 5-, 20-mL vials (800-1,200 units/mL) • Device kit containing lyophilized powder for reconstitution, use with gelatin sponge

Frozen (≤–18°C) for ≤2 y 2°C-8°C for ≤30 d unopened RT for ≤24 h

Do not inject Do not use for massive or brisk arterial bleeding Risk for plasma-derived infectious disease Anaphylactic or severe systemic reaction to human blood products

Recombinant • Recothrom50

Powder for solution • 5,000-IU vial + 5-mL prefilled diluent syringe with sterile needle-free transfer device, 5-mL empty syringe, preprinted label • 20,000-IU vial + 20-mL diluent syringe with 2 sterile needle-free transfer devices, 20-mL empty syringe, preprinted label • 20,000-IU applicator kit with spray pump, spray bottle, syringe spray tip, syringe, bowl, 2 blank labels

2°C-25°C unopened 2°C-25°C for ≤24 h after reconstitution

Do not inject Do not use for massive or brisk arterial bleeding Hypersensitivity to hamster or snake proteins

RT, room temperature

for controlling minimal bleeding. Bovine collagen and polysaccharide spheres are considered most effective, and the efficacy of porcine gelatins may be improved when used with topical thrombin.30 Active hemostats (Table 5)14,49,50 promote clotting by converting fibrinogen to fibrin, with the rate of clot formation proportional to the concentration of both thrombin and fibrinogen.51 Topical thrombins are approved for broad surgical use, and standalone thrombin products can be combined with absorbable gelatin sponges. Because topical thrombins are supplied in a number of formulations there are some differences in their requirements for storage and preparation. They are useful for a variety of bleeding scenarios and can be applied locally, with a syringe when bleeding may be difficult to reach, or sprayed over a large area for rapid coverage. Thrombins of all 3 biologic origins are equally effective at controlling local or diffuse bleeding and only slightly more costly than mechanical hemostats.30 Topical thrombins will not work unless bleeding is present. Intravascular injection is contraindicated, and thrombin products must not be permitted to enter devices dependent on heparin anticoagulation (eg, blood salvage systems).35

Flowable hemostats (Table 6)30,35,52,53 combine both active and mechanical hemostat components—and some of the most favorable characteristics of both—to promote clot formation and wound healing. They control bleeding mechanically by obstructing blood flow and, because thrombin is a component, via the rapid conversion of fibrinogen into fibrin. Preparation involves reconstituting thrombin and mixing it with absorbable gelatin particles,52,53 a process that may take operating room (OR) staff several minutes but can allow for customized consistency, thorough coverage of a local wound,30 and accurate administration (eg, spreading) compared with a liquid thrombin. The FDA also has approved a kit containing porcine gelatin absorbable powder matrix and lyophilized pooled human thrombin, which can be stored at room temperature and prepared quickly. Swelling is a concern with flowable hemostats; excess product should be removed because of this possibility. Fibrin sealants (Table 7)54-57 function by increasing the rate of blood clot formation via fibrinogen and thrombin concentrations that are higher at the bleeding site than would normally occur in blood.30 These products can be applied locally with a syringe

Table 6. Flowable Agents30,35,52,53 Clinical Considerations Porcine gelatin ± thrombin • Surgiflo52

Powder, syringe + flexible applicator tip Store at controlled RT (2°C-25°C) Preparation involves mixing (do not use immediately out of package) Remove excess

Bovine gelatin + pooled human thrombin • FloSeal53

Granular Store at RT 3-min reconstitution, mixing30; use mixed product within 2 h Apply as paste, gentle pressure May be reapplied with blunt applicator tip35 Remove excess

Risks, Precautions

Swelling; viral/prion disease transmission Risks associated with particular standalone thrombin that is chosen Do not inject or use intravascularly

RT, room temperature

Table 7. Fibrin Sealants54-57 Clinical Considerations

Pooled human plasma • Tisseel54

Freeze-dried: store at 2°C-25°C; do not refrigerate/freeze reconstituted solution Frozen: store at ≤–20°C; thaw 5-105 min (water bath/incubator); do not refrigerate/refreeze after thawing Use within 4 h after reconstitution/thawing Best applied to as dry a field as possible

Pooled human plasma • Evicel55

1 vial each of fibrinogen and thrombin frozen solutions + spray applicator Frozen: store at ≤–18°C for ≤2 y; must be thawed; temerature must be ≤37°C After thawing, use within 24 h if stored at RT, 30 d if stored refrigerated

Individual human plasma with bovine collagen and bovine thrombin • Vitagel56

Single-use 5 mL treatment syringe + sterile delivery components, transfer syringe Combine with an equal volume of patient plasma Store at 2°C-8°C; do not freeze

Individual human plasma • Cryoseal57

Single-use unit produces 4 sterile sets of 2 syringes (total volume, 6-16 mL; conditions may affect harvest volume) Store at ≤–18°C for ≤1 y Use within 6 h (at 34°C-37°C)

RT, room temperature

Risks, Precautions

Viral/prion disease transmission (with pooled human plasma derivatives) Antibody formation (with bovine thrombin) Swelling (with bovine collagen) May require intact coagulation Air/gas embolism has occurred with fibrin sealant administered using pressurized gas Tisseel contains aprotinin, a protein associated with anaphylactic reactions

Why wait? Access this program and post-test at topical-hemostats.com or sprayed over a large area, a feature that makes them beneficial in local and diffuse bleeding. Their use is appropriate in patients with coagulopathy who do not have sufficient fibrinogen to form a clot; however, intact coagulation may be required. Safety concerns include viral or prion disease transmission associated with human plasma derivatives; antibody formation with bovine thrombin; and swelling with bovine collagen.30 Although a ready-to-use, absorbable patch was FDA-approved for cardiovascular surgery in 2010,58 a key concern with fibrin sealants generally is the need for surgeons to master skillful application techniques.30 Another concern is the complexity of coordinating the reconstitution and preparation of these 2-component products by hospital staff. In some clinical scenarios, non-fibrin sealants (Table 8)30,59-67 or adhesives may be more appropriate. As noted, adhesives are fastsetting agents that join tissues without need for an intact clotting mechanism and polymerize within approximately 30 seconds. For example, albumin plus glutaraldehyde—a polymer with sealant and adhesive properties—is used for vascular sealing of large blood vessels, often in cardiovascular surgeries; it should be used sparingly and applied carefully because of its strong adhesiveness. The surgical team should be familiar with labeling and the clinical particulars associated with each agent, such as coordination of preparation time and application techniques.30,35,62

Surgeon Perspectives on Topical Hemostats, Sealants, and Adhesives The surgeon’s approach to hemostasis is influenced by training, judgment, technical skill, and area of expertise and is viewed through a prism of clinical experience. Clinician choice may be influenced heavily by product availability within the hospital. In different surgical scenarios, the type of bleeding encountered will dictate selection of a topical hemostat. For example, in minimal or mild bleeding proximal to an anastomosis (ie, connection of 2 cut ends of a structure to form a continuous channel) after coronary artery bypass graft, surgeons often will select the least expensive type of hemostat (eg, mechanical). Topical thrombin use is appropriate for bleeding from needle holes after suture; cauterization in this scenario would compromise the integrity of the anastomosis. Compression hemostatic agents (eg, oxidized regenerated cellulose and microfibrillar collagen) are the most commonly used adjuncts for anastomotic hemostasis.16 These agents also are useful in highly vascularized liver surgery, in which diffuse bleeding can be significant and coagulopathy present11 and the use of compression in combination with application of a mechanical hemostat is a common initial approach. Oxidized regenerated cellulose is bacteriostatic, and there is some evidence—and widespread clinical acceptance—of its effectiveness for suture line bleeding.16 Oxidized cellulose requires a normal clotting system, and its mechanism appears to be a physical effect rather than via alteration of intrinsic clotting. In contrast, microfibrillar collagen provides some hemostatic effect by initiating of platelet activation and aggregation.16 Surgeons may favor specific attributes of products in this class. For example, absence of bulkiness and the degree to which a material will conform to anastomosis may be important at the conclusion of hepatectomy, which is likely to be associated with substantial bleeding in the retroperitoneum “bare area.” Similarly, microfibrillar collagen—which is available in many forms—conforms well to bleeding surfaces of the type encountered in a broad spectrum of vascular surgeries.

