The April 2012 Digital Edition of Pharmacy Practice News by McMahon Group

ed Spo ic tli ct io at gh n io t o be n gi ns Sa n on pa fe t

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The Pharmacist’s News Source Hematology/Oncology Pharmacy Edition

pharmacypracticenews.com

Volume 39 • Number 4 • April 2012

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Printer-friendly versions available online

ISMP Launches New Oncology Med Safety Self-Assessment Tool

ospitals and clinics providing care to patients with cancer have a new tool to help them improve oncology medication safety. In March, the Institute for Safe Medication Practices (ISMP) with ISMP Canada launched the International Medication Safety Self Assessment for Oncology. Ann Shastay, RN, MSN, AOCN, managing editor at the ISMP, showcased the tool at a webinar in February. Ms. Shastay noted that managing chemotherapy agents is particularly challenging, and Sylvia Bartel, RPh, MHP, vice president of pharmacy services at the Dana-Farber Cancer Institute, in Boston, agreed. “These regimens are very complicated. The same drugs can be used differently, in different doses and schedules depending on the disease and stage,” said Ms. Bartel, who also

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see ASSESSMENT TOOL, page 29

Anti-Seizure Drugs, HIV Medications Don’t Always Yield Safe Mix

in this issue Policy

Compliance A primer on drug waste management.

Reimbursement Matters Coding tips, other strategies for getting the most out of payers.

Communicating hope and vision—a primary focus for the servant leader.

Clinical

Medication Safety Two overlooked treatments for reversing cardiac drug toxicity.

Safety Pearls Avoiding intrathecal methotrexate mishaps, boosting IV oxytocin safety, handling investigational drugs, and more.

Technology

Opinion

Educational Review

see HIV MIX, page 33

Leadership in Action

Why the time is now to comment on stage 2 ‘meaningful use’ IT provision—and its impact on bar coding.

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Critical care pharmacists play major role in update

Operations & Mgmt

International panel finds loss of efficacy, serum concentrations with several drug combinations ertain anti-seizure drugs and HIV medications may interact in such a way as to alter the efficacy or serum concentrations of these agents, according to an international panel of investigators. But some of the panel’s suggested strategies for mitigating the interactions have been criticized by specialists who treat HIVinfected patients. The panel, convened by the American Academy of Neurology and the International League Against Epilepsy, analyzed 42 papers that provided data about the concomitant use of antiseizure and HIV drugs. The analysis showed that several combinations may warrant dose adjustments to prevent potentially serious adverse reactions (Neurology 2012;78:139-145).

Pain, Agitation and Delirium Guidelines To Be Unveiled

Medication Errors: The Year in Review See insert after page 30

Medication Safety Systems In the ICU See page 35

Houston–Pharmacists, nurses and physicians will soon have an updated set of guidelines to help them manage pain, agitation and delirium (PAD) in the intensive care unit (ICU). At the recent annual meeting of the Society of Critical Care Medicine (SCCM), clinicians who helped develop the guidelines provided a snapshot preview for attendees. “We’ve been working hard for the last six years, and it is now time to give birth to this product,” said Gil Fraser, PharmD, FCCM, clinical pharmacist in critical care at Maine Medical Center, in Portland, and professor of medicine at Tufts University School of Medicine, in Boston. According to Juliana Barr, MD, chair of the PAD Guideline Taskforce, the methodology used to develop the 2012 guidelines is more rigorous than that used for the 2002 guidelines. “The recommendations in these guidelines are more patientcentered, integrated and interdisciplinary in their approach, with less emphasis on

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see DELIRIUM, page 22

Antimicrobial Stewardship Program Cuts Drug Costs—and CDI Rates New Orleans—Not only can antimicrobial stewardship programs (ASPs) reduce inappropriate antibiotic use and lower pharmacy costs, they also can lower Clostridium difficile infection (CDI) rates, according to a recent study. Lead researcher Kevin Tapia, PharmD, clinical pharmacist at Mercy San Juan Medical Center, noticed that

CDI rates were at an all-time high in 2009 at the 370-bed acute care hospital in Carmichael, Calif. He initiated an ASP in the hope of improving patient outcomes and minimizing the negative consequences of misuse of antimicrobial treatment. The 18-month study showed that the antibiotic cost per patient-day

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Late-Breaker ASHP blasts Utah bill allowing office-based physicians to dispense oral cancer drugs. See page 12.

see STEWARDSHIP, page 7

New Product CutisPharma, Inc. announces FIRST® Mouthwash BLM 4oz and 6oz compounding kits. See page 32.

Up Front 3

Pharmacy Practice News • April 2012

Capsules

surf

Medication Reconciliation Toolkit Helps Hospitals Improve Patient Safety

APRIL 2012

watch

The five most-viewed articles last month on pharmacypracticenews.com: 1. ISMP: CMS Storage Standards May Be Worsening Drug Shortages 2. Hospitals Feeling The Pain of Severe Sedative Shortage 3. Gloom and Doom Swirls Around Sepsis Research 4. Immunoglobulins and Obesity (FAQ by Jerry Seigel, PharmD) 5. Drug With Novel Mechanism May Improve Prostate Cancer Survival Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here first

‘You have a choice to stand on the sidelines and fight or get involved and make sure that [the bill] goes through in a fashion you can live with.

n time for Patient Safety Awareness Week (March 4-10), the Agency for Healthcare Research and Quality (AHRQ) has made available a new toolkit designed to help hospitals improve their medication reconciliation processes to reduce adverse drug events. Entitled Medications at Transitions and Clinical Handoffs (MATCH) Toolkit for Medication Reconciliation, the toolkit was published in December and provides step-by-step instructions on how to improve medication reconciliation. The MATCH toolkit is based on the MATCH Web site developed by Gary Noskin, MD, and Kristine Gleason, RPh, of Northwestern Memorial Hospital in Chicago, through the support of AHRQ and collaboration between Northwestern University Feinberg School of Medicine and the Joint Commission. Ms. Gleason is the lead author. The toolkit incorporates the experiences and lessons learned by Northwestern and other health care facilities that have implemented the MATCH strategies. The MATCH toolkit states that medication reconciliation is a “complex process…. It is a comparison of the patient’s current medication regimen against the physician’s admission, transfer, and/or discharge orders to identify discrepancies. Any discrepancies noted are discussed with the prescriber, and the order is modified, if necessary.” The MATCH toolkit begins at the beginning, building the foundation of a medication reconciliation improvement project. This includes gaining leadership support and identifying and assembling an interdisciplinary team. Later chapters discuss designing the medication reconciliation process, pilot testing, education and training, and assessment and evaluation. The final chapter concerns high-risk situations for medication reconciliation, such as patients who have limited health literacy, who are cognitively impaired or who have been transferred from a hospital outside the hospital’s own system. The toolkit ends with a MATCH work plan, with worksheets to make it easier to carry out the instructions. To download a copy of the toolkit, go to http://www.ahrq.gov/qual/match.

I chose the latter.’ —Evan Vickers, RPh (R), cosponsor of a House bill that allows oncologists in outpatient clinics to dispense oral cancer medications without a pharmacy license under Utah’s Pharmacy Practice Act.

See article, page 12

Special Section: Spotlight on Medication Safety

n the heels of Patient Safety Awareness Week (March 4-10), we’ve put together a special section on safety that features advances in the treatment of cardiac drug toxicity, safety pearls from the ASHP Midyear Clinical Meeting, new dosing tips for warfarin reversal, an award-winning anticoagulation stewardship program, and more. Don’t miss this special section, which begins on page 23.

EDITORIAL BOARD

ART/PRODUCTION STAFF

ADMINISTRATION

Michele McMahon Velle, MAX Graphics/Creative Director

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Ernest R. Anderson Jr., MS, RPh, Boston, MA

Volume 39 • Number 4 • April 2012 • pharmacypracticenews.com

ANESTHESIOLOGY/PAIN Julie A. Golembiewski, PharmD, Chicago, IL Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY

INTERNAL MEDICINE

EDITORIAL STAFF

David S. Craig, PharmD, BCPS, Tampa, FL

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BIOTECHNOLOGY

NUCLEAR PHARMACY

David Bronstein, Editorial Director davidb@mcmahonmed.com

Indu Lew, PharmD, Livingston, NJ

Jeffrey Norenberg, PharmD, Albuquerque, NM

CARDIOLOGY

ONCOLOGY

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

Robert T. Dorr, PhD, RPh, Tucson, AZ

Kevin Horty, Don Pizzi, Adam Marcus, Cynthia Gordon, Kate O’Rourke, Contributing Editors

Robert Ignoffo, PharmD, San Francisco, CA

James Prudden, Group Editorial Director

Philip E. Johnson, MS, RPh, FASHP, Tampa, FL

Robin B. Weisberg, Manager, Editorial Services

Larry Ereshefsky, PharmD, San Antonio, TX

Cindy O’Bryant, PharmD, Aurora, CO

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Ali McBride, PharmD, MS, BCPS, St. Louis, MO

Cathy Rosenbaum, PharmD, Cincinnati, OH

Sara S. Kim, PharmD, BCOP, New York, NY

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4 Policy

Pharmacy Practice News • April 2012

Compliance

The webinar titled “Pharmaceutical Waste: Is Your Facility at Risk?” is available for CE credit. Scan the adjacent barcode to access.

Taking Control of Pharmaceutical Waste Pharmaceutical waste is not the hospital pharmacist’s favorite topic, and the worst part of it may be the regulations. The federal laws that govern waste management can be confusing; updates can be hard to keep track of; and in some instances, there are policies from different agencies that can seem in conflict. Given those challenges, it may not be surprising that some pharmacists question whether they really need to heed the rules governing drug waste management. “One of the questions I usually get asked is, ‘Why should I comply with the regulations?’” said Lisa M. Lauer, a federal official with the Materials Recovery and Waste Management Division of the U.S. Environmental Protection Agency (EPA), in Washington, D.C. Her answer: It’s the law, and you can be fined if you don’t. She gave an example in which violations and penalties added up to a total proposed penalty of $190,111. “While it can be expensive to get a hazardous waste management program up and running, it can also be expensive if you are caught in violation,” Ms. Lauer noted during a Jan. 20 webinar titled “Pharmaceutical Waste: Is Your Facility at Risk?” CareFusion Corporation, a medical technology company that markets the Pyxis EcoStation system, an automated pharmaceutical waste management system, moderated the webinar. The nonprofit Educational Review Systems, Inc. developed the program.

Regulations Ms. Lauer summarized the federal regulations that pharmacists need to follow to manage pharmaceutical waste. The 1976 Resource Conservation and Recovery Act (RCRA) gave the EPA the authority to control hazardous waste from “cradle-to-grave.” However, “there are no specific RCRA regulations that are directed toward hospitals or healthcare facilities,” said Ms. Lauer. “So health care facilities are subject to the same exact RCRA requirements as any other industry.” If the EPA lists a substance as a hazardous waste, or if the substance exhibits a characteristic of hazardous waste (e.g., ignitability, corrosivity, reactivity or toxicity), it is a hazardous waste whether it is generated by a pharmacy or any other concern. “The more waste you generate that’s hazardous, the more stringent the regulations become for you,” said Ms. Lauer. Pharmacists with even a modicum of experience in medication waste disposal are probably familiar with “P and U” lists, which are EPA’s lists of commercial chemical products (CCP) in unused form. Those on the P list, such as nicotine and warfarin, are considered acutely

‘Somebody needs to get a grasp of [managing pharmaceutical waste]. In an ideal world, the CEO or COO should initiate, but it usually comes up from pharmacy or environmental services.’ —Charlotte Smith, RPh, MS hazardous and thus more stringently regulated than the U list. To count as CCP, the products must not have been used for their intended purpose—for example, leftover pharmaceuticals not given to patients. A nicotine patch that went on a patient’s arm, then was peeled off, for example, was used for its intended purpose and thus is not a hazardous waste. But a nicotine patch sitting in a pharmacy is considered hazardous waste. “One of the RCRA regulations that causes much angst and confusion in the health care sector is the management of containers that have held a drug that meets the definition of a hazardous waste,” Ms. Lauer said. In a container of a P-listed drug, she explained, “It’s not the container per se that’s considered hazardous waste; it’s the residue within the container.” One way to manage a container that has held hazardous P-listed waste is to triple-rinse it and manage the rinsate as a hazardous waste. But this is impractical and it may be easier to manage the container itself as hazardous waste. Ms. Lauer explained that the EPA is in the process of developing a regulatory scheme geared to health care facilities; it is due out for public comment in spring 2013.