Table 8. Non-Fibrin Sealants and Adhesives30,59-67 Clinical Considerations

Risks, Precautions

PEG Polymers • Coseal59 • DuraSeal60 • ProGel61

Apply to as dry a field as possible Avoid dripping to undesired locations

Swelling

Cyanoacrylates • Dermabond62 • Omnex63 • Histoacryl/ Histoacryl Blue64 • Indermil65 • SurgiSeal66

Use to avoid wound dehiscence associated with deep dermal sutures Keep skin edges exposed for ≥20 sec Avoid dripping to undesired locations External use only; with deep dermal sutures

Strong adhesiveness

Bovine serum albumin + glutaraldehyde • BioGlue67

Use carefully, sparingly Wall off critical zones of surgical field with sponges/pads to avoid nerve/vessel injury

Potential for tissue necrosis, adhesive embolism30

In the presence of localized or diffuse bleeding, topical thrombin may represent a reasonable approach because of its versatility in preparation and application. Localized bleeding may be controlled with topical thrombin applied using a sponge, porcine gelatin sponge, or absorbable porcine gelatin powder to create a putty- or caulk-like consistency; diffuse bleeding may be controlled with the use of topical thrombin applied by spraying to ensure coverage of large, raw, diffuse surface areas (eg, vascular suture lines, adhesions, burn wounds, muscle bleeding, organ parenchyma). In the event of arterial or venous bleeding from adhesions following repair of acute abdominal aneurysm, spray application of thrombin or fibrin sealant may be appropriate so that the product can be applied quickly to a large area. A fibrin sealant also might be used over sutures in neurologic tumor resection to seal the dura and prevent cerebrospinal fluid loss.

Clinical Experience With Topical Thrombins Topical thrombins have well-recognized clinical utility. Since the first of these—derived from bovine origins—was introduced in the 1940s, the have continued to increase in prevalence and now are used in more than 1 million patients annually in the United States at a cost of $250 million.13,68 The currently available bovine thrombin product was approved in 1995.14 Compared with earlier versions that contained 20% to 30% thrombin, it is purified chromatographically and processed by ultrafiltration to contain fewer protein contaminants and has been shown to be 96% thrombin.14,69 In the past 5 years, thrombins of human49 and recombinant50 origins have become available. In 2007, pooled human plasma-derived thrombin became the second topical thrombin product approved in the United States. It is manufactured using pooled human source and recovered plasma obtained from US-licensed plasmapheresis centers and has a potential risk for viral or prion disease transmission, despite manufacturing steps designed to reduce this risk.49 Recombinant thrombin was FDA-approved in 2008. Derived from a genetically modified Chinese hamster ovary cell line, it has a molecular structure very similar to that of human thrombin. Allergic reactions to hamster or snake proteins also used in 7

manufacturing are potential risks associated with its use50; genetic engineering reduces the risks for antibody formation and eliminates the risk for pathogen transmission. All 3 thrombin types have similar efficacy,70,71 are labeled as aids to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible, and are indicated for use with an absorbable gelatin sponge.14,49,50 Thrombin concentration correlates with reaction rate—the speed at which thrombin causes clot formation30,51; thrombins of all 3 biologic origins are available in concentrations of 1,000 units/mL. As noted, thrombins often are combined with other hemostats or materials and administered in a variety of ways (eg, dripped, sprayed, moistened on gauze, used with gelatin sponge or powder, or combined with gelatin matrix or fibrinogen). Systemic injection is contraindicated for all topical thrombins and can result in extensive clotting, hypotension, and even death.14,49,50 Surgeons should note the labeled contraindications to use for all hemostatic agents; the boxed warning on bovine thrombin states that patients with known antibodies to bovine thrombin preparations should not be re-exposed to these products.14 A heightened awareness of previous thrombin exposure may be of particular concern in types of surgery in which subsequent operations may be anticipated (eg, pediatric heart surgery). Concerns about the potential of relatively higher risks for antibody production with the use of bovine thrombin, compared with recombinant thrombin, are noted in guidelines issued in 2011 by the STS Blood Conservation Guideline Task Force.16 Conclusions regarding the clinical significance of differences in antibody formation cannot be drawn.

Efficacy and Effectiveness of Topical Thrombin Bovine thrombin—the oldest form of topical thrombin product—has been used effectively in an array of surgical settings. Its efficacy also has been validated in RCTs in which it has been the active comparator in studies evaluating the newer topical thrombins.70,71 Human plasma-derived thrombin was compared with bovine thrombin in a prospective, double-blind, multicenter Phase III RCT of 305 patients.71 Doria and colleagues randomized patients undergoing cardiovascular, neurologic, or general surgeries to receive either bovine (n=152) or human (n=153) thrombin administered with a gelatin sponge. Individuals with known antibodies to bovine thrombin were excluded. In both groups, 97.4% of patients achieved the primary end point of hemostasis at 10 minutes. Equivalency in the human and bovine thrombin treatment groups also was demonstrated for hemostasis at 6 minutes (94.8% vs 92.8%, respectively) and 3 minutes (73.2% vs 72.4%, respectively). AEs in both groups were similar and as expected for the procedures, with pruritus being the most common. No patients in the human thrombin group seroconverted for anti-human thrombin or anti-human factor V/Va antibodies, compared with 2.38% (3 of 126) in the bovine thrombin group who developed seroconversion for anti-human thrombin and 7.94% (10 of 126) who developed anti-bovine thrombin antibodies (P=0.0015). No significant differences were noted in need for transfusions, duration of surgery, or hospital LOS.71 Recombinant thrombin was evaluated for relative efficacy compared with bovine thrombin in a study of 411 patients undergoing spinal surgery, hepatic surgery, peripheral arterial bypass, or placement of an arteriovenous graft.70 In this double-blind, multicenter Phase III RCT by Chapman and colleagues, subjects were randomized to receive either recombinant (n=205) or 8

bovine thrombin (n=206), at a concentration of 1,000 U/mL, with an absorbable gelatin sponge; 401 patients completed the study. In both treatment groups, 95% of patients achieved the primary efficacy end point of hemostasis at 10 minutes (bovine thrombin group, 95.1%; recombinant thrombin group, 95.4%), demonstrating comparable efficacy (Figure 2). However, in a post hoc analysis by Weaver and colleagues of patients undergoing peripheral arterial bypass surgery (n=88), hemostasis at 3 minutes was achieved in a significantly greater proportion of subjects receiving recombinant thrombin (55%) than those receiving bovine thrombin (39%).72 Incidence of AEs in the Chapman study was similar for the 2 groups; most AEs were as expected for the surgery type and moderate in severity.70 Antiproduct antibody development was reported in 1.5% (3 of 198) of the recombinant group, compared with 21.5% (43 of 200) of the bovine group (P=0.0001) (Figure 3).70 There was no causal association between antibody development and any AEs in either treatment group. Pooled safety data from 8 clinical trials also have shown that recombinant thrombin is well tolerated with a low rate of antibody formation.73 The clinical effects of immunogenic response to topical bovine thrombin also have been evaluated. An open-label, prospective, observational case cohort study by Paterson et al assessed the effect on clinical hemostasis of human antibodies to bovine thrombin or factor V/Va in response to topical bovine thrombin in patients with and without preexisting anti-bovine antibodies.74 The study enrolled 550 patients who underwent surgery with bovine thrombin administered at surgeon’s discretion. Patients were assigned to 1 of 4 cohorts based on presurgery presence or absence of antibody to bovine thrombin (aBT), and use or nonuse of bovine thrombin during study surgery; 481 patients assigned to cohorts completed the study. The hypothesis was that patients with presurgery aBT administered the bovine thrombin during surgery would experience postsurgical changes from baseline aPTT that were not clinically different (ie, were noninferior) to those in patients without presurgery aBT and who did not receive bovine thrombin in surgery. Based on adjusted mean change in aPTT values at 48 hours postsurgery, the study failed to establish noninferiority between primary cohorts (noninferiority was defined as 15% shift from baseline; reference value, 30 seconds). In secondary end point analyses, the number of bovine thrombin-treated patients with human anti-bovine factor V/Va antibodies (aBV/Va) increased at weeks 4 and 8 postsurgery compared with 48 hours. At 4 weeks postsurgery, 70% of evaluable patients (n=50) in the cohort of patients with (+)presurgery aBT/ (+)bovine thrombin exposure had cross-reacting antibodies to factor V, compared with 52% (n=39) at 48 hours; in the cohort with (−)presurgery aBT/(−)bovine thrombin exposure during surgery, 12% of patients (n=14) had cross-reacting antibodies to factor V at week 4, compared with 8% (n=10) at 48 hours. However, no immunologic markers at 48 hours or weeks 4 or 8 were related to changes in coagulation parameters. The study’s major limitation was its observational design, which precluded drawing conclusions about causality.