Strategies for Compliance Firouzan “Fred” Massoomi, PharmD, FASHP, pharmacy operations coordinator, Nebraska Methodist Hospital, Omaha, discussed strategies to comply with regulations through effective pharmaceutical waste management. “In which pharmacy class did we actually learn about pharmaceutical waste?” In

no classes, he said; “legacy of habit” is how most people learn. For pharmacies looking to begin a pharmaceutical waste program, a useful document is Managing Pharmaceutical Waste: A 10-Step Blueprint for Healthcare Facilities in the United States (2008). Produced by Practice Greenhealth and funded by a grant from the EPA, the document outlines a 10-step process, from getting started to launching the program. Dr. Massoomi cautioned that Practice Greenhealth is not a regulatory agency, so readers should check state and federal regulations. Charlotte Smith, RPh, MS, a coauthor of Managing Pharmaceutical Waste, noted that the guide should be used primarily as a framework. “Go to your state for current regulations,” she said in an interview with Pharmacy Practice News. (Ms. Smith was not affiliated with the webinar.) To start a pharmaceutical waste program, get the necessary education and pull together a team, Dr. Massoomi said. The entire hospital should be involved. “This is not a pharmacy issue, this is not an environmental services issue, this is an everybody in health care issue.” The main person responsible, he said, is the CEO or president. There should be a gap analysis of current practices, showing where the hospital is in compliance and where there are gaps, and there should be a continuous formulary assessment, taking account of new drugs as they are added. Ms. Smith stressed the importance of pharmacist involvement in pharmaceutical waste management programs. “The

pharmacist may or may not initiate,” she said, but “the pharmaceutical waste management program will not work if the pharmacist is not involved.” Ms. Smith, whose company, PharmEcology Services, Houston, Texas, provides consulting services for pharmaceutical waste management, advised obtaining a consultant to get started. She called four months the minimum amount of time to get “everything up and running.” She recommended “as much automation as possible,” and cautioned, “If you push too hard and too fast, the organization does not assimilate well.” She said: “Empower the organization so that the core team knows enough so that they understand what to do and why.” Ms. Smith added that not everyone in the pharmacy needs to understand all the RCRA regulations and state rules, but someone, such as the director of pharmacy or pharmacy operations manager, needs to have an in-depth knowledge. “Somebody needs to get a grasp of it,” she said. “In an ideal world, the CEO or COO should initiate, but it usually comes up from pharmacy or environmental services.” Still, she said, “you have to get buy-in at the C-suite.” Ms. Smith recommended forming a core team, noting that “nursing is pivotal. If they don’t buy into it, it won’t be successful.” Cheryl Chisholm, CPhT, pharmacy technician, Northern Michigan Regional Hospital, in Petoskey, knows firsthand what is involved in implementing a pharmaceutical waste management program, having spearheaded her hospital’s program. In an interview, she said having a consultant is “invaluable”; her consultant was Ms. Smith’s company, and Ms. Chisholm’s was the first hospital certified by that company. The initiative came from the pharmacy, but it soon involved the entire hospital. Ms. Smith led them through a process that was similar to Managing Pharmaceutical Waste; however, Ms. Chisholm emphasized, “We didn’t have someone coming in and doing it for us. I learned a ton.” The process began in 1996, and the program is still underway.

Another Hospital’s Experience Despina Kotis, PharmD, director of pharmacy, Northwestern Memorial Hospital, Chicago, Ill. also has firsthand knowledge of starting a pharmaceutical waste management program. “I had to take a Tylenol after my first meeting because there was so much to learn,” she said in an interview. The key, she said, is having a “team passionate about doing

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see TAKING CONTROL, page 24

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Size up the opportunity. Add even more ﬂexibility to your pharmacy with VIAL-MATE Adaptors. Contact your Baxter pharmacy representative at 888-229-0001.

Baxter, Mini-Bag, Mini-Bag Plus, the More Balance Delivered logo, Viaﬂex and Vial-Mate are trademarks of Baxter International Inc.

Medication Delivery

111620A 11/11

6 Policy

Pharmacy Practice News • April 2012

Reimbursement Matters

Striking a Balance Between Patient, Billing O

ne of the most common questions I get from pharmacists about reimbursement is the following: “I’m sure we used the correct health care common procedure coding system (HCPCS) code, but payment was denied. What went wrong?”

tractors (MACs) (Figure), who serve as the intermediary between your facility and the Centers for Medicare & Medicaid Services (CMS). Having an accessible contact with your MAC and knowing any peculiarities in the contractor’s payment policies that can affect your region is

Table 1. Quick Review of Charging • ICD-9 codes are used by hospitals to designate disease types; a move to ICD-10 codes is planned. • CPT codes: ✓ Are used by physicians or other recognized health care providers to describe procedures they perform ✓ Are determined by the American Medical Association ✓ May include payment for all products used during the procedure ✓ Cover MTM services and vaccine administration, among others

Health Problems (ICD)-9-CM diagnosis codes are specified and the documentation required is clearly outlined. This is a clinical decision that must be made and documented before the drug is ordered and given; there won’t be any payment if you try to fix this after the fact. Action: Know which drugs have NCD or LCD requirements, add this to the messaging in your computerized prescriber order entry system and provide a link to the requirements. Use the searchable database for NCDs (http://www.cms.hhs. gov/mcd/search.asp?clickon=search). Go to your MAC’s Web site to search LCDs.

What Do Modifiers Do? Modifiers are codes that, when applied

• HCPCS Codes that apply to products including drugs are maintained by CMS-HCPCS working group with an annual release. See http://www.cms. hhs.gov/HCPCSReleaseCodeSets/ANHCPCS/list.asp#TopOfPage CPT, Current Procedural Terminology; HCPCS, Healthcare Common Procedure Coding System; ICD, International Statistical Classification of Diseases and Related Health Problems; MTM, medication therapy management

Unfortunately, there’s no easy answer to that question. In fact, figuring out where reimbursement got derailed first may require that a few additional questions be asked. Perhaps the most important one is: Are the clinicians on your staff doing their part? That’s a key factor, and here’s why. Reimbursement for drugs and biologics used in the outpatient setting is just one part of the overall episode of care; each step along the way plays a role. The actual dispensing of the product itself is somewhat technical in nature and usually is handled by the infusion pharmacy. However, there is a clinical component to reimbursement for many drugs and biologics and this often is where the problems lie. Did conditions of a local coverage determination (LCD) or national coverage determination (NCD) need to be met? Was a coding modifier necessary? Was documentation required and who did that? As you can see, the answers to those questions often depend on the degree to which your clinicians can keep the needs of the patient and your billing department in mind. To help you in that process, a few basic payment principles are worth reviewing.

Reimbursement Review Because all transactions are electronic, coding rather than words is used to describe what was done and what was used and is the link to coverage and payment. See Table 1 for a listing of code types. However, having a code does not imply automatic payment. That is left to the discretion of Medicare and its contractors or Medicare administrative con-

important. These contractors determine whether a particular therapy is reasonable and necessary to treat the beneficiary’s condition and whether it is included or excluded from payment. CMS releases updates and software to MACs as well as quarterly and provider education articles, which the MACs send on to hospitals and other care facilities. This is how you learn the policies that affect payment for the clinic visit, drug administration and the drug itself. Action: Add yourself to the distribution list for the updates provided by your MAC. It’s also a good idea to sign up for MedLearn Matters releases, which include policy changes affecting reimbursement. These are searchable back to 2007 and will offer a wealth of info on requirements and how to meet them. Keep the ones related to drugs and biologics in a safe searchable file. See: http:// www.cms.gov/MLNMattersArticles.

Figure. Medicare administrative contractors.

“Reimbursement Matters” is a tool for maintaining your health-system’s fiscal health. Please e-mail the author at bkirschen@aol.com with suggestions on reimbursement issues that you would like to see covered.

Bonnie Kirschenbaum, MS, FASHP

to CPT procedural codes or HCPCS codes, affect reimbursement for a treatment, indication or product. Two important examples are modifiers that apply to the use of erythropoiesis-stimulating agents (ESAs) and those that apply to pharmaceutical waste billing. In the case of ESAs, the modifiers could specify why the drug is being administered: for example, in an ESRD patient or in a non-ESRD patient for anemia caused by chemotherapy, radiation therapy or for non-cancer conditions. In each case, the proper modifier must be used to ensure proper reimbursement. (See Table 2 for more details on pharmaceutical waste billing. For more information on ESA coding, see chart in online version of this article at www.pharmacypracticenews.com) Bottom line: Think of reimbursement as an important step in clinical decision making, learn the intricacies and apply them for a more lucrative outpatient practice.

Table 2. Hints for Billing for Pharmaceutical Waste • Medicare created the ability to bill for expensive pharmaceutical waste shortly after moving to the concept of “billing units representing actual dose given” and away from the “whole vial” method of billing. • Medicare doesn’t mandate billing for waste, but makes it possible to recoup some lost revenue if you choose to bill for the waste, paying strict attention to the rules. • Only applies to outpatients. • Only applies to Medicare unless your state’s Medicaid also has added this component. • Might apply to private insurers, depending on your negotiated contract. • Only applies to drugs that Medicare actually pays for that cost more than $75 per day.

What Are LCDs and NCDs?

• These drugs are the ones listed on the quarterly ASP/NDC CMS updates.

NCDs and LCDs establish the criteria for billing and reimbursement of a particular product and the effective dates of service to which these criteria apply. These determinations are the “clinical decision support” steps to reimbursement or the clinical component to billing, leading you through a series of steps to determine whether the drug is the right fit for the patient. In some cases, CMS will issue an NCD for an on-label, FDA-approved use of a medication; offlabel indications are determined by the local contractor. In any case, the specific applicable International Statistical Classification of Diseases and Related

• Only applies to single-dose vials for these drugs. • The quarterly ASP NDC matched tables show you exactly how many billing units are in each vial so you can correctly calculate the waste. • You can’t bill for overfill in the vials. • MAC/FI determine how they want waste billing to happen and what kind of documentation they require • Don’t just copy from someone else if they’re not in the same MAC/FI that you are. • You can do this if you break down the steps and make it as simple as possible. • Probably will end up billing for waste for only a very few expensive drugs and that’s worth the time it takes! ASP, average sales price; CMS, Centers for Medicare & Medicaid Services; FI, fiscal intermediaries; MAC, Medicare administrative contractors; NDC, National Drug Code

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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26. Despotis G, Avidan M, Eby C. Prediction and management of bleeding in cardiac surgery. J Thromb Haemost. 2009;7(suppl 1):111-117.

54. Tisseel [fibrin sealant] [package insert]. Westlake Village, CA: Baxter Healthcare Corp; 2012.

27. Mann KG. Thrombin formation. Chest. 2003;124(3 suppl):4S-10S.

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

56. Vitagel surgical hemostat [package insert]. Malvern, Pennsylvania: Orthovita, Inc; 2007. 57. CryoSeal (fibrin sealant) [brochure]. Rancho Cordova, California:Thermogenesis Corp; 2006. 58. TachoSil (Absorbable Fibrin Sealant Patch) [package insert].Westlake Village, CA: Baxter Healthcare Corp; 2010. 59. Coseal Surgical Sealant [package insert]. Hayward, CA: Baxter Healthcare Corp; 2009. 60. DuraSeal Dura Sealant System [package insert]. Waltham, MA: Confluent Surgical, Inc; (no year given). 61. ProGel pleural air leak sealant [instructions for use]. Irvine, CA: Neomend, Inc; (no year given). 62. Dermabond Advanced Topical Skin Adhesive [package insert]. San Lorenzo, Puerto Rico; Ethicon, LLC; 2011. 63. Omnex Surgical Sealant [package insert]. Somerville, NJ: Johnson & Johnson Wound Management; 2010. 64. Histoacryl, Histoacryl Blue [Web site]. Ann Arbor, MI: TissueSeal, LLC; 2005. http://www.tissueseal.com/. Accessed February 10, 2012.