Recognition and Management of IMC Distinctions are recognized between technical causes of surgical bleeding (eg, inadequate repair of vessels, intraoperative injury, or damage to organs) and coagulopathy, or disorders of hemostasis.15,75 These can result from therapeutic coagulation, acidosis, enzymatic

Why wait? Access this program and post-test at topical-hemostats.com

100

Recombinant thrombin (n=198) Bovine thrombin (n=203)

81 (160) 72 (146)

80 60

92 88 (183) (178)

95 95 (189) (193)

48 46 (95) (93)

1.5

Time, min Figure 2. Cumulative incidence of hemostasis over time.50,70

dissolution of fibrin related to CPB, heparin-induced thrombocytopenia, liver dysfunction, disseminated intravascular coagulation, inaction or dissolution of fibrinogen in the blood (fibrinogenolysis), consumptive loss of coagulation factors, hypothermia, or other mechanical and metabolic derangements.76 Postsurgical coagulopathies may be hemorrhagic or thrombotic; inherited (eg, hemophilia, von Willebrand disease); or acquired (vitamin K deficiency, liver disease). IMCs are caused by an autoimmune reaction or crossreacting antibodies in the coagulation system. Despite the fact that bovine thrombin is highly purified, its use can result in the development of these antibodies to endogenous human coagulation factors, notably factor V and thrombin.77 Although rare, acquired factor V deficiency can induce coagulation defects and severe bleeding complications.68,78-80 Although its precise incidence is not known, bovine thrombinassociated IMC has been recognized for more than 20 years as a distinct type of acquired coagulopathy, and identified by the Joint Commission as an iatrogenic and preventable complication that poses a threat to patient safety and warrants increased attention.81 Its recognition poses clinical challenges, partly because clinician awareness of IMC is believed to be low—particularly among surgeons— and its incidence may be underreported.76 Manifestations of bovine thrombin-associated IMC may be subtle, ranging from asymptomatic coagulation laboratory changes with bleeding risk, or minor bleeding (eg, epistaxis or hematuria), to major bleeding events or persistent, uncontrolled, life-threatening bleeding. Late-onset bleeding that develops after a patient has been discharged from the hospital can further complicate clinical recognition of IMC82; inhibitors typically develop 7 to 10 days after a primary exposure during surgery, and the inhibitors can last for several weeks to months.76,83 Prior exposure to bovine thrombin has been identified as the most common causal factor in the development of IMC.72,84-90 However, documentation of such exposure is not routinely available in patient medical records; even when it is, records may not be seen by the surgeon. Thus, a patient’s history of conditions for which multiple surgeries are likely (ie, pediatric congenital cardiac disease) or history of previous surgery in which bovine thrombin use was likely (eg, multiple cardiac, pediatric, neurologic, or vascular surgeries or wound debridement) may provide the best clues to

21.5 (43/200)

Recombinant thrombin Bovine thrombin

20 15 10 5

20 0

Patients With AntiThrombin Antibodies, %

Patients Achieving Hemostatis, %

100

5.0 (10/200) 1.5 (3/198)

Baseline

1.5 (3/198)

Day 29

Figure 3. Antibody production in thrombin Phase III study.70

detection.76,79,89,91 Clinicians should exercise vigilance in obtaining and reviewing such history, including any documentation. Because thrombin products enter hospitals via central surgical supply rather than being purchased through the pharmacy department, however, such documentation often is not available. Coagulation factor inhibitors should be suspected in patients with unexplained postoperative bleeding in the presence of prolonged PT and aPTT; if a mixing study (1:1 mix of patient plasma with normal pooled plasma) fails to correct, an inhibitor may be considered the presumptive cause, and a hematology consult should be requested. Specific quantitative assays of factor V and factor V inhibitor may be conducted (factor V assays are available readily in most laboratories, but specific factor V antibody assays generally are not).76 The challenges of managing an acquired factor inhibitor are formidable. One reason for this is the lack of a predictable pattern of antibody response or coagulopathy development.83 A consensus panel’s review of 64 case reports in which exposure to bovine thrombin was known or presumed found near-equal representation of bleeding and nonbleeding presentations.76 There is incomplete evidence to guide the management of IMC, particularly when it is accompanied by clinically significant bleeding. Platelet therapy may be reasonable because of the store of factor V on platelet surfaces,76 although treatment approaches are speculative, and supportive care is patientspecific. Corticosteroids, IV immunoglobulin therapies, and plasmapheresis have been used with varying degrees of success.76 A bleeding IMC may increase hospital LOS by a factor of 2 to 2.5 if transfusion of blood products is required.33,92 However, the clinical and economic consequences of IMC can be severe even if bleeding is not present; coagulation studies are costly and time-consuming, and prolonged clotting time may delay therapeutic procedures. Other direct costs associated with IMC management include specialist consults, and coagulation monitoring (sidebar, An IMC Case Report).

Roles for the Hospital Pharmacist and Nurse In Optimizing Topical Hemostasis Together with medical staff, the hospital pharmaceutical service shares responsibility for formulary selections and the development of policies that minimize drug errors and assure 9

An IMC Case Report

he significant consumption of blood and blood products, LOS, and use of other resources are incremental cost drivers in the management of IMC, as illustrated in a recent case report of a 76-year-old woman who developed severe hemorrhagic complications after surgical exposure to bovine thrombin.93 Initially she was diagnosed with disseminated intravascular coagulation but continued to experience episodic bleeding. Eventually, mixing studies and clotting factor assays revealed significantly reduced factor V activity (<5% of normal) and an ongoing IMC, and inhibitor titer assay confirmed the presence of a factor V inhibitor. The patient’s critical care hospitalization lasted 64 days and required 282 units of blood products and 2 reoperations in addition to other resources (Table 9)93 for a total cost of $444,996.

medication safety.92,94 Surgical hemostasis is an area that presents many opportunities for multidisciplinary collaboration by pharmacists, surgeons, anesthesiologists, hematologists, nurses, and others—particularly in the setting of the Pharmacy & Therapeutics (P&T) Committee. The primary responsibility of the P&T committee is formulary management via the clinical judgment of a range of professionals in the diagnosis, prevention, or treatment of disease and promotion of health.94 The formulary itself represents the ongoing selection of the most medically appropriate and cost-effective products and therapies to serve the health interests of a given patient population.94,95 This process is informed primarily by published reports (eg, RCTs, reviews, drug monographs, addenda), which provide new evidence concerning drug efficacy, stability, tolerability, methods of administration, cost, and pharmacoeconomics and may warrant reevaluation of agents used, dosage strengths, or formulations stocked by a hospital or health system.94 Information for appraisal in P&T also comes from practice guidelines, labeling revisions, AE updates, FDA announcements, expert opinion, and internal data. These sources may be particularly important in therapeutic areas for which there is a limited evidence base to guide clinical decision making. For example, a 2010 Joint Commission newsletter reported that bovine thrombin-associated IMC may occur days to weeks after surgery and should be considered in the differential diagnosis in cases of unexplained postoperative bleeding or unexplained PT, aPTT, or thrombin time in the absence of bleeding.81 Although the perception among medical staff may be that the P&T committee is an entity best left alone to do its work, the literature shows that safety is best evaluated by an interdisciplinary group of health care providers who may uncover potential hazards of use before an agent is introduced to the formulary.95 In fact, adherence to department “silo” mentalities or budgets may suggest an unwillingness to take into account available evidence reflecting improved patient outcomes or decreased total costs.24 A physician who deals with acute or surgical bleeding can contribute to formulary decision making by sharing clinical, safety, and availability concerns about drug classes or specific agents, especially if scientific evidence or direct comparisons of various agents are lacking. All P&T members should be involved in disseminating information on the decisions made and the rationales thereof. For pharmacists, a primary responsibility is the effective communication of actions related to the medication use evaluation process to ensure 10