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.

67. BioGlue Surgical Adhesive [instructions for use]. Kennesaw, GA: CryoLife; 2010. 68. Ham S, Lew E, Weaver F. Thrombin use in surgery: an evidence-based review of its clinical use. J Blood Medicine. 2010;1:135-142.

89. Streiff MB, Ness PM. Acquired FV inhibitors: a needless iatrogenic complication of bovine thrombin exposure. Transfusion. 2002;42:18-26.

69. Crean SM, Michels SL, Reynolds MW. Exogenous bovine thrombin as a biomarker of exposure and outcome. Expert Rev Mol Diagn. 2008;8(5):651-661.

90. Chouhan VD, De La Cadena RA, Nagaswami C, et al. Simultaneous occurrence of human antibodies directed against fibrinogen, thrombin, and factor V following exposure to bovine thrombin: effects on blood coagulation, protein C activation and platelet function. Thromb Haemost. 1997;77:343-349.

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.

91. Crow SS, Sullivan VV, Aysola AE, et al. Postoperative coagulopathy in a pediatric patient after exposure to bovine topical thrombin. Ann Thorac Surg. 2007;83:1547-1549.

71. Doria C, Fischer CP, Wood CG, et al. Phase 3, randomized, double-blind study of plasma-derived human thrombin versus bovine thrombin in achieving hemostasis in patients undergoing surgery. Curr Med Res Opin. 2008;24:785-794.

92. Lomax C. Safety of topical thrombins: the ongoing debate. Patient Saf Surg. 2009;3(1):21.

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.

79. Foster KN, Kim H, Potter K, Matthews MR, Pressman M, Caruso DM. Acquired factor V deficiency associated with exposure to bovine thrombin in a burn patient. J Burn Care Res. 2010;31(2):353-360.

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

Clinical 7

Pharmacy Practice News • April 2012

Infectious Disease

STEWARDSHIP continued from page 1

at Mercy San Juan was $29.62 when the ASP began in the third quarter of 2009. As of the third quarter of 2011, the program had lowered the cost to $16.92—a reduction of 43%. The CDI rate dropped as well. When the program began, the rate was 9 (number of CDIs per patient-days × 10,000). As of the third quarter of 2011, the rate was 3.5, according to the results, which were presented as a poster abstract (3-148) at the 2011 American Society of Health-System Pharmacists (ASHP) Midyear Clinical Meeting. Dr. Tapia and his colleague, clinical pharmacist Gary Chan, PharmD, developed the ASP team under the guidance of Richard Stack, MD, an infectious disease (ID) physician at the medical center. The team also included an infection preventionist and a microbiologist. “With antimicrobial stewardship programs, everyone wins,” Dr. Tapia said. “Patients have less risk for acquiring a hospital infection and suffer fewer side effects. Pharmacists and doctors communicate better, so doctors don’t feel like we’re just out to police them. Hospitals can discharge patients sooner and save money.” Dr. Tapia added another important benefit to ASPs: “The community benefits because antibiotics are less likely to be misused and create resistance.”

Using CDI Rates To Measure Effectiveness Infection from C. difficile, a bacterium that can cause symptoms ranging from diarrhea to life-threatening inflammation of the colon, is rapidly increasing in incidence and severity, while also becoming more difficult and expensive to treat. Misuse of antibiotics—including keeping patients on mul-

Clostridium difficile colonies after 48 hours’ growth on a blood agar plate. Magnified 4.8x. Source: CDC

tiple antibiotics for lengthy amounts of time—can lead to the infection. An estimated 500,000 cases of CDI occur in the United States each year, causing 15,000 to 20,000 deaths and costing an estimated $1 billion annually. Dr. Tapia’s mother-in-law died last year at age 60 of severe complications related to CDI. “It was an unfortunate consequence of her antibiotic treatment,” he said. “It definitely hits home when it happens to someone close to you.”

How Stewardship Programs Work Each day at Mercy San Juan, the stewardship team pharmacist reviews computer-generated reports of antibiotic-managed patients in the following five categories: • Patients on restricted antibiotics. • Patients on antibiotics for more than 10 days. • Patients on multiple antibiotics for more than three days. • Patients with multidrug-resistant (MDR) pathogens. • Patients with C. difficile–positive cultures.

If necessary, recommendations for modification of therapy are made directly to the physician. Clinical pharmacists are responsible for the majority of antibiotic management throughout the hospital; however, ID physician specialists are available for consultation in more complex cases. Dr. Tapia said the program is thriving. “We’ve seen improvements in the prescribing practices of many physicians,” he said. “There’s also been an increase in the number of consultations doctors seek with the pharmacists regarding antibiotic selection, dose optimization, duration of treatment and assistance with outpatient regimens upon discharge.” To improve communication, the stewardship team meets monthly to discuss new drugs, develop policies and review cases in which doctors have rejected their recommendations. Dr. Tapia said a phone call from the ID physician on the team is usually all it takes to convince a resistant doctor to follow the policy. Dr. Tapia is pleased that

‘First, get your infectious disease physician on board. Then do the research and write the proposal. Don’t hesitate, because [creating an ASP is] definitely worth it.’

—Kevin Tapia, PharmD

Improving Patient Outcomes With ASPs: A Case Study

evin Tapia, PharmD, clinical pharmacist at Mercy San Juan Medical Center, in Carmichael, Calif., shares this example of his hospital’s antimicrobial stewardship plan in action. “In accordance with the guidelines of our antimicrobial stewardship program, I was reviewing a patient’s antibiotics regimen because he was taking restricted antibiotics, in addition to having Staphylococcus capitis in his blood. His labs were fine and he had no overt signs of infection, so his physician was planning to send him to a nursing facility the next day. However, I noticed he had grown this same staph species two other times during recent visits to our facility. I realized this began a few weeks after he had a pacemaker placed. I was pretty confident this patient actually had an infection of his pacemaker, and was at great risk for developing endocarditis. I felt strongly that this patient needed to be treated for the staph infection. I contacted the infectious disease physician immediately and ran the case by him. He saw the patient that day, ordered tests and started treatment for a pacemaker infection. Luckily, the patient did not develop endocarditis, but he did require six weeks of IV antibiotics to cure the infection. Had the stewardship team not been reviewing the use of antibiotics on this patient, he probably would have developed endocarditis, which can result in the need for heart surgery and possibly death. It’s nice not only to save money but also to save lives.”

physicians at Mercy San Juan have rejected only 2% to 3% of the clinical pharmacists’ recommendations over the past two years. Patricia Caruso, MS, RPh, associate director of clinical pharmacy services at Maimonides Medical Center in New York City, also stressed that communication and developing relationships with the ID physician and other doctors is key. “Some physicians see pharmacists as just trying to saving money; they don’t always think we have the best interests of patients at heart,” said Ms. Caruso, who coordinates the activities of the clinical pharmacists and ID pharmacists on her stewardship team. “So you have to take the team approach, and make sure they understand that you’re not usurping their authority— that you share the same goal of positive patient outcomes.”

Keeping Program on Track To keep Mercy San Juan’s program on track, Dr. Tapia’s stewardship team follows these guidelines: • Formulary restriction and pharmacist preauthorization. The pharmacists established a list of restricted antibiotics and antifungals, with an approval process for their use. Each morning they review the restricted antibiotics doripenem (Doribax, Janssen), ertapenem (Invanz, Merck & Co.), daptomycin (Cubicin, Cubist), linezolid (Zyvox, Pfizer) and tigecycline (Tygacil, Pfizer). Dr. Tapia’s study showed a significant decrease in the use of these agents. The pharmacists also restrict ceftaroline (Teflaro, Forest Labs), telavancin (Vibativ, Astellas) and fidaxomicin (Dificid, Optimer). “They are very expensive and don’t offer a great advantage over other agents,” he said. • Optimization of drug dosing. When a patient has a severe infection, Dr. Tapia said his team not only reviews the antibiotics for appropriate use, but also makes sure the dosing is correct for the patient’s age, and renal and liver function, weight and type of infection. Patients with highly resistant bacteria sometimes require non–FDAapproved dosing to maximize efficacy. • Timely de-escalation of broad-spectrum antibiotics. Mercy San Juan’s team established a protocol that spells out when antibiotics can be de-escalated or discontinued. “This is where we have our biggest impact,” Dr. Tapia said. His team follows recommendations for duration of treatment based on the current infectious disease guidelines. “Many times, antibiotics are continued long after the infection has resolved,” Dr. Tapia said. “This is when patients

•

see STEWARDSHIP, page 10

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7KURPELQ PDGH ZLWK D WZLVW RECOTHROM is human thrombin produced using recombinant DNA technology Â˛ ,Q D JHQHWLFDOO\ PRGLĂ&#x20AC;HG &+2 &KLQHVH KDPVWHU RYDU\ FHOO OLQH Q 1RW GHULYHG IURP FDWWOH RU KXPDQ SODVPD Q &RQYHQLHQW DQG HDV\ WR XVH Â˛ 5(&27+520 &RQYHQLHQFH .LWV DOORZ IRU TXLFN DQG HDV\ UHFRQVWLWXWLRQ Q )OH[LEOH SURGXFW OLQH ZLWK PXOWLSOH DSSOLFDWLRQ PHWKRGV Â˛ 0D\ EH DSSOLHG GLUHFWO\ RU LQ FRQMXQFWLRQ ZLWK DEVRUEDEOH JHODWLQ VSRQJH 863

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&#x2021; Topical use only â&#x20AC;&#x201C; DO NOT INJECT directly into the circulatory system Â&#x2021; Do not use for the treatment of massive or brisk arterial bleeding Â&#x2021; Do not administer to patients with known hypersensitivity to RECOTHROM, any components of RECOTHROM or hamster proteins Warnings and Precautions Â&#x2021; Potential risk of thrombosis if absorbed systemically Â&#x2021; In patients with known hypersensitivity to snake proteins, there may be a potential for allergic reaction Adverse Reactions Â&#x2021; 7KH VHULRXV DGYHUVH HYHQW WKDW RFFXUUHG LQ Â&#x2022; 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.

10 Clinical

Pharmacy Practice News • April 2012

Infectious Disease

STEWARDSHIP continued from page 7

can develop adverse reactions such as C. difficile. So we give the physicians a polite call and request the antibiotics be stopped.” • Improvement in duration of treatment. Once a patient is stabilized and improving, the ASP team asks physicians to place stop dates on antibiotic treatment. They also handle the stop dates for patients requiring four to six weeks of antibiotics. “The exciting thing

is, since we started the program, we’ve seen doctors writing in their notes what day of therapy their patients are on, what antibiotics they’re taking and what the planned duration is,” Dr. Tapia said. • How to initiate a plan. The growing trend toward pharmacist-managed stewardship programs is expected to continue. One reason: the Joint Commission’s National Patient Safety Goals’ provision to reduce the risk for health care–associated infections by preventing the emergence of MDR organisms through appropriate antibiotic manage-

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

—Dana Hawkins-Simons

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

AE Category* Patients with any event category Bleeding Cardiac Hypersensitivity Nausea + vomiting Other infection Post-operative wound infection Thromboembolic

ment. “Stewardship programs are going to be a hot topic for the next 10 years,” Dr. Fletcher said. “Especially with C. diff rates going up and a lack of new antimicrobial agents being approved.” Dr. Tapia agreed, and advises his fellow pharmacists to begin now to initiate a stewardship program. “First, get your infectious disease physician on board. Then do the research and write the proposal,” he said. “Don’t hesitate, because it’s definitely worth it.”

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

Procalcitonin Possible Marker For Infection New Orleans—Elevated levels of the biomarker procalcitonin (PCT) often correlate with bacterial infection and could serve as an antimicrobial stewardship tool to reduce inappropriate antibiotic use, according to a new study. PCT is a precursor of the hormone calcitonin that is secreted in response to proinflammatory stimulation, particularly by bacterial infections. It remains low with viral infections or other inflammatory conditions, according to Nancy Williams, PharmD, BCPS, professor of pharmacy practice at Southwestern Oklahoma State University, Weatherford, and clinical pharmacy specialist at Norman Regional Health System (NRHS). Presenting the results of the study at the American Society of Health-System Pharmacists Midyear Clinical Meeting, Dr. Williams said that she and her colleagues analyzed PCT levels in 105 adult patients (mean age, 66 years) who had the levels drawn during their visit to NRHS from Jan. 1 to March 31, 2011. The PCT levels correlated with the presence or absence of bacterial infections in 85 (81%) of the patients. Of those, 57 patients had elevated PCT levels consistent with the diagnosis of a bacterial infection, and 28 had normal values, indicating a viral infection or other inflammatory disease, noted Dr. Williams. She added that NRHS runs the test on-site for $68; results come back in approximately one hour. Addressing the study’s limitations, Dr. Williams said PCT levels can increase in patients with renal impairment, making it more predictive in younger patients. Of the four patients with false-positive results, three had elevated serum creatinine. Of the 16 patients with false-negative results, six were on antibiotics prior to having their PCT level drawn. For patients with multiple PCT levels drawn, only the first one was included in the study. “It’s an interesting study, but PCT is still in its infancy,” said Patricia Caruso, MS, RPh, associate director of clinical pharmacy services at Maimonides Medical Center, in New York City. “No one is going to want to delay time to antibiotic administration unless they’re quite confident the patient does not have a bacterial infection.” PCT should not be used “in isolation,” Dr. Williams said. “But there’s definitely a role for it as an adjunct to other clinical lab and radiographic findings to help decide whether someone has a bacterial or viral infection.” —D.H.

Pharmacy Practice News • April 2012

Clinical 11

Critical Care

Study Bolsters Use of Lower Fixed rFVIIa Dose for Warfarin Reversal Houston–Adding to the growing evidence that a low, fixed dose of recombinant activated factor VII (rFVIIa) can effectively stabilize international normalized ratio (INR) values in patients with warfarin-associated intracerebral hemorrhage (ICH), a study presented at the recent annual meeting of the Society of Critical Care Medicine demonstrated that a 2-mg dose appears to be as effective as an 80-mcg/kg dose (abstract 110). “I can’t say that everybody should be using this lower dose, but it appears to be working at our institution,” said Adele Robbins, PharmD, BCPS, a postgraduate year 2 cardiology pharmacy resident at UMass Memorial Medical Center in Worcester, who led the study. “To our knowledge, this is the first study to look at comparisons of doses.” To date, there is no specific dose of rFVIIa recommended for warfarin reversal. Some hospitals use fixed doses and others use weight-based dosing.

Journal Study Spurred Practice Change Historically, UMass Memorial Medical Center had used the 80-mcg/kg dose of rFVIIa for warfarin-associated ICH. In June 2010, the hospital amended its protocol to a fixed dose of 2 mg based, in part, on a 2006 study published in the journal Pharmacotherapy (2006;26:10911098). In that study, 16 patients who had been taking warfarin and had an acute major bleeding event were given 1.2 mg of rFVIIa. A rapid onset of response for achieving a desirable hemostatic effect was identified in 14 of 16 patients. The smallest dose now available on the market is 1 mg, but UMass has been using 2 mg because data with rFVIIa doses lower than 1.2 mg have not been published, said Dr. Robbins. She and her colleagues compared data at UMass from 29 patients who received 80 mcg/kg of rFVIIa with 29 patients who received 2 mg. “Our historical data came from another UMass residency project a few years before mine looking at the addition of rFVIIa 80 mcg/kg to standard therapy of vitamin K and blood products,” Dr. Robbins explained. To be included in the study, patients had to be older than 18 years, have known ICH on computed tomography scan and documented use of warfarin therapy with an INR greater than 1.5. Patients were excluded if they had cir-

rhosis, cerebral infarct or myocardial infarction on admission, sepsis, disseminated intravascular coagulation or hemorrhagic shock. The primary end point was time to INR normalization (dose to first INR <1.3). Patients in the weight-based dosing arm received an average of 79 mcg/kg of rFVIIa and patients in the fixed 2-mg dose arm received an average dose of 26.6 mcg/kg (P<0.01). Baseline characteristics were similar in both groups. The median time to INR normalization was lower in the fixed-dose arm (165 vs. 257 minutes; P=0.02). The difference in the median time to sustained INR normalization was not statistically significant (736 minutes, fixed-dose group vs. 648.5 minutes, weight-based group; P=0.68). Four patients in the fixed-dose group required an additional dose of 1 mg. Mortality and hospital length of stay were not statistically different between the two groups. Dr. Robbins noted the study was limited in that it was a retrospective study. Importantly, using the lower dose can reduce health care costs. According to Dr. Robbins, on average, UMass Memorial Medical Center saved $4,300 per patient who received fixed-dose rFVIIa. Over an entire year of implementing the low-dose option, he noted, the hospital is projected to save $80,000.

Not a One-Dose-Fits-All Approach Scott Chapman, PharmD, associate professor in the Department of Experimental and Clinical Pharmacology, at the University of Minnesota College of Pharmacy, in Duluth, said that there is not enough collective evidence to say that all hospitals should be using a low, fixed dose of rFVIIa for warfarin reversal, but the study certainly bolsters the argument and is consistent with the experience at his hospital. Based on the 2006 Pharmacotherapy study, the hospital where Dr. Chapman practices—North Memorial HealthCare, in Robbinsdale, Minn.—uses a 1-mg dose of rFVIIa to reverse the effects of warfarin.

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Hem/Onc Pharmacy

Pharmacy Practice News • April 2012

In Focus

After Fiery Debate, Physician Dispensing Bill Passes in Utah I n Utah, a bill that will allow oncologists in outpatient clinics to dispense oral cancer medications without being licensed under the state Pharmacy Practice Act has passed both houses of the state legislature and is expected to be signed into law. While some herald the bill as a win for cancer patients, several pharmacy associations have actively fought its passage. William Nibley, MD, an oncologist at Utah Cancer Specialists, in Murray, Utah, said the bill will help resolve a common problem: cancer patients who live in rural areas and who try to obtain their cancer medications close to home, only to find that the local Walgreens or other retail pharmacy doesn’t stock the medications. “That’s certainly understandable—retail pharmacies typically don’t handle these agents,” Dr. Nibley said. “So the best solution is to let me dispense the medications directly to my patients.” As for the backlash triggered by the bill, he noted, most of that is coming from hospital pharmacists at large cancer centers that dispense—and want to continue dispensing—oral cancer drugs. “That’s just not always workable,” Dr. Nibley said. “Most people choose to get treated in the community, close to their homes; they are 300 miles away from these big pharmacies. So they go to the Walgreens.” And unless that drugstore is a specialty pharmacy or otherwise set up to stock and dispense oral chemotherapy, “patients can’t get their meds,” he said. Another problem with trying to fill cancer drug prescriptions in the community is the frustration that results when patients discover they have a $500 copay at the register. “There’s not a lot of expertise at the community pharmacy level about what to do,” Dr. Nibley said. “There are copay foundations and programs to help, but the community pharmacists aren’t really aware of those programs.” He said patients often leave without their medications and this further discourages pharmacists to stock these drugs.

ASHP, ISMP Oppose Bill The American Society of HealthSystem Pharmacists (ASHP), the Utah Society of Health-System Pharmacists (USHP) and the Institute for Safe Medication Practices (ISMP) are among the organizations that lobbied against the bill. The Utah State Board of Pharmacy wrote a letter to the Utah House Health and Human Services Committee expressing patient safety concerns and recommending further study before implementation. “Not only does the bill exempt oncologists from licensure under the Pharmacy Practice Act to dispense cancer drugs, but it also exempts ‘medical personnel

acting under the direction of an oncologist’ from licensure,” said Karen Noonan, MA, ASHP’s director of state affairs and grassroots advocacy. “ASHP has serious patient safety concerns about the absence of regulatory oversight of the dispensing of cancer drugs, especially when supervised, non-physician personnel are permitted to dispense these high-toxicity, narrow-therapeutic-index drugs. We recognize that physician dispensing is pervasive, and also that it is appropriate. But it needs to be regulated as part of the practice of pharmacy.” Many states allow physicians to dispense medications but in a restricted manner, such as by requiring physicians to register with their state boards of pharmacy and abide by the same rules that bind pharmacists regarding, for example, proper drug labeling, record keeping and patient counseling. North Carolina requires dispensing physicians to register as such with the Board of Pharmacy. In Texas, a physician may dispense a drug in an amount greater than “immediate need” only as a free sample or if the patient lives in a rural area. Maryland and Arkansas allow physician dispensing if a doctor has a special permit.

Six Revisions The Utah bill exempts physicians from the Utah Pharmacy Practice Act, which has made many pharmacists dissatisfied, but it is certainly more palatable than it was when it was first introduced. “The bill underwent a total of six revisions throughout the legislative process, and each of those attempted to add some safety parameters,” said Melissa Skelton Duke, PharmD, BCPS, a USHP board member and clinical pharmacy manager at Intermountain Healthcare, Salt Lake City. “However, there are still too many unanswered questions to allow the members of USHP and certainly our advocacy committee to feel comfortable moving forward, particularly around the regulatory oversight.” The bill was sponsored by Sen. Curt Bramble (R-Provo), who was personally invested in its passage—his father died from cancer. Evan Vickers, RPh, a Republican member of Utah’s House of Representatives and a pharmacist, cosponsored the bill. “You have a choice to stand on the sidelines and fight or get involved and make sure that [the bill] goes through in a fashion you can live with. I chose the latter,” said Mr. Vickers. “If we are going to allow this, physicians should have to go through the same policies that the pharmacist does in terms of record keeping and storage and all the other things that pharmacists do—counseling, etc—so that was the attempt.” Although the bill permits oncologists

and medical personnel acting under the direction of an oncologist to dispense cancer therapeutics without a license, it

provides large profit margins for specialty and retail pharmacies.” The bill states that physicians cannot

‘As a pharmacist, it is troubling to me that [ASHP and USHP] are standing with such a firm fist, instead of looking at it as an opportunity to come together and work with physicians.’ —Karen Kellogg, PharmD

was amended to require practitioners to notify the Utah Division of Occupational and Professional Licensing (DOPL) of the intent to dispense and to follow the division’s purchasing and distribution requirements. Language was added to make it “unprofessional conduct” for a prescribing practitioner “to dispense the drug in violation of the Pharmacy Practice Act.” The bill also was amended to direct the DOPL to conduct a study of physician dispensing and report the findings to the legislature. This will be a “thorough study of other state laws and recommendations for how Utah should proceed with allowing or not allowing physician dispensing in our state,” Mr. Vickers said. “The report is not directed specifically to oncologist dispensing and safety, but the overall practice of physician dispensing and safety.”