Table 9. Costs Associated With IMC Case93 Resource

Cost/ Unit, $

ICU LOS (no ventilator) Blood products Packed RBCs FFP Platelets IVIG Total estimated cost

Units

Total Cost, $

4,022/d

64 d

257,408

1,459 72 656

78 129 62

113,802 9,288 40,672

181

132

23,826 444,996

FFP, fresh frozen plasma; ICU, intensive care unit; IVIG, intravenous immunoglobulin; LOS, length of stay; RBC, red blood cell

that policy is integrated into therapeutic decision making.94 Specifically, in-service education, grand rounds, interaction with other clinicians at the time of dispensing, staff meetings, email, newsletters, mailings, prescriber detailing, and pharmacy or institutional Web sites offer opportunities for targeted communication.94 These and other methods can be used by pharmacists to help establish and support a culture of medication safety. In the setting of surgical hemostasis and acute bleeding, pharmacists may participate in a range of efforts to reduce transfusion rates or enhance the safety of topical hemostat use. One example pertains to minimizing the risk for accidental intravascular administration, a danger addressed in warnings from both the FDA and the Institute for Safe Medication Practices.96,97 Despite cautionary labeling on all topical thrombin products, instances of inadvertent injection are documented, and one such event was fatal.97 Similarities in packaging for topical thrombin and parenteral products (ie, vial and syringe) may contribute to the potential for misadministration. This suggests opportunities for pharmacist involvement in communicating with clinicians who make therapeutic decisions at the point of care; for example, auxiliary “Do Not Inject” labeling of syringes used in thrombin reconstitution may help reduce the risk for misadministration. Nurses are on the front lines of safety in the OR and perioperative setting as well and should be involved in safe-use initiatives, such as safety checklists (Figure 4).97 Nurses are responsible for communicating the presence of topical thrombin in the sterile field and are expected to try to delay introducing it until after all parenteral products have been administered. Manufacturers of topical hemostats recognize this and include OR nurses as a key target audience for instructional information. Similarly, some fibrin sealant product labeling specifically addresses scrub and circulating nurses, providing detailed information on safe transfer of the fibrinogen component to the sterile field. Pharmacoeconomic review is another important element in the review of all products. Generally done by pharmacists working with other health care professionals and the purchasing department, this evaluation considers acquisition price as well as indirect costs related to storage, preparation, management of complications associated with use and effect on patient care. Among average wholesale prices for topical hemostats, topical thrombins generally are less costly than flowables and somewhat more costly than mechanical hemostats, with fibrin sealants generally the most

Why wait? Access this program and post-test at topical-hemostats.com expensive topical hemostats. Pricing for thrombins of all 3 biologic origins is competitive, with human thrombin products incrementally—although not excessively—more costly than bovine thrombin; acquisition costs vary by institution based on contract pricing, purchasing group criteria, and volume usage. Waste reduction is a key consideration in the pharmacoeconomics review process. In a 9-month university hospital study that evaluated a switch from the formulary thrombin (bovine-derived, 20,000-IU vials with spray applicators) to recombinant thrombin (5,000-IU vials with or without a spray kit), the switch yielded a savings of $92,396 (38%), an apparent consequence of reducing product waste and mixing smaller quantities of thrombin for use with a sponge or sprayer.98

Making Sense of the Science: Understanding Clinical Research As noted, formulary decisions are based in part on a critical evaluation of the literature. With the dynamic flow of research and increasing demands on health care providers, many clinicians report that they cannot always read the medical literature critically.99 Thus, a review of concepts is appropriate. Studies must be evaluated and understood in the context of the research hierarchy. Often, this is represented as a pyramid with systematic reviews and meta-analyses at the top, followed by evidence guidelines and summaries; RCTs, case cohorts and nonrandomized controlled studies; clinical research critiques; literature reviews; case reports, case series, and practice guidelines; and clinical reference texts. Because meta-analyses and systematic review are only as strong as the quality of research being reviewed, it is important to understand the additional elements of study design and appraise commonly used measures. Most clinical research can be categorized broadly as experimental (randomized or nonrandomized) or observational (analytical or

descriptive). The experimental RCT represents the gold standard of investigations designed to evaluate an intervention because the assignment of a subject to an exposure is done purely by chance rather than by the investigator.99 A good RCT also minimizes selection and confounding biases in the determining outcomes.99 One limitation is the potential for an RCT to lack external validity—the extent to which results can be generalized to the broader community as opposed to a more homogenous trial population. Observational studies track subjects forward in time from exposure or nonexposure to outcome (or involve control subjects who are identified retrospectively). Finally, case–control studies trace backward from outcome to exposure (eg, epidemiologic studies to track outbreaks of food-borne illness), and descriptive studies (eg, case series reports) do not have a comparison group; thus investigators cannot examine associations. Insightful review of design and methodology, including dropout rate, patient demographics, interventions, and power, can shed light on the complexities of any study and determine the applicability of that work to the practice changes. In meta-analyses, attention to study selection is key. The authors of the 2007 STS/SCA practice guideline for blood transfusion and conservation used a systemic, comprehensive literature search to make their recommendations.100 In so doing, they searched MEDLINE, EMBASE, CINAHL, and the Cochrane Collaboration. Had they used only used one database, MEDLINE, for example, their results would have been skewed; MEDLINE only contains approximately one-third of the world’s medical literature, with poor representation in such subspecialties as cardiothoracic surgery. It is also important to understand the various parameters that are to report study results. Commonly used are relative risk, the probability of the event occurring in the exposed group versus a non-exposed group, and absolute risk reduction, the amount by which therapy reduces the risk for an undesirable outcome. These and other measures of association express results of dichotomous

Have pharmacy prepare label, dispense drug, including doses for operating room

✓

Never leave vial/syringe at patient’s bedside where it could be confused with parenteral product

✓

Apply auxiliary warning labels to syringes containing thrombin: “For topical use only— do not inject”

✓

Communicate presence of product in sterile field, delay doing so until all parenteral products have been administered

✓

Differentiate parenteral, topical products by using absorbable gelatin sponge or dry form when possible

✓

Consider using spray kits to differentiate thrombin from parenteral products; never leave syringe unlabeled before applying spray mechanism

✓

Figure 4. Thrombin safety checklist.97

outcomes (eg, sick vs healthy). Studies also often use P-value and/ or confidence interval to report statistical data. Confidence interval may be particularly useful because it indicates strength, direction, and a plausible range of effect, as well as the likelihood of chance occurrence. Finally, another useful tool is the number needed to treat (NNT), defined as the number of patients who must be treated to prevent one additional undesirable outcome (Figure 5). The result is useful in determining how much of an effect a study outcome will have on the care of a patient population and how many patients might benefit versus the number exposed to the treatment.