ADE Reporting a Challenge Niesha Griffith, MS, RPh, FASHP, director of pharmacy and infusion services at the Arthur G. James Cancer Hospital, The Ohio State University in Columbus, believes conducting a safety study post-implementation will be challenging. “Without the infrastructure to report and trend medication errors that most hospitals and pharmacies have, independent physicians are not likely to report and may not even know when bad things happen as a result of nonadherence, misunderstanding of directions, drug interactions, or a prescription misfill,” she said. “Adverse events, in some cases, may even be attributed to disease progression.” Ms. Griffith is also skeptical about language in the bill that says that physicians cannot make a profit from the venture. “I have to believe that there is somewhat of a financial incentive for this move,” she said. “Dispensing of oral chemotherapy

profit from medication sales, but they can obtain payment for expenses and services related to providing the cancer drug regimen. According to Dr. Duke, pharmacists have very unique and specific training to recognize therapeutic duplications, underdoses and drug interactions, and to provide targeted and comprehensive patient education. The absence of medication reconciliation is another concern. “We don’t want patients to be in a situation where a physician is dispensing and doesn’t have an overview of [the patient’s] complete medication record and history, because that can lead to adverse drug events,” ASHP’s Ms. Noonan said. Dr. Nibley pointed out that whereas oncology pharmacists might have expertise with cancer medications, community pharmacists do not. “There are a number of things that are more ideally done in the physician office where we already administer chemotherapy, educate patients, have these systems in place to make sure all this is accurately done, do all the preauthorization, and have all the resources available in terms of copay assistance,” said Dr. Nibley. Ms. Griffith is not reassured. “I have had exposure to independent physician practices and I can tell you that the way they practice, not having a pharmacist on site is very different from, in my opinion, the standard of care that you get when you have the involvement of the entire health care team that includes a pharmacist,” she said. “In many institutions, there are multiple pharmacy checks at various steps in the medication use process.” Allen Vaida, PharmD, executive vice president of the ISMP, said he is also concerned that not having the pharma-

•

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Hem/Onc Pharmacy

Pharmacy Practice News • April 2012

In Focus

Study May Resuscitate Gemtuzumab for AML Therapy San Diego—Eighteen months after gemtuzumab ozogamicin was withdrawn from the market, a multicenter Phase III study suggested that the agent may still have a valuable role to play in acute myeloid leukemia (AML) induction therapy. The study was conducted with a lower per-dose amount of gemtuzumab (Mylotarg, Pfizer) relative to previous protocols to see if that would lessen the side effects that had led to the drug’s withdrawal from the market, particularly induction-related deaths. Among the patient population of previously untreated patients with AML between the ages of 50 and 70 years, those who received gemtuzumab did better with respect to the primary end point of event-free survival (EFS) as well as overall survival (OS) than those who did not receive the drug, with a similar rate of induction-related deaths (abstract 6). “On the basis of these results, we think that gemtuzumab can benefit AML patients, with acceptable toxicity,” said investigator Sylvie Castaigne, MD, from the Department of Hematology, Hôpital de Versailles, in France. Presenting the data on behalf of the Acute Leukemia French Association (ALFA) at the 2011 annual meeting of the American Society of Hematology (ASH), Dr. Castaigne said she hoped the data would lead regulatory agencies and Pfizer to reconsider the role of this agent in AML. The results of this 280-patient Phase III study corroborate the results of two previous Phase II trials in patients with relapsed disease. In the latest study, patients received a single induction of 60 mg/m2 daunorubicin (DNR) on days 1 to 3 along with 200 mg/m2 of cytarabine (AraC) on days 1 to 7 of a

UTAH BILL continued from page 12

cist in the loop removes a crucial second check. He added that he worries about the proficiency of the office staff to conduct adjudication of medications with third-party payers. According to Dr. Nibley, community oncologists already are skilled at conducting second checks with intravenous chemotherapy. As for the concerns over billing, “there is not a single oncologist in the country who is going to want to distribute these medications without having the ability to bill [for] them,” he said.

ASHP Stance ‘Troubling’ Karen Kellogg, PharmD, director of pharmaceutical services at Utah Cancer Specialists, Salt Lake City, has been

28-day cycle and were randomized to receive either 3 mg/m2 of gemtuzumab on days 1, 4 and 7 or no third agent. If marrow blasts persisted at day 15, patients received 35 mg/m2 of DNR on days 1 and 2 and 1,000 mg/m2 of AraC every 12 hours on days 1 to 3. Patients who achieved a complete response or a complete response with incomplete platelet recovery were given two consolidation courses of 60 mg/m2 of DNR on day 1 and 1,000 mg/m2 of AraC every 12 hours on days 1 to 4, with or without 3 mg/m2 of gemtuzumab on day 1 depending on the randomization arm. The EFS at two years was 41.4% among patients who received gemtuzumab versus 15.6% among those who did not, a 43% improvement (hazard ratio, 0.57; 95% confidence interval, 0.45-0.77; P=0.0018). Diseasefree survival was 18.1% versus 48.5% (P=0.0009). This correlated with an increase in OS, with a median OS of 15.3 months in the arm without gemtuzumab versus 25.4 months in the arm that did receive gemtuzumab (P=0.037). The advantage for EFS was similar in patients over the age of 65 and those younger. Moreover, the EFS advantage for gemtuzumab remained significant even after censoring the 39 patients in this study who underwent stem cell transplantation (P=0.015). The greatest advantage of gemtuzumab, an anti-CD33 antibody linked to a cytotoxic calicheamicin, was observed in patients with favorable cytogenetics. Although the EFS advantage for

gemtuzumab remained significant even among those with unfavorable cytogenetics, the OS advantage was lost in this group. The only factors predictive of an advantage for the primary outcome were treatment with gemtuzumab and favorable cytogenetics. The most commonly used schedule at the time that the FDA recommended withdrawing gemtuzumab’s indication for AML was 9 mg/m2 on days 1 and 14 of a 28-day schedule. The rate of adverse events, particularly the higher fatal toxicity rate associated with this dose in the SWOG (Southwest Oncology Group) S0106 induction trial (5.7% vs. 1.4%; P=0.01), was the primary reason that Pfizer agreed to a voluntary withdrawal after the FDA recommendation (http:// www.cancer.gov/cancertopics/druginfo/ fda-gemtuzumab-ozogamicin). In the new trial evaluating 3 mg/ m2 on days 1, 4 and 7, there was no significant difference between the two groups in the rate of induction deaths possibly related to treatment (8.7% for gemtuzumab vs. 6.7%; P=0.65). The rates of grade 3 or higher neutropenia (P=0.0049) and thrombocytopenia (P=0.0001) were significantly higher in the gemtuzumab arms, but the rates of severe sepsis and intensive care unit admissions did not differ significantly. “The study suggests that the lower dose of gemtuzumab used in this study [relative to that used in such studies as SWOG S0106] is active but … less toxic,” Dr. Castaigne explained. She said that she believes that gemtuzumab

puzzled by the adamant stance of ASHP and USHP. “As a pharmacist, it is troubling to me that they are standing with such a firm fist, instead of looking at it as an opportunity to come together and work with physicians,” Dr. Kellogg said. “The law is that if a physician is going to dispense, they have to follow the same practices as in the Pharmacy Practice Act. [Physicians] are going to need to have access to pharmacists to help explain that. This is an opportunity for some additional consulting in their job, that they can go work with the oncologist and set up this practice.” Mark Steinagel, director of Utah DOPL, confirmed that the law requires DOPL to treat dispensing practitioners the same as pharmacists. “That basically means the division can inspect them and discipline them, either under the

Pharmacy Practice Act or under another practice act that gives the prescribing practitioner their primary license.” Dr. Kellogg noted that the major opposition to the bill came from hospital, not retail, pharmacists. “There is really a lack of understanding from the [hospital] pharmacists as to what really happens in community oncology,” she said. “Eighty-five percent of all chemotherapy regimens and treatments are given in the community setting, not the hospital.” Unfortunately, she noted, retail pharmacies presented with chemotherapy prescriptions often can’t meet the medication needs of cancer patients—a shortcoming “that is addressed effectively” by the physician dispensing bill.

Retail Makes Its Case James Cohn, a spokesperson for

has a role over the current standard for newly diagnosed AML patients between the ages of 50 and 70 years. Reviewing the data during the Plenary Program at the ASH meeting, Martin S. Tallman, MD, chief of the Leukemia Service at Memorial Sloan-Kettering Cancer Center, in New York City, indicated that there have been few improvements in the standard of care for older patients and those with unfavorable karyotypes over the past several decades. Dr. Tallman said that the degree of activity reported in the trial indicates that gemtuzumab has the potential to become a new standard of care in AML, but he noted that additional trials are needed to determine the optimal dose and schedule and to better determine which patients are the best candidates for this treatment.

Pharmacist’s Perspective “This revised dosing schedule for gemtuzumab is promising,” said Ali McBride, PharmD, specialty practice pharmacist, Stem Cell Transplant, Arthur G. James Cancer Hospital, The Ohio State University Department of Pharmacy, in Columbus. “It brings back another agent for use in elderly AML. However, further studies need to be conducted to compare and contrast the drug against other regimens, including standard-of-care induction therapy and hypomethylating agents that may provide similar responses, once stratified based on AML diagnosis, cytogenetics and performance scores.” —Ted Bosworth Dr. Castaigne reported that she has been a consultant for and has received honoraria from Pfizer. Dr. Tallman reported no relevant financial conflicts of interest.

Walgreens, challenged the implication that all community pharmacies are ill-equipped to handle cancer patients. “Walgreens has pharmacists who have received dedicated oncology medication training and this clinical expertise, combined with the convenient access we offer patients, makes our specialty pharmacy locations an optimal dispensing channel for these drugs,” he said. In fact, the Walgreens approach actually offers some advantages over physician-based dispensing, Mr. Cohn noted. “Our clinical programs are built in a rules-based IT environment so that all care is standardized, and this standardization of managing drug therapy would be absent if medications were dispensed directly from physicians.” —Kate O’Rourke

Hem/Onc Pharmacy 15

Pharmacy Practice News • April 2012

In Focus

Industry-Sponsored Studies More Likely To Generate Positive Results San Diego—Randomized controlled trials sponsored by a pharmaceutical company for cancer treatments were more likely to generate positive results than trials generated by a public agency, according to a recent analysis. “The differences in the results clearly point to differences in research agendas between publicly versus industry-sponsored trials,” according to investigator Benjamin Djulbegovic, MD, PhD.

Two concepts come into play when considering the differences between results of randomized controlled trials (RCTs). The first is the equipoise principle, which hypothesizes that investigators cannot predict the effects of treatments in advance. As a result, based on the fact that the new treatment will sometimes be superior to the standard, sometimes inferior and sometimes comparable, the overall success of discovery

of new treatments should be around 50%. The second concept is known as design bias, which postulates that trials are undertaken only if there is high likelihood of detecting therapeutic success in favor of the sponsor’s treatment. Speaking at the 2011 annual meeting of the American Society of Hematology, Dr. Djulbegovic reported that the equipoise hypothesis appears to drive the results observed in publicly sponsored trials,

Spotlight On Our Very Best As 2011 drew to a close, the McMahon Group bestowed honors on several employees within its talented workforce. Throughout the year, McMahon’s portfolio of clinical news magazines maintained readership numbers that solidiﬁed their best-read status, and sales revenues increased despite a challenging economic climate. The diverse talents and collaborations among McMahon’s staff allowed the company to maintain its position as a trusted source of news and educational initiatives. McMahon’s publishing success was on display both in print and on the Web sites of its publications and custom media platforms.

2011

Here is a look at those recognized for their unique contributions during 2011.

SUPPORT/PRODUCTION/IT/FINANCE PERSON OF THE YEAR:

GRAPHIC DESIGNER OF THE YEAR:

Employees were asked to select the two most outstanding members from these departments. The first winner was JOHN CABA, software developer, for his tireless devotion toward improving the company’s digital platforms.

The second winner was ROSA DIMICCO, accounting associate, for diligently ensuring that freelance writers and key opinion leaders are paid in a timely manner for their exceptional work.

JEANETTE MOONEY won the award in recognition of her creative talents as art director for Pain Medicine News, along with her superb layout designs for a host of Special Reports and custom newsletters.

MOST IMPROVED SALESPERSON OF THE YEAR:

SPECIAL PROJECTS EDITOR OF THE YEAR:

NEWSMAGAZINE EDITOR OF THE YEAR:

Each member of the sales staff seeks to improve throughout the year; however, one inevitably displays accelerated growth. DAVID NATHANSON, account manager, managed to do just that across several publications in 2011.

SETH KANDEL was voted best projects editor for his exemplary work on numerous custom media programs for medical industry clients as well as his management of the editorial in Infectious Disease Special Edition.

DONALD PIZZI, managing editor of Pain Medicine News, was recognized for the excellence of his news coverage throughout 2011. Under Don’s discerning eye, the magazine offers a comprehensive resource for clinicians involved in the management of pain.

SALES ACHIEVEMENT AWARD:

SALESPERSON OF THE YEAR:

DAVE KAPLAN, publication director of Pharmacy Practice News, was the 2011 winner in this category. Dave has proven himself to be an innovator among his peers by championing exciting new platforms and marketing opportunities for his many clients.

Whereas the other awards are decided by a jury of one’s peers, this honor is bestowed on the one salesperson who brings in the most revenue. For a record-breaking sixth year in a row, the winner was RICHARD TUORTO, senior group publication director for Anesthesiology News and Pain Medicine News. Richard’s dedication to his clients’ marketing needs and intimate knowledge of their products enable him to reach the zenith of sales proficiency year after year.

PERSON OF THE YEAR

PARTNERS AWARD

PERSON OF THE YEAR 2011:

PARTNERS SPECIAL RECOGNITION AWARD 2011:

This award recognizes the cream of the crop, and MARY LOU CAMPANELLA, chief financial officer, was the 2011 Person of the Year. Mary Lou has been able to streamline the company’s finances by thwarting inefficiencies and highlighting excess expenditures. Her constant professionalism, hard work and keen eye for detail have proven to be invaluable commodities that are greatly appreciated by her peers.

The partners of McMahon Publishing occasionally present an award to someone who has contributed to the success of the company over many years of service. This year’s winner was URBAN S. MULVEHILL, who has provided legal services to the company since 1983. He became a partner at his law firm, O’Neill DiManno and Kelly, in 1980 after having served as a trial lawyer for several years at the U.S. Department of Justice. Urban’s relaxed demeanor and sage advice over the past three decades have been greatly appreciated.

whereas the design-bias hypothesis can explain the outcomes obtained in the industry-sponsored trials. This conclusion was based on a retrospective analysis of the results of all the Phase III studies sponsored by GlaxoSmithKline or the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) from 1980 through June 2010. Using three metrics to assess treatment success in clinical trials, Dr. Djulbegovic, of the Center for EvidenceBased Medicine and Health Outcomes Research, University of South Florida and H. Lee Moffitt Cancer Center & Research Institute, Tampa, and his colleagues found that new treatments are favored over standard treatments in industry-sponsored trials in comparison with trials funded by the public agency by each metric used. Of the 40 trials funded by GlaxoSmithKline (19,889 patients) and the 77 trials funded by NCIC CTG (33,260 patients), 42% of the industry-sponsored studies and 25% (P=0.04) of the public sector–sponsored studies showed a statistically significant superiority of the experimental treatment over the control arm for the primary end point. Investigators themselves concluded that new treatments were superior to standard treatments in 80% of GlaxoSmithKline versus 44% of NCIC CTG trials (relative risk, 1.81; P<0.001). In addition to equipoise versus design bias, a number of other explanations are possible for the results. They include a possibility that the results can be explained by the larger proportion of industry-sponsored trials relying on the use of placebo as a comparator, as well as differences in mix between the proportion of explanatory and pragmatic trials in industry- versus public-sponsored trials. Pragmatic trials are rarely done by industry and the effect sizes are expected to be larger in explanatory trials, which can explain the differences in the results. Commenting on these results, Smita Bhatia, MD, director of outcomes research, City of Hope, Duarte, Calif., called this “a well-conducted study” that generated “intriguing findings,” but she said she considered the conclusions to be preliminary. “While the findings provide food for thought,” Dr. Bhatia said, “they need to be confirmed in future studies that include representation by more than one pharmaceutical company, unlike the current study that relied on data from only one.” —Ted Bosworth Dr. Djulbegovic reports receiving research funding from Millennium; Dr. Bhatia reports no relevant financial conflicts of interest.

16 Operations & Management

Pharmacy Practice News • April 2012

Leadership in Action

Hope—The Vision That Lies Within W

hat motivates us to greatness? Is it not hope and a vision? Is it not a passion toward an end that achieves a goal, makes things better and motivates others toward that same end? Hope is that one motivator that keeps us going when we are inclined to quit because it’s too hard. Hope fights through the tension, which can be debilitating. As leaders, it is up to us to communicate this theme of hope and to serve others

in a way that demonstratively shows hope by our actions. We all recognize that the challenges in this day and age are greater than in the past and it could be easy to lose heart. The sheer volume of information and data that crosses our paths—and the need to remain constantly connected— grows at an exponential pace. That may give us more knowledge at our fingertips, but it comes at a price: This con-

“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, System Vice President of Pharmacy, Steward Health Care System, Boston, Mass. Mr. Anderson welcomes your input on leadership issues, at ernest.anderson@ steward.org.

Ernest R. Anderson Jr., MS, RPh

stant stream of sensory input pushes out the reflective times that are so crucial to strategic thinking and planning. As leaders, we must sort this out and find the time to carry the torch of hope and thereby motivate others through our service to them. Every great leader must earn his or her position as a true leader, not just his or her positional authority but also his or her volitional authority. Positional authority is that job into which you are placed that gives you authority over others. Volitional authority is power that is given to a leader when subordinates volunteer to follow the leader because the leader is deserving of this authority. Don’t we really want others to continually volunteer their best efforts, not because it earns a paycheck, but because they have this burning desire to do the right thing that is motivated by the hope that lies within—a hope that you can help kindle? It is the responsibility of the leader to earn that level of respect. Earning respect comes first from the position but more importantly from how the leader serves others and sustains respect and authority.

Marks of the Servant Leader Servant leadership results from decisions that one has to make. It comes from those deep-seated values that put others first, before ourselves. It is motivated by selflessness not selfishness. Servant leaders synthesize direction from assimilation of surrounding inputs combined with an intuition that instill trust and confidence from others. Here are some questions by which you might gauge your level of servant leadership:

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Operations & Management 17

Pharmacy Practice News • April 2012

Leadership in Action ‘My greatest sense of personal satisfaction has been the numerous pharmacists in my career whom I have watched blossom and aspire to great leadership positions.’ from Robert Greenleaf in Servant Leadership, A Journey into the Nature of Legitimate Power and Greatness (Paulist Press, 2002): “The servantleader is servant first; it begins with a natural feeling that one wants • Is it your desire to see and help others advance? • Are you mentoring others and thereby serving? • Is your heart’s motivation to serve others or yourself? • Do you instill hope in those you lead and strive to do better in serving others? • Are you doing succession planning that will bring someone to your level? • Are you too busy doing things to respond to people needs? • Are you making servant leaders? • Do you have a spirit tenacious enough to allow you to serve even in the midst of adversity? • Do you build and value others by listening first and speaking second? • Do you accept the person you are leading and empathize with him or her? • Do you possess an intuitive insight that places you out in front of the general population, which leads others to seek you out? • Are you a trusted and dependable leader in the eyes of those you serve?

to serve, to serve first, as opposed to, wanting power, influence, fame or wealth. … That’s really why I’m here— to serve.” Oh that people would say the same of us.

WITH TAYLST’S PHARMACY W AUTOMATION, WE HAVE SIGNIFICANTLY REDUCED MED ERRORS TO IMPROVE Y OUR PATIENTS’ SAFETY. Tim Cmelik, Director of Pharmacy, Parkview Health

The Power of a Servant Leader A servant leader is in a position of power not out of selfish ambition or conceit, but from the heart’s desire to serve others. When your motives toward others come from a caring attitude, you are uniquely positioned with power and authority that is earned as opposed to sought. Human nature responds to caring and concern. This voluntary response gives the leader power and authority that is relationally inspiring. In our institutions and in society at large, servant leadership is the single best motivational tool one has in his or her personal power to command. When we value others by serving them, we actually give them power and freedom to be creative and to grow personally and professionally. My greatest sense of personal satisfaction has been the numerous pharmacists in my career whom I have watched blossom and aspire to great leadership positions. I end with this reflective quote

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Clinics: 150 Out-Patient Pharmacies: 2 Years with Talyst: 9

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PREMIXED AMIODARONE. Indications and Usage NEXTERONE (amiodarone HCl) Premixed Injection is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. Use NEXTERONE for acute treatment until the patient's ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary.

Important Risk Information NEXTERONE (amiodarone HCl) Premixed Injection is contraindicated in patients with: •

Known hypersensitivity to any of the components of NEXTERONE, including iodine

•

Cardiogenic shock

•

Marked sinus bradycardia

•

Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available

• NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment.

• Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported in 16% (288/1836) of patients treated with intravenous amiodarone. Monitor the initial rate of infusion closely and do not exceed the recommended rate. In some cases, hypotension may be refractory and result in a fatal outcome. Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including: vasopressors, positive inotropic agents and volume expansion.

• In 4.9% (90/1836) of patients in clinical trials, drug-related bradycardia that was not dose-related occurred while patients were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available.

• Like all antiarrhythmics, NEXTERONE may cause worsening of existing arrhythmias or precipitate a new arrhythmia. • The most common adverse reactions leading to discontinuation (1-2%) of intravenous amiodarone therapy are hypotension, asystole/cardiac arrest/pulseless electrical activity, VT, and cardiogenic shock.

• Other important adverse reactions are torsade de pointes (TdP), congestive heart failure, liver function test abnormalities, pulmonary disorders, and thyroid abnormalities. • Drug Interactions: Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and

increase serum concentration of amiodarone. Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates for p-glycoprotein. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly.

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NEXTERONE (amiodarone HCl) Premixed Injection for intravenous use Brief Summary of Prescribing Information. See PI for Full Prescribing Information. 1 INDICATIONS AND USAGE NEXTERONE is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with NEXTERONE, patients may be transferred to oral amiodarone therapy [see Dosage and Administration (2) in full prescribing information]. Use NEXTERONE for acute treatment until the patient's ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary. 4 CONTRAINDICATIONS NEXTERONE is contraindicated in patients with: • Known hypersensitivity to any of the components of NEXTERONE Premixed Injection, including iodine. Hypersensitivity reactions may involve rash, angioedema, cutaneous/mucosal hemorrhage (bleeding), fever, arthralgias (joint pains), eosinophilia (abnormal blood counts), urticaria (hives), thrombotic thrombocytopenic purpura, or severe periarteritis (inflammation around blood vessels). • Cardiogenic shock. • Marked sinus bradycardia. • Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available. 5 WARNINGS AND PRECAUTIONS NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment. 5.1 Hypotension Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse effect in 288 (16%) of 1836 patients treated with intravenous amiodarone. Clinically significant hypotension during infusions was seen most often in the first several hours of treatment and was not dose related, but appeared to be related to the rate of infusion. Hypotension necessitating alterations in intravenous amiodarone therapy was reported in 3% of patients, with permanent discontinuation required in less than 2% of patients. Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion. Monitor the initial rate of infusion closely and do not exceed the recommended rate [see Dosage and Administration (2) in full prescribing information]. In some cases, hypotension may be refractory and result in a fatal outcome [see Adverse Reactions (6.2) in full prescribing information]. 5.2 Bradycardia and Atrio-ventricular Block In 90 (4.9%) of 1836 patients in clinical trials, drug-related bradycardia that was not dose-related occurred while they were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. In some patients, inserting a pacemaker is required. Despite such measures, bradycardia was progressive and terminal in 1 patient during the controlled trials. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available. 5.3 Liver Enzyme Elevations Elevations of blood hepatic enzyme values [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)] are commonly seen in patients with immediately life-threatening VT/VF. Interpreting elevated AST activity can be difficult because the values may be elevated in patients who have had recent myocardial infarction, congestive heart failure, or multiple electrical defibrillations. Approximately 54% of patients receiving intravenous amiodarone in clinical studies had baseline liver enzyme elevations, and 13% had clinically significant elevations. In 81% of patients with both baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment. Acute, centrolobular confluent hepatocellular necrosis leading to hepatic coma, acute renal failure, and death has been associated with the administration of intravenous amiodarone at a much higher loading dose concentration and much faster rate of infusion than recommended [see Dosage and Administration (2) in full prescribing information]. In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of NEXTERONE therapy. Carefully monitor patients receiving NEXTERONE for evidence of progressive hepatic injury. In such cases, consider reducing the rate of administration or withdrawing NEXTERONE.