Clinical Application of RCT Data Both the Chapman and Doria investigations are of good quality and highlight the application of some of the principles discussed above. One notable aspect of the Chapman study is its group sequential design with a flexible sample size; investigators sought to enroll 400 to 600 patients to provide an adequate safety evaluation and expose a minimum of approximately 200 patients to recombinant thrombin.70 This design allowed as many as 3 interim analyses (2 were conducted), and the maximum number of patients was computed to maintain 99.5% power to declare comparable efficacy when the 2 treatments were equivalent. At the second interim analysis, available data were deemed sufficient, and the independent data monitoring committee recommended that the study continue as planned until 400 patients with evaluable efficacy data were enrolled. On the primary end point of hemostasis at 10 minutes, the study showed no difference between the 2 thrombin products. A limitation of the work is that no placebo group was included. In the Doria RCT, a sample size of 278 was selected based on the assumption that the success rate in the control group would be 77%.71 This allowed investigators to ascertain equivalence with 95% confidence and 90% power; the sample size was increased to 304 to allow for potential dropouts. Efficacy and safety analyses were

performed using an intent-to-treat population. Hemostasis equivalency was demonstrated in both treatment groups. Limitations included no placebo-control group, potential intersurgeon variability in application technique and hemostasis assessment, and antibody assessment not evaluable for all patients. In both the Chapman and Doria studies, the surrogate marker of hemostasis at 10 minutes was the primary efficacy end point—a very practical measurement of the desired clinical effect, absence of bleeding from the surgical site. There was no difference in the primary outcome, so a NNT could not be calculated.

Conclusion Excess bleeding is associated with a continuum of clinical and economic outcomes. A multimodal approach to perioperative hemostasis requires familiarity with hemostat characteristics and limitations. Topical hemostats are integral elements of the surgeon’s tool kit, and all members of the multidisciplinary care team must be knowledgeable about these important adjuncts to hemostasis. Among the most widely used topical hemostats are thrombins, which are available for use as standalone products or in conjunction with other agents. Topical thrombins have demonstrated similar efficacy in a limited number of studies; however, the risks for viral or disease transmission or development of cross-reacting antibodies against endogenous coagulation factors may be higher with human- and bovine plasma-derived products, respectively. Crossreacting antibodies have been implicated, although rarely, with IMC and carry the potential for clinically severe bleeding events. As such, clinicians would be prudent to remain vigilant about the issues with use and documentation of thrombin products in the surgical setting, whether as standalone or combination products, as well as the diagnosis and management of IMC. Surgeons, pharmacists, and perioperative nurses share in the responsibilities—in the OR and beyond—of achieving intraoperative hemostasis through the optimal selection and use of available hemostatic agents.

Is this a meaningful parameter? YES





Can this end point be phrased as a “yes/no” question? YES





Is there a statistical difference between the 2 groups? YES



Calculation 1 / (pB – pA) • pA, probability of desired outcome in intervention group • pB, probability of desired outcome in control group

Figure 5. Number needed to treat. NNT, number needed to treat

Interpretation • Ideal NNT = 1, indicating that all subjects improve with treatment and none improves with control • Increasing NNT = less effective treatment

Cannot be calculated

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55. Evicel Fibrin Sealant (Human) [package insert]. Somerville, NJ: Ethicon, Inc; 2009.

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80. Sarfati MR, Dilorenzo DJ, Kraiss LW, et al. Severe coagulopathy following intraoperative use of topical thrombin. Ann Vasc Surg. 2004;18:349-351. 81. Joint Commission Resources. Bovine Thrombin-Associated IMC: A Threat to Patient Safety and the Bottom Line. Joint Commission Perspectives on Patient Safety. 2010;10:5-6. 82. Christie RJ, Carrington L, Alving B. Postoperative bleeding induced by topical bovine thrombin: report of two cases. Surgery. 1997;121:708-710. 83. Savage WJ, Kickler TS, Takemoto CM. Acquired coagulation factor inhibitors in children after topical bovine thrombin exposure. Pediatr Blood Cancer. 2007;49:1025-1029. 84. Ortel TL, Mercer MC, Thames EH, et al. Immunologic impact and clinical outcomes after surgical exposure to bovine thrombin. Ann Surg. 2001;233:88-96. 85. Ortel TL, Moore KD, Quinn-Allen MA, et al. Inhibitory anti-factor V antibodies bind to the factor V C2 domain and are associated with hemorrhagic manifestations. Blood. 1998;91(11):4188-4196. 86. Zehnder JL, Leung LL. Development of antibodies to thrombin and factor V with recurrent bleeding in a patient exposed to topical bovine thrombin. Blood. 1990;76(10):2011-2016.

65. Indermil tissue adhesive [instructions for use]. Norwalk, CT: United States Surgical, a division of Tyco Healthcare Group LP; (no date given).

87. Banninger H, Hardegger T, Tobler A, et al. Fibrin glue in surgery: frequent development of inhibitors of bovine thrombin and human factor V. Br J Haematol. 1993;85(3):528-532.

66. SurgiSeal Topical Skin Adhesive (2-octyl cyanoacrylate) [package insert]. Wyomissing, PA; Adhezion Biomedical, LLC; 2010.

88. Dorion RP, Hamati HF, Landis B, et al. Risk and clinical significance of developing antibodies induced by topical thrombin preparations. Arch Pathol Lab Med. 1998;122:887-894.

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70. Chapman WC, Singla N, Genyk Y, et al. A phase 3, randomized, double-blind comparative study of the efficacy and safety of topical recombinant human thrombin and bovine thrombin in surgical hemostasis. J Am Coll Surg. 2007;205(2):256-265.

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72. Weaver FA, Lew W, Granke K, et al. A comparison of recombinant thrombin to bovine thrombin as a hemostatic ancillary in patients undergoing peripheral arterial bypass and arteriovenous graft procedures. J Vasc Surg. 2008;47:1266-1273. 73. Ballard JL, Weaver FA, Singla NK, Chapman WC, Alexander WA. Safety and immunogenicity observations pooled from eight clinical trials of recombinant human thrombin. J Am Coll Surg. 2010;210(2):199-204. 74. Paterson CA, Pixton GC, Proskin HM, et al. Immune responses associated with perioperative exposure and reexposure to topical bovine thrombin do not impair hemostasis. Clin Appl Thromb Hemost. 2011;17(6):620-632. 75. Barnard J, Millner R. A review of topical hemostatic agents for use in cardiac surgery. Ann Thorac Surg. 2009;88(4):1377-1383. 76. Ness P, Creer M, Rodgers GM, et al. Building an immune-mediated coagulopathy consensus: early recognition and evaluation to enhance post-surgical patient safety. Patient Saf Surg. 2009;3(1):8. 77. Voils SA. Thrombin products: economic impact of immune-mediated coagulopathies and practical formulary considerations. Pharmacotherapy. 2009;29(7 Pt 2):18S-22S. 78. Lawson JH, Lynn KA, Vanmatre RM, et al. Antihuman factor V antibodies after use of relatively pure bovine thrombin. Ann Thorac Surg. 2005;79(3):1037-1038.

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93. Rodgers G, Kraiss L. Severe postoperative immune-mediated coagulopathy associated with bovine thrombin exposure. Pharmacotherapy. 2010;30:319e-324e. 94. Tyler LS, Cole SW, May JR, et al. ASHP guidelines on the pharmacy and therapeutics committee and the formulary system. Am J Health Syst Pharm. 2008;65(13):1272-1283. 95. Institute for Safe Medication Practices. The truth about hospital formularies survey. February 10, 2005. http://www.ismp.org/newsletters/acutecare/articles/20050210.asp. Accessed January 19, 2012. 96. FDA. Danger giving topical thrombin intravascularly. August 15, 2008. http://www. youtube.com/watch?v=OopHG7c81rY. Accessed January 19, 2012. 97. Institute for Safe Medication Practices. Danger of giving topical thrombin intravascularly. 2008;6:1. Medication Safety Alert. 98. Lyda CM, et al. Presented at: American Society of Health-System Pharmacists Annual Meeting; December 8, 2009; Las Vegas, NV. [Poster 6-088]. 99. Grimes DA, Schulz KF. An overview of clinical research: the lay of the land. Lancet. 2002;359(9300):57-61. 100.Ferraris VA, Ferraris SP, Saha SP, et al. Perioperative blood transfusion and blood conservation in cardiac surgery: the Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists clinical practice guideline. Ann Thorac Surg. 2007;83 (5 suppl):S27-S86.