5.4 Proarrhythmia Like all antiarrhythmic agents, NEXTERONE may cause a worsening of existing arrhythmias or precipitate a new arrhythmia. Proarrhythmia, primarily torsade de pointes (TdP), has been associated with prolongation, by intravenous amiodarone, of the QTc interval to 500 ms or greater. Although QTc prolongation occurred frequently in patients receiving intravenous amiodarone, TdP or new-onset VF occurred infrequently (less than 2%). Monitor patients for QTc prolongation during infusion with NEXTERONE. Reserve the combination of amiodarone with other antiarrhythmic therapies that prolong the QTc to patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly [see Drug Interactions (7) in full prescribing information]. Amiodarone causes thyroid dysfunction in some patients, which may lead to potentially fatal breakthrough or exacerbated arrhythmias. 5.5 Pulmonary Disorders Early-onset Pulmonary Toxicity There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with intravenous amiodarone. Findings have included pulmonary infiltrates and masses on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure or death. ARDS Two percent (2%) of patients were reported to have adult respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy. Pulmonary Fibrosis Only 1 of more than 1000 patients treated with intravenous amiodarone in clinical studies developed pulmonary fibrosis. In that patient, the condition was diagnosed 3 months after treatment with intravenous amiodarone, during which time the patient received oral amiodarone. Pulmonary toxicity is a well-recognized complication of long-term amiodarone use (see package insert for oral amiodarone). 5.6 Loss of Vision Cases of optic neuropathy and optic neuritis, usually resulting in visual impairment, have been reported in patients treated with oral amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. Perform an ophthalmic examination if symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision. Re-evaluate the necessity of amiodarone therapy if optic neuropathy or neuritis is suspected. Perform regular ophthalmic examination, including fundoscopy and slit-lamp examination, during administration of NEXTERONE. 5.7 Long-Term Use There has been limited experience in patients receiving intravenous amiodarone for longer than 3 weeks. See package insert for oral amiodarone. 5.8 Thyroid Abnormalities Amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased T4 levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. Amiodarone is also a potential source of large amounts of inorganic iodine and can cause either hypothyroidism or hyperthyroidism. Evaluate thyroid function prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid function tests may persist for several weeks or even months following NEXTERONE withdrawal. There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone. In some instances hyperthyroidism was also present [see Adverse Reactions (6.2) in full prescribing information]. Hyperthyroidism and Thyrotoxicosis Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. Consider the possibility of hyperthyroidism if any new signs of arrhythmia appear.

Identify hyperthyroidism by relevant clinical signs and symptoms, subnormal serum levels of thyroid stimulating hormone (TSH), abnormally elevated serum free T4, and elevated or normal serum T3. Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone. Amiodarone hyperthyroidism may be followed by a transient period of hypothyroidism.

Table 4 lists the most common (incidence â&#x2030;Ľ2%) adverse reactions during intravenous amiodarone therapy considered at least possibly drug-related. These data were collected in clinical trials involving 1836 patients with life-threatening VT/VF. Data from all assigned treatment groups are pooled because none of the adverse reactions appeared to be dose-related. Table 4: ADVERSE REACTIONS IN PATIENTS RECEIVING INTRAVENOUS AMIODARONE IN

The institution of antithyroid drugs, Î˛-adrenergic blockers or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning. Neonatal Hypo- or Hyperthyroidism Amiodarone can cause fetal harm when administered to a pregnant woman. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism associated with oral administration. Inform the patient of the potential hazard to the fetus if NEXTERONE is administered during pregnancy or if the patient becomes pregnant while taking NEXTERONE. Hypothyroidism Hypothyroidism has been reported in 2% to 4% of patients in most series, but in 8% to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the NEXTERONE dose and considering the need for thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue oral amiodarone in some patients. 5.9 Surgery Perform close perioperative monitoring in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction defects of halogenated inhalational anesthetics. 5.10 Corneal Refractive Laser Surgery Advise patients that most manufacturers of corneal refractive laser surgery devices contraindicate corneal refractive laser surgery in patients taking amiodarone. 5.11 Electrolyte Disturbances Correct hypokalemia or hypomagnesemia whenever possible before initiating treatment with NEXTERONE, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

CONTROLLED AND OPEN-LABEL STUDIES (> 2% INCIDENCE) Study Event

Controlled Studies (n=814)

Open-Label Studies (n=1022)

Total (n=1836)

Body as a whole Fever

Body as a whole 24 (2.9%)

Body as a whole 13 (1.2%)

Body as a whole 37 (2.0%)

Cardiovascular System Bradycardia Congestive heart failure Heart arrest Hypotension Ventricular tachycardia

Cardiovascular 49 (6.0%) 18 (2.2%) 29 (3.5%) 165 (20.2%) 15 (1.8%) Digestive System 35 (4.2%) 29 (3.5%)

Cardiovascular 41 (4.0%) 21 (2.0%) 26 (2.5%) 123 (12.0%) 30 (2.9%) Digestive System 29 (2.8%) 43 (4.2%)

Cardiovascular 90 (4.9%) 39 (2.1%) 55 (2.9%) 288 (15.6%) 45 (2.4%)

Digestive System Liver function tests normal Nausea

Digestive System 64 (3.4%) 72 (3.9%)

Other adverse reactions reported in less than 2% of patients receiving intravenous amiodarone in controlled and uncontrolled studies included the following: abnormal kidney function, atrial fibrillation, diarrhea, increased ALT, increased AST, lung edema, nodal arrhythmia, prolonged QT interval, respiratory disorder, shock, sinus bradycardia, Stevens-Johnson syndrome, thrombocytopenia, VF, and vomiting. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of amiodarone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: anaphylactic/anaphylactoid reaction (including shock), fever Cardiovascular: hypotension (sometimes fatal), sinus arrest Dermatologic: toxic epidermal necrolysis (sometimes fatal), exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, skin cancer, pruritus, angioedema Endocrine: syndrome of inappropriate antidiuretic hormone secretion (SIADH) Hematologic: pancytopenia, neutropenia, hemolytic anemia, aplastic anemia, thrombocytopenia, agranulocytosis, granuloma Hepatic: hepatitis, cholestatic hepatitis, cirrhosis Injection Site Reactions: pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing Musculoskeletal: myopathy, muscle weakness, rhabdomyolysis Nervous System: hallucination, confusional state, disorientation, and delirium, pseudotumor cerebri Pancreatic: pancreatitis

In a total of 1836 patients in controlled and uncontrolled clinical trials, 14% of patients received intravenous amiodarone for at least one week, 5% received it for at least 2 weeks, 2% received it for at least 3 weeks, and 1% received it for more than 3 weeks, without an increased incidence of severe adverse reactions. The mean duration of therapy in these studies was 5.6 days; median exposure was 3.7 days.

Renal: renal impairment, renal insufficiency, acute renal failure

The most important adverse reactions were hypotension, asystole/cardiac arrest/pulseless electrical activity (PEA), cardiogenic shock, congestive heart failure, bradycardia, liver function test abnormalities, VT, and AV block. Overall, treatment was discontinued for about 9% of the patients because of adverse reactions. The most common adverse reactions leading to discontinuation of intravenous amiodarone therapy were hypotension (1.6%), asystole/cardiac arrest/PEA (1.2%), VT (1.1%), and cardiogenic shock (1%).

Vascular: vasculitis

Respiratory: bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary infiltrates and /or mass, pleuritis Thyroid: thyroid nodules/thyroid cancer

Baxter Healthcare Corporation Deerfield, IL 60015 Baxter, Galaxy, Nexterone and the Sphere Graphic are trademarks of Baxter International Inc.

Sourced from: 07-19-65-459 Rev. November 2010

22 Clinical

Pharmacy Practice News • April 2012

Critical care

DELIRIUM continued from page 1

recommending specific drugs in certain clinical circumstances,” said Dr. Barr, associate professor of anesthesia, Stanford University School of Medicine, and acting medical director, VA Palo Alto Health Care Systems, Palo Alto, Calif. “There is a greater evidence-based [focus] on pathophysiology, risks and management of delirium and its relationship to pain, sedation and outcomes in critically ill patients.” To update the PAD guidelines, teams of experts sorted through a database of 19,300 references and evaluated the quality of evidence available. The recommendations, from 20 multidisciplinary expert panel voting members, come in three strengths: strong (we recommend), weak (we suggest), or a “no recommendation,” when there is insuf-

ICU: either the Confusion Assessment Method for ICU or the Intensive Care Delirium Screening Checklist. Dr. Puntillo said that recommending only these six assessment tools does not mean the other available tools are “bad,” just inadequately studied. She added that they did not recommend that objective measures of brain

‘Hemodynamic changes are no longer thought to be valid correlates of pain nor analgesic response.’ —Gil Fraser, PharmD, FCCM

ficient data to draw conclusions. Evidence quality was ranked using a grading system: high (A), moderate (B) and low/very low (C). The updated guidelines include 53 statements and recommendations, almost twice as many as the 2002 guidelines. According to Kathleen Puntillo, RN, DNSc, professor emeritus and research scientist at the University of California School of Nursing in San Francisco, one of the biggest changes in the guidelines is the strong emphasis on assessing PAD. “There was little emphasis on assessment in the 2002 guidelines,” Dr. Puntillo said. “There has been a major increase in the science of assessment-scale development that we were able to tap into.” The new guidelines identify which pain sedation and which delirium assessment tools are considered to be the most valid and reliable for use in ICU patients.

Routine Pain Monitoring Urged The guidelines recommend that pain be routinely monitored in all adult ICU patients using either patient selfreports or one of two pain assessment scales—the Behavioral Pain Scale or the Critical-Care Pain Observation Tool— for patients who are unable to selfreport. They recommend using either the Richmond Agitation-Sedation Scale (RASS) or the Sedation-Agitation Scale (SAS) for assessing sedation. They also recommend using one of two scales for routinely monitoring delirium in the

function be used as the primary method to monitor depth of sedation in noncomatose, nonparalyzed, critically ill adult patients. Vital signs, or observational pain scales that include vital signs, should not be used alone for pain, but they can be used as a cue to begin further assessment of pain. “Hemodynamic changes are no longer thought to be valid correlates of pain nor analgesic response,” said Dr. Fraser.

Music Therapy, Other Non-Drug Options Cited Preemptive treatment of pain is recommended prior to chest tube removal and suggested for other invasive and potentially painful procedures. Nonpharmacologic interventions include biofeedback, music therapy and relaxation, and the pharmacologic interventions include opioid and nonopioid agents, Dr. Fraser said. IV opioids are recommended for treatment of non-neuropathic pain, with the choice largely being determined by patient response, pharmacokinetics, pharmacodynamics and side effects. Enteral gabapentin or carbamazepine, in addition to IV opioids, are recommended for neuropathic pain. “We are offering a weak suggestion—and it is weak only because data that are specific to the ICU is pretty skimpy—with regard to acetaminophen, nonsteroidal antiinflammatories and ketamine,” said Dr. Fraser. “Most of the evidence suggests

‘You may disagree with some of the [new recommendations], but I hope we have minimized the wailing and gnashing of teeth.’

that the use of these adjuncts can reduce the dosing requirements of the opioids or even obviate their need.” Dr. Fraser said the recommendation to start analgesia before adding sedation for the vast majority of patients will change practice for many. Analgesia-first sedation, he said, may not be appropriate in patients with either drug or substance withdrawal (with the exception of opiates), drug-induced agitation or any agitation associated with a clear and reversible etiology. Curtis Sessler, MD, Orhan Muren Professor of Medicine, Pulmonary & Critical Care Medicine at Virginia Commonwealth University Health System, in Richmond, said the two major themes that changed for sedation in these guidelines are a recommendation to prioritize non-benzodiazepine agents (either propofol or dexmedetomidine [Precedex, Hospira]) over benzodiazepines (either midazolam or lorazepam) and a recommendation to maintain light sedation using structured approaches such as daily interruptions of sedation or titration of sedative therapy using either RASS or SAS scores, both shown to improve outcomes in critically ill patients.

Increased Mortality From Delirium Is a Factor Richard Riker, MD, professor of medicine at Tufts University School of Medicine, in Boston, and critical care specialist at Maine Medical Center, in Portland, previewed the delirium recommendations. “Ten years ago, we did not have a lot of information about the best way to approach delirium,” he said. “We now know that delirium is associated with increased mortality in ICU patients, prolonged ICU and hospital length of stay and prolonged post-ICU cognitive impairment.”