Why wait? Access this program and post-test at topical-hemostats.com Post-Test

Circle your answers in the Post-Test Answer Section

1. Review the case and rate each statement as consistent or not consistent with your current clinical approach. A 62-year-old man is planning to undergo peripheral arterial bypass in 30 days. He previously underwent sequential total knee arthroplasty operations; after the first, he had mild postoperative bleeding-related complications. He has a history of hypertension, and 7 years ago had cardiac surgery. His blood pressure (BP) is controlled with medication; his hemoglobin (Hb) count is being monitored by his primary care physician. Family history: father had hypertension and Alzheimer’s disease and died of a myocardial infarction at age 80; mother has type 2 diabetes, age 85; sister has hypertension, age 59 Current medications: captopril 100 mg twice daily; chlorothiazide 125 mg/d (divided dose); aspirin 81 mg/d; gingko biloba 120 mg twice daily Physical examination: BP, 129/82; weight, 165 lb; height, 69 inches. Visible scar from prior cardiac surgery; otherwise unremarkable Laboratory findings: Hb, 12.8 (reference, 13.5-17.5 g/dcL)

d. Introduce thrombin to sterile field before administering parenteral products e. Document, in medical records, the type of thrombin used 6. Excessive perioperative bleeding is associated with ___. a. increased morbidity and mortality b. extended procedure times c. transfusion of blood products d. all of the above 7. Active hemostats (ie, topical thrombin) ___. a. will not work unless bleeding is present b. polymerize, activate, and form a sealing barrier c. fully polymerize, activate, and glue together tissues d. must not be used with absorbable gelatin sponges 8. Which of the following statements about topical thrombin is false? a. Each is available at concentration of 1,000 IU/mL

a. Consider red blood cell and Hb laboratory results of minimal clinical concern before peripheral arterial bypass.

b. All have similar efficacy and effectiveness

b. Reduce this patient’s aspirin dose by half, but do not discontinue it.

d. All may be used with absorbable gelatin sponge

c. Instruct this patient to discontinue ginkgo biloba as soon as possible. d. Examine this patient’s medical records (if possible) to determine whether active hemostats (ie, topical thrombins) were administered during previous surgeries. e. Consider that flowable hemostats’ toothpaste-like consistency makes them a good choice for control of diffuse, raw surface bleeding. f. If fibrin sealants are being considered for surgical hemostasis, consider that these agents combine concentrated fibrinogen and thrombin to create a fibrin clot and may require intact coagulation. g. In selecting mechanical hemostats, keep in mind that swelling is a safety concern. h. Consider that active hemostats do not require the presence of blood to achieve surgical hemostasis. 2. How confident are you in making optimal therapeutic decisions on hemostasis in the care of patients with surgical bleeding? Based on a scale of 1 to 5, with 1 = Not at all confident and 5 = Very confident

c. All require thawing

9. Which of the following may be associated with elevated clotting times? a. Non-fibrin sealant b. Recombinant thrombin c. Pooled human plasma thrombin d. Bovine thrombin 10. A 56-year-old woman is preparing to undergo peripheral arterial bypass surgery. Her history is unremarkable except for scars from a series of operations she underwent as a child to correct a congenital heart defect. In the absence of a conclusive determination, you consider that ___ might strongly suggest prior exposure to bovine thrombin. a. family history of von Willebrand disease b. multiple prior cardiac, neurologic, or vascular surgeries c. prior blood product transfusion d. known use of therapeutic anticoagulation

Post-Test Answer Section

3. How confident are you in differentiating the functional characteristics of mechanical, active, flowable, and fibrin sealant topical hemostats? Based on a scale of 1 to 5, with 1 = Not at all confident and 5 = Very confident

1a.

Consistent

Not Consistent

5a.

1b.

Consistent

Not Consistent

5b.

1c.

Consistent

Not Consistent

5c.

4. How confident are you in minimizing the risk for and implications of surgical bleeding preoperatively, intraoperatively, and postoperatively? Based on a scale of 1 to 5, with 1 = Not at all confident and 5 = Very confident

1d.

Consistent

Not Consistent

5d.

1e.

Consistent

Not Consistent

5e.

1f.

Consistent

Not Consistent

1g.

Consistent

Not Consistent

1h.

Consistent

Not Consistent

5. How often do you use the following measures to ensure the safe use of topical hemostats? Based on a scale of 1 to 5, with 1 = Never and 5 = Always a. Have pharmacy dispense and label products b. Avoid leaving vial or syringe at patient’s bedside c. Apply auxiliary labels: “Do Not Inject”

10.

Answer Sheet and Evaluation Form Optimizing the Selection and Use of Topical Hemostats Release Date: April 1, 2012

Participant Information

Expiration Date: April 1, 2013

Participate online at topical-hemostats.com Or fax to AKH Inc., (904) 683-3803 Or mail to: AKH Inc., PO Box 2187, Orange Park, FL 32067-0534

(please print)

First Name: __________________________________ Last Name: __________________________________ Degree: ____________________________ Address: ______________________________________________________________________________________________________________________ City: ___________________________________________________________________ State: _______________ ZIP: _____________________________ Daytime Phone: ___________________________ Fax: __________________________ Email: _______________________________________________ License #: ___________________________________________________________________________ State of Licensure: ________________________ ❏ Physician I am claiming _____ AMA PRA Category 1 Credit(s)™

❏ Pharmacist

❏ Nurse

❏ Other (specify): ______________________________________________________________________________________________________________

Evaluation Questions What is your overall rating of this course? (Based on a scale of 1 to 5, with 1 = Poor and 5 = Excellent)

• Describe key clinical factors that influence the selection and use of topical hemostats as adjuncts for achieving surgical hemostasis.

• Delineate clinical characteristics and pharmacoeconomic (direct and non-medication costs) considerations by which topical hemostats should be evaluated, acquired, and used in hospitals.

• Develop a plan for reconciling cautionary guidance and clinical best practices with regard to the selection and use of the full range of topical hemostats.

• Meet your educational goals

• Provide evidence-based information that will be useful in your practice

• Provide information that was objective, scientifically rigorous, and free of commercial bias

• Use teaching methods and educational materials that enhanced your learning experience

How relevant was this course to your clinical practice (Based on a scale of 1 to 5, with 1 = Not at all and 5 = Extremely)

Please rate your level of interest in the information provided in this course (Based on a scale of 1 to 5, with 1 = Not at all and 5= Extremely)

How well did this course achieve the following learning objectives? (Based on a scale of 1 to 5, with 1 = Not at all and 5 = Completely) • Appraise the clinical and economic effects of excessive intraoperative or postoperative bleeding and common preoperative strategies for minimizing bleeding events.

To what degree did this course accomplish the following? (Based on a scale of 1 to 5, with 1 = Not at all and 5 = Completely)

Based on the information presented in this course, I will ❏ Do nothing, as the content was not convincing ❏ Do nothing, as my practice reflects the course’s recommendations ❏ Seek additional information on this topic ❏ Change my practice in the following way(s): ____________________________________________________________________________________ ❏ Do nothing, as the following barriers prevent my adoption of the course recommendations: ______________________________________________________________________________________________________________________________ The most important concept learned during this course that may effect a change in patient care is:

_____________________________

What issue(s) related to the therapeutic area discussed in this course, or other topics, would you like addressed in future continuing education? _______________________________________________________________________________________________________________________________ Are you willing to participate in a future survey to assess outcomes from this course? (If yes, please be sure to include your email address above) ❏ Yes ❏ No Additional comments: _________________________________________ _____________________________________________________________

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What method(s) of learning do you prefer? (Check all that apply) ❏ Visiting faculty activities ❏ Monographs ❏ Symposia ❏ Internet-based ❏ Workshops ❏ Case-based ❏ Self-study ❏ Other (please specify):

MN1112

In the News

GEnERAlSURGERynEwS.cOM / GEnERAl SURGERy nEwS / APRIl 2012

Surgical innovation continued from page 1

from around the world who have devised innovative and inexpensive solutions to real-world problems. The session was inspired by a class at the Stanford Institute of Design, called “Entrepreneurial Design for Extreme Affordability.” Students in the class develop affordable products for the impoverished parts fo the world. One of their great successes is the JaipurKnee, a polymerbased polycentric knee joint that can be manufactured

for less than $20 and is designed for amputees in the developing world. “Surgeons make a lot of decisions about the technologies we use, and this is an area where we have an opportunity to lead through our ability to innovate,” said Liane Feldman, MD, director of the Division of General Surgery, McGill University, Montreal, Canada. Dr. Feldman, who moderated the ACS session, says surgeons push boundaries all the time. “We innovate in the operating room every day, every week. Sometimes we tinker with things to make them a little bit better,

sometimes we’re forced by the circumstance we are in to use what is available to us for that patient in that circumstance.” Over the next months, General Surgery News will profile a series of surgeons who have found affordable solutions—often under $5—to vexing surgical and clinical issues. The group includes an American military surgeon, a Canadian laparoscopic surgeon and surgeons who practice in crisis situations around the world.

With Stakes High and Resources Low, Military Surgeons Innovate Lives Saved With Inexpensive Solutions

Part 1 of a 3-Part Series

B y C hristina F rangou

he U.S. military is famous for many things, but extreme affordability certainly isn’t one of them. However, that’s exactly how surgeons describe some of the key innovations in trauma care that U.S. military personnel have developed over the past decade. The innovations were born out of urgent circumstances, when surgeons looked around at their surroundings and used a little creativity to make something work. “Through necessity, we learned to take rather mundane objects beyond what their original use was intended and that has saved lives,” said Alec Beekley, MD, associate professor and trauma surgeon at Thomas Jefferson University, Philadelphia. Dr. Beekley was deployed to Iraq with the U.S. military in 2004 and then again in 2007. Both times, he worked on farthest-most forward surgical teams and combat support hospitals on the front lines. That’s where he learned to make do with very little in times of crisis. The skills in “extreme affordability” saved soldiers’ lives in Iraq, Dr. Beekley noted, but those same skills have value at home in U.S. hospitals, saving the lives of civilians. “Some of the techniques and experiences that I had there, I use at home,” he said.

rejuvenation and Innovations Tourniquets are considered by many to be the most significant medical development to come out of the wars in Iraq and Afghanistan. The tourniquet, which has been used to control bleeding since the Roman Empire, was even named one of the top 10 Army inventions of the year in 2005. What’s changed is how the U.S. military uses tourniquets. Until recently, tourniquets were considered a treatment of last resort, but since 2004, more troops carry tourniquets, and use them earlier to prevent lethal blood loss. “By the time I arrived in 2007, patients came in and they almost always had modular tourniquets applied. … We found that the tourniquets were able to preserve the physiology somewhat to keep patients from arresting, keep them out of shock so that we could do damage control and limb-salvage procedures on them.” Orthopedic surgeon Col. John F. Kragh, MD, and colleagues published an analysis of emergency tourniquet use over a six-month period in a Baghdad hospital (Mil Med 2011;176:817-823). Of the 499 patients who had 862 tourniquets applied on 651 limbs, no limbs were lost when the surgeons used tourniquets. “We found that morbidity was minor in light of major

Top left: operative report written on patient’s abdominal dressing. courtesy of matthew J. martin, mD. Bottom left: Improvised tourniquets reinforced with cAT-1 tourniquets. courtesy or Alec Beekley, mD. right: Tourniquet ”at the ready.” courtesy of John F. Kragh, mD. survival benefits consistent with prior reports,” said the authors. The experience of military surgeons in Iraq and Afghanistan is the latest chapter in an ongoing story of war and medicine, said Philip L. Glick, MD, MBA, vice chair of surgery, State University of New York, Buffalo. “War is an environment where surgeons make some of the greatest advances in clinical care. For instance, in Vietnam we learned that if you evacuate casualties back to field hospitals immediately, you markedly improve survival. And these things are then brought back to the civilian world,” said Dr. Glick. Military surgeons also have repurposed Army food supplies and consequently have seen substantial savings. The military’s MREs (Meal, Ready-To-Eat) are calorie-dense food packets (“they don’t taste great but they’re useful,” said Dr. Beekley). The MREs contain chemical packets that, when combined with water, create an

exothermic reaction to heat the food. Surgeons use the chemical bags from the MREs as fluid warmers. This saves about $140 compared with the cost of purchasing conventional fluid warmers, based on current online prices, said Dr. Beekley. The Marines use body bags when transporting injured civilians. They wrap the casualty in blankets and put him or her in a body bag with space cut out around the patient’s head. If needed, MREs are placed inside the bag to keep fluids warm. “For about $35, you can have a pretty effective way to warm the patient or you buy the modular unit for three times that much,” said Dr. Beekley. When proper vascular shunts are not available, military surgeons have invented makeshift shunts. Army surgeons use vascular shunts more often than those in civilian hospitals. Additionally, the patient with a shunt see savings page 20

letters to the editor medical Arms race To the Editor: [Re: The Medical Arms Race, February 2012, page 1] Dr. Jon White is saying what all physicians and Congress should be addressing. I am all for technology if it is more cost effective and better for the patient. Unfortunately, surgeons are inventing procedures to justify the equipment (robot) rather than the reverse. End-of-life care is called rationing by Congress and the media. It is being rational as far as I can see. Dr. White for president. Jack Matyas, MD Columbus, Ohio

GEnERAlSURGERynEwS.cOM / GEnERAl SURGERy nEwS / APRIl 2012

more Spam in a can

prepared to pay for it in we control the means especially surgical residents To the Editor: some way. of production and have (products of the most com[Re: Spam in a Can, January 2012, I don’t think that surto parlay that on the petitive training course, sort page 1] gical exceptionalism was of like Marines and Navy negotiating table. Dr. Cossman’s predication that if we ever a monopoly held SEALS), the end result is just work hard, do our work and do the by the solo practice surthinking that you are better right thing for our patients, then every- geon, no matter how great that surgeon and tougher than anyone else and, hence, thing else will take care of itself, we will thought he was. He was usually a per- invulnerable. In the civilian world, you end be well compensated, never have to bat- son who was once well trained, but his up thinking that the world owes you a livtle government or insurance companies, exceptionalism soon lapsed into medioc- ing. In the military, you are humbled by never sued and so on, is sheer retro-fantasy. rity because he was so busy and fearful of the fact that the enemy is trying to take The ownership–labor divide is an artifi- leaving his solo roost to further train him- your life from you. The distinction contincial one. Surgeons are, by definition, labor. self for fear of a competitor horning in on ues, because the Marine assumes that he They have a skill and do a manual/tech- his practice. Thus his pining for the good is in a hostile environment and involves nical job; it just depends old days (before Obama, himself in understanding it and managing on who owns them. All HMOs and Medicare it, whereas the surgeon (with a doctoral labor issues are funfor the really old among degree and an IQ of 145) assumes that the damentally capitalistic us) actually had some world owes him a living and that his work ACOs: The Latest Experiment In Health Care Delivery Spam in a Can ones. You have a techmerit. is too important to set aside for a moment A F nical or intellectual skill I completely disagree in order to become involved in making the and you put it out there that labor doesn’t have a environment around him less hostile. on the market. Its value strong history of innovaDr. Cossman raises very important is determined by supply tion or quality or trans- issues, as he always does, and brings into and demand. Small busiparency. This is one of sharp focus the difficulties we face in trynesses ultimately have the most offensive state- ing to care for patients, while being amply trouble surviving because ments that management rewarded for our efforts, investing in edularger ones economize on can make, smacking of cation and training and sacrificing our managerial costs such as intellectual elitism at its family and personal life, while at the same rent, staff and economies worst and belying the time needing to be involved in important of scale in purchasing of goods and less reality that unless you labor and produce, political and managerial issues that impact expensive labor. If you truly believe that you have no idea of what the requirements all of these things. The bottom line is that you have a rare and marketable skill then and limitations of the current system are there is just not enough time for all of it, you ask what you think is a proper price and where innovation can be applied. All and we must cheat on everything. But if for it and you soon find out just how com- innovation comes from labor, employed we renege on any of these things, we can petitive you are. or self-employed, if management makes count on paying the price. Ultimately, we The prime reason surgeons went from its rounds and listens to the voice of labor. are labor, very rare and valuable labor. We ownership to labor was that there was What has blinded us to our own self- control the means of production and have more money and less hassle in it. You interest? It was both arrogance and a mis- to parlay that on the negotiating table. worked for someone else who dealt with guided sense of our invulnerability. This Negotiations are tough, but ultimately we all the hassle and was willing to engage was acquired by most of us in high school hold all the cards. We just have to be prethe outside entities that controlled reim- and college, where hard study and work pared to say “no,” and to pay the price, as bursements, litigation, guidelines, licens- pushed us on to our goal, ahead of oth- “real labor” has shown us we must do. ing and so on. If you are going to pass ers who weren’t as bright or didn’t work John Norris Childs, MD that engagement buck, you have to be as hard. It is inevitable that for many, and Philadelphia, Pa. CONVENTION ISSUE:

International Hernia Congress

GENERALSURGERYNEWS.COM

The Independent Monthly Newspaper for the General Surgeon

To the Editor: I would like to express my gratitude to Dr. White for his clear, concise, wellinformed, nonpartisan commentary on health care reform and medical economics. It is experts like him that we need to get behind on the national level. When I go to meetings, I hear derogatory terms like “Obama-care,” “jammed down our throats,” etc. This is not a partisan issue! This is a human issue, and until we have leadership at the helm like Dr. White, we will continue to be weak and divided. At the last SAGES meeting [2011] we were shamed with the abysmal ineffectiveness of the ACS lobby in size, participation and funding. The message was to join and help with money. I cannot give money to such a partisan effort as two of the three speakers continued to propagate. Until we unite behind veterans who have seen all aspects of medicine such as Dr. White— who don’t bring the 24-hour-a-day campaign insults to their messages—we will be impotent in guiding reform. Mark J.Saleem MD, FACS Pittsburg, Pa.

SavingS

continued from page 19 who is being treated by an Army surgeon typically travels quite far. These patients might have a shunt placed by a far-forward surgical team in Afghanistan and be flown all the way to Germany with the shunt open. Conventional vascular shunts rarely are available in some of the urgent settings of the far-forward surgical team. Thus, surgeons need to use whatever is available— Foley catheters, chest tubes and nasogastric tubes. “Really, all you need is a tube,” said Dr. Beekley. This system was recently described by British surgeons based in Baghdad (J Craniomaxillofac Surg 2011 Nov 7. [Epub ahead of print]). They used Foley catheter tamponade, packs and/or vessel ligation for severe facial/neck hemorrhage to replace “non-battlefield” civilian techniques for injuries from improvised explosive devices. “One should always keep in mind that the best technique used is that which saves the patient’s life and not the most expensive and/or technologically advanced,” wrote lead author Sabri Shuker, BDS, MMSc, FDSRCS,

J anuary 2012 • V olume 39 • n umber 1

Opinion

b y D aViD C ossman, mD

while back, I joined in on a conference call between the American College of Surgeons (ACS) and heads of the surgical specialty societies, including orthopedics, neurosurgery, ENT, vascular and thoracic. On this call (which was open to surgeons of the societies), I could listen but could not speak—a communication format family and friends have recommended I use more often. But nobody said I couldn’t write, so here goes. To my surprise, the atmosphere on the call that night seemed tense. Accountable care organizations (ACOs) and private contracting and balance billing were on the table. The ACS supported the former and opposed the latter, whereas the subspecialty societies lined up unanimously on the opposite side. When it was asked if there was any representative from the specialty societies who supported the ACS’s positions on these issues, the silence, in my opinion, felt long, awkward and deeply meaningful. If nothing else, it begged the question: Why would any surgeon be a member of both a specialty surgery association and the ACS? For those of you who have been

First Accountable Care Organizations To Be Unveiled Soon; The Theory: Cost Savings by Pooled Patient Risk, Coordinated Care b y G abriel m iller

pam in a

see aCCountable Care page 7

AMA Delegates Balk at ICD-10 Implementation

Docs Voice Frustration: “Burdensome,” “Expensive,” “Worthless”

new orleanS—At its 2011 Interim Meeting held in November, the House of Delegates of the American Medical Association (AMA) approved a number of resolutions its members felt would affect patient access to care and the organization’s

San FranciSco—One in every six American surgeons meets the criteria for alcohol abuse or dependence, according to a new study presented at the 2011 Clinical Congress of the American College of Surgeons (ACS). Of 7,164 surgeons surveyed, 1,112 (15.5%) had scores consistent with alcohol abuse or alcohol dependence. Among women, excess alcohol consumption was even higher: 25.6% of female surgeons screened positive for alcohol abuse or dependence compared with 13.9% of male surgeons. “The results are very compelling; these are high numbers and I would suggest that they are very accurate,” said lead author Michael Oreskovich, MD, clinical professor of psychiatry at the University of Washington, Seattle, and

see alCohol abuSe page 11

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b y C aroline h elwiCk

EXTENDED HERNIA COVERAGE

Pullout Section Page 15

b y C hristina F ranGou

or physicians, one of the most talked about phrases to come out of the Affordable Care Act two years ago has been “accountable care organization” (ACO). As a concept, ACOs represent a change far broader than many other aspects of the health care reform bill, promising to change health care delivery on a systemwide scale. And yet,

EXTENDED see HERNIA COVERAGE S C page 42

Alcohol Abuse High Among Surgeons

Higher Than General Population; Researchers Find Predictors

own financial bottom line. Delegates voted to “work vigorously” to stop the implementation of ICD-10 diagnostic coding system. The International Classification of Diseases and Related see iCD-10 page 41

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see insert at page 24 and announcement at page 33

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INSIDE

In the News

Surgeons’ Lounge

Torso Gunshot Victims Require at Least 24 Hours of Observation. ................... 6

Case Study of a Difficult Hernia........................ Hernia. ....................... 35

See ”Gut Reaction” page 24

consultant at Maxillofacial Surgery and formerly head of the Department of Oral and Maxillofacial Surgery, Baghdad Medical City, Iraq. One noteworthy technique is writing notes directly on patients, usually on their dressings. Dr. Beekley said he does this when he has important messages to transmit to the next treating physician. It’s a bare-bones but accurate system that was developed in the Army. In Iraq, surgeons often struggled to transmit accurate information about a patient as the injured soldier was transferred from one point of care to another. Field surgeons would get a patient stabilized and then send the casualty on to other physicians who might be as far as away as Germany. But the surgeon’s notes rarely traveled along with the patient. “I’ve written out a nice note about the patient’s operation, all his injuries, only to have medics come and bring me a zip lock bag just a half hour later [with the note] and say, ‘Hey sir, we found this on the LZ [landing zone],’” he said. “My colleagues have had similar cases where they prepared a bunch of notes and x-rays, placed them on the patient’s chest and as the medics rolled him to the helicopter, the folder was pulled up into the rotor

and turned into confetti.” So instead, surgeons started writing their notes directly on their patients. The system was so effective that Dr. Beekley still uses it when he is transferring patients between different hospitals. “I did this a month ago at my inner-city civilian hospital when I had an injured patient on whom I did damage control. I simply wrote ‘8 lap packs’ on his wound vac,” Dr. Beekley said. “My colleagues told me when the patient got there, they didn’t have to go looking through paper. They knew exactly what was in his abdomen. This is something that you can apply in everyday use in transfer and it works pretty darn well.” Asked what surgeons working in civilian hospitals could take away from the military’s recent experience, Dr. Beekley said there must be a willingness to innovate, “not only on the part of surgeons but on the part of ERs [emergency rooms] and hospital executives.” But, he added, every innovation needs evidence. “It should be done right. If a surgeon has an idea on how a simple device or workaround could be just as effective as a more expensive one, it should be studied to be sure that we are not harming patients.”

G N I C

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