—Joseph Dasta, MSc Dr. Riker added, “There have been a lot of great steps forward. We do not suggest that haloperidol or atypical antipsychotics [should] be administered to prevent delirium. We have no published evidence that haloperidol reduces the duration of established delirium in the ICU. We do have data that suggest that atypical antipsychotics might reduce the duration of delirium, and we do not recommend rivastigmine in ICU patients.” The PAD guidelines recommend early mobilization of adult ICU patients whenever feasible to reduce delirium, and they do not recommend the use of antipsychotics in patients who are at risk for torsades de pointes. They suggest that either propofol or dexmedetomidine, rather than benzodiazepine infusions, should be used in adult ICU patients with delirium not related to alcohol or benzodiazepine withdrawal. To provide a stepwise process to managing patients, however, the guideline committee is developing an ICU PAD (IPAD) Bundle Toolkit. It will include instructional videos, PowerPoint presentations for staff education, pocket cards with bundle and guideline recommendations, and templates for checklists, goal sheets, and protocols. “You will have many ways to apply these data to your patients,” Dr. Fraser said. The final version of the document is under review by SCCM and the American Society of Health-System Pharmacists. It will soon be published in the journals Critical Care Medicine and the American Journal of HealthSystem Pharmacy. Joseph Dasta, MSc, professor emeritus at The Ohio State University College of Pharmacy, in Columbus, said that he doesn’t foresee a backlash from clinicians. “You may disagree with some of the things, but I hope we have minimized the wailing and gnashing of teeth.” —Kate O’Rourke The guidelines were developed with no industry funding or involvement. Dr. Sessler disclosed speaker fees from Hospira. Dr. Riker disclosed research support from AstraZeneca, Canyon, Eli Lilly, Hospira, Takeda and The Medicines Company. Drs. Fraser and Barr reported no relevant financial conflicts of interest. Dr. Dasta reported being a consultant for AcelRx Pharmaceuticals, Cadence Pharmaceuticals, Hospira, and Pacira Pharmaceuticals.

Spotlight on Medication Safety 23

Pharmacy Practice News • April 2012

S P E C I A L S E C TI O N

New Treatments Tested for Cardiac Drug Poisonings Houston—Over the past 20 years, the number of calls to poison centers for calcium channel blocker (CCB) exposures has doubled to roughly 10,000 annually and for β-blockers has increased fivefold to more than 25,000 per year. Fortunately, two emerging treatments for these overdoses—high-dose insulin and IV lipid emulsion (ILE)—have solid data suggesting that they can be potentially lifesaving rescue therapies. At the recent annual meeting of the Society of Critical Care Medicine (SCCM), two emergency medicine pharmacists discussed the evidence supporting these treatments and recommended two protocols for clinicians to follow when managing patients experiencing an adverse drug reaction to these cardiac medications.

Table 1. Protocol for HDIT Step 1: Nonsaline fluid bolus with 20-40 mL/kg over the first hour. Goal of minimum urine output of 0.5 mL/kg/h. Step 2: Infuse calcium IV with a goal of total calcium of 12 mg/dL. Step 3: Administer 50 mL of 50% dextrose IV if blood glucose is <200 mg/dL. Step 4: Give bolus of regular insulin at 1 unit/kg IV push. Step 5: Start insulin infusion at 1 unit/kg/h in NS with 10% dextrose infusion at 100 mL/h to keep blood glucose >100 mg/dL. Use D50 if central line is available to avoid fluid overload. Step 6: Increase insulin infusion 1 to 2 units/kg/h to a maximum of 10 units/kg/h every 10 to 15 min to clinical response. Step 7: Maintain K+>3 and <4.5 mEq/L. Other considerations: Taper off vasopressors as soon as possible after cardiac output begins to increase. Consider the use of IV fat emulsion during HDIT. Avoid HDIT in patients with hypertrophic cardiomyopathy. D50, dextrose 50% in water; HDIT, high-dose insulin therapy; K, potassium; NS, normal saline

High-Dose Insulin The primary effects of CCB and β-blocker overdoses are bradydysrhythmias and hypotension, according to Richard Thomas, PharmD, emergency department pharmacy team leader at Primary Children’s Medical Center in Salt Lake City. He noted that CCBs also cause hyperglycemia, and he explained how high-dose insulin therapy (HDIT) can help reverse these types of reactions. In a nonstressed state, he noted, the heart primarily catabolizes free fatty acids for its energy needs. In β-blocker and CCB overdoses, the heart relies on carbohydrates as energy substrates. The greater the degree of shock a patient has, the higher the demand for carbohydrates. Limited glycogen stores are quickly depleted. Insulin facilitates the use of carbohydrates by myocardial tissue and restores pyruvate dehydrogenase activity. In 1999, researchers reported they had successfully used HDIT for druginduced shock in four individuals who had failed traditional therapy. Insulinglucose therapy has since been used in more than 90 published case reports of drug-induced shock, with more than 90% involving CCB overdoses (J Toxicol Clin Toxicol 1999;37:463-474). A review of the literature shows that bolus doses up to 10 U/kg and continuous infusions as high as 22 U/kg per hour have been administered with good outcomes and minimal adverse events (AEs) (Clin Toxicol 2011;49:277-283). In a recent case series, researchers showed that HDIT using a 1- to 10-U/kg per hour dosing guideline appears to be an effective treatment for toxin-induced cardiogenic shock in the absence of vasopressors (Clin Toxicol 2011;49:653-658). In another case series, three patients received insulin by bolus without a continuous infusion—an approach that still

‘Experience shows that this therapy can be used safely and should be considered early in the treatment of these patients.’ —Richard Thomas, PharmD

ids, atropine, calcium, vasopressors and glucagon, but there is enough evidence to support the use of HDIT early in treating CCB and β-blocker overdoses, he said. “Experience shows that this therapy can be used safely and should be considered early in the treatment of these patients.”

Lipid Emulsion Therapy Maria Rudis, PharmD, clinical pharmacy specialist in emergency medicine and associate professor of emergency medicine and pharmacy at Mayo Clinic in Rochester, Minn., discussed the evidence for using ILE as a rescue for toxic reactions to cardiac medications. Dr. Rudis pointed out that ILE, most commonly used as a 20% formulation, has been used to treat toxic reactions triggered not only by cardiac drugs, but also by other types of medications, such as local anesthetic agents, for a number of years. There are three postulated mechanisms of action for using ILE as a reversal agent. First, ILE has the potential to act as a lipid sink, whereby fat droplets form a separate pharmacologic compartment in the intravascular space into which lipophilic drugs are partitioned. Second, ILEs can increase intracellular fatty acid content, and third, they provide functional improvement in calcium and sodium channels on cell membranes. The evidence for using ILE for CCB and β-blocker overdoses consists of a handful of case reports. Scanning through the literature, Dr. Rudis said she identified 10 cases in which ILE was used for β-blocker overdose (Emerg Med J 2011;28:991-993). The drug worked in all four cases that she identified for

•

improved hemodynamics without AEs (Intensive Care Med 2007;33:2019-2024). Patients have been shown to respond relatively quickly. In a 24-patient series, improvement was typically seen within 15 to 60 minutes, and the average duration of HDIT was 33 hours with a range of 0.75 to 96 hours (Intensive Care Med 2007;33:2019-2024). Hypoglycemia, the most frequent AE with HDIT, occurs in roughly 60% of patients. Additionally, Dr. Thomas said

that clinicians should avoid using HDIT with either catecholamines or vasopressin because results from animal studies and human case reports suggest a negative effect (Clin Toxicol 2011;49:653-658; Clin Toxicol 2007;45:396-401). Dr. Thomas advocates using the highdose insulin protocol developed by the Toxicology Service at Regions Hospital in St. Paul, Minn. (Table 1). Clinicians and pharmacists can start patients on traditional therapies that include IV flu-

Table 2. Lipid Resuscitation 20% Intralipid:

see DRUG POISONINGS, page 24

InSIdE Use of opioid agents for abdominal pain rises dramatically .......................................... 25 St. Louis health system fine-tunes its CDS system to catch more ADEs .......................

Presenters at SCCM meeting offer tips to improve warfarin reversal ..............................

University of Wisconsin Health System wins award for anticoagulation stewardship program .....................

1.5 mL/kg as an initial bolus, followed by 0.25 mL/kg/min for 30 to 60 min. Bolus can be repeated 1 to 2 times for persistent asystole. Infusion rate can be increased if the blood pressure declines.

24 Spotlight on Medication Safety

DRUG POISONINGS continued from page 23

overdoses of propranolol. Spontaneous circulation, blood pressure and mental status improved; seizures subsided; normal sinus rhythm returned; and patients were able to be weaned off vasopressors and extubated. Success also was identified in two cases involving carvedilol, one of two cases involving atenolol and one case of metoprolol. Dr. Rudis identified five cases of ILE being used for CCBs, specifically verapamil overdose. In one case (Resuscitation 2009;80:591-593), a 32-year-old man overdosed on verapamil and presented to the emergency department with a heart rate of 55, blood pressure 69/26 mm Hg, lactate 5.4, arterial blood gas pH 7.09/51/89/14, bibasilar crackles and a junctional rhythm at four hours. After discussions with officials at the poison center, doctors started therapy that included 6 L of normal saline, glucagon and norepinephrine. After seeing the junctional rhythm starting to evolve, they gave 100 mL of ILE 20% over 20 minutes and then 0.5 mL/ kg per hour for 24 hours. Within one hour, the doctors were able to decrease the vasopressors and stop the gluca-

Pharmacy Practice News • April 2012

gon, and the patient’s blood pressure enews ad.indd returned Current to file:normal. ppn The concentrations of Full verapamil and norverapamil Name of project were elevated at 20 and 36 hours, but Style chges at 48 hours, thefr. prev. patient was extubated. # he was Proof 1 home. Five daysRevision later, sent Layout Date/Time April 2, 2012 have 1:25 PM been She also noted that there Editorialof Date/Time case reports ILE being used to treat Trim Size TABLOID 63p X 78p patients with toxic ingestions of cocaine, Color Specs 4C propafenone, haloperidol, quetiapine File Path ppn enews ad.indd and tricyclic antidepressants. According to Dr. Rudis, the Weinberg protocol (Table 2) is the recommended dosing strategy for lipid rescue

FILE SLUG be used only after standard STATUS ANDpreliminary HISTORY to cardiac drugs, evidence and should 1ST PROOF LAYOUT APPROVED FINAL OK PROOF 1: 1/28 PICKED UP FROM: suggests that it does, Dr. Rudis noted. “I resuscitation fails. Clinicians should INITIALS AND DATE INITIALS AND DATE APPLIED TO: REV 1: 1/29 beMAXwatchful for the three main AEs REV 2: 1/30think it [ILE] does have a place in thersign-off AD LAYOUT EXPT’D: REV 3 1/30 LAYOUT RECEIVED: apy,” sheADsaid, “likely in cardiac arrest or associated with lipid rescue therapy: Senior Editor REV 4 Copy Editorlung injury, lipemia and deep shock refractory to standard therapy, if acute EDIT LAYOUT EXPT’D: REV 5 LAYOUT RECEIVED: REV 6 Sales thrombosis. “You will theoretiyou are EDIT suspecting ingestion of a lipidvein REV 7 TO: David Production soluble drug.” cally see more adverse effects if the REV 8 FROM: Frank REV 9 Creative For more information, visit www. ILE infusion rate or duration exceeds theCOMMENTS: clearance capacity of lipoprotein Lipidregistry.org and www.lipidrescue. lipase, the enzyme responsible for ILE org. —Kate O’Rourke clearance,” she said. Although it is too early to know whether ILE provides a real attributable Drs. Thomas and Rudis reported no relevant financial conflicts of interest. benefit in patients with toxic reactions

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POLICY

TAKING CONTROL continued from page 4

the right thing, so we don’t find drugs in our water supply that could affect our children and grandchildren.” She recommends using one vendor for all the waste streams except nuclear, which is highly regulated. Her vendor is Stericycle, a Lake Forest, Il.-based company that offers a wide range of waste management consultant services. “They’re very proactive. Any time there’s a change in the law or regulations, they communicate effectively,” Dr. Kotis said. “Our relationship is truly a partnership.” Debra Gillmeister, MBA, vice president of healthcare services for Stericycle, said that one key to an effective pharmaceutical waste management strategy is for pharmacists to become familiar with the categories of drug waste established by the American Society of Health-System Pharmacists and the National Institute for Occupational Safety and Health, as well as approximately 20 Joint Commission standards. She said in an interview that her firm helps pharmacists in that knowledgegathering process with a variety of education and outreach efforts. For example, in a recent 18-month period, Stericycle held 32 lunch-and-learn programs that were attended by leaders at 600 hospitals. —George Ochoa

Get the latest news delivered directly to your computer and PDA. The interactive format has embedded Web Site links that give you instant access to additional information, unique searching features and printing capabilities. Each installment contains brief summaries of the most important articles from the current month’s issue, as well as breaking news ahead of print.

Spotlight on Medication Safety 25

Pharmacy Practice News • April 2012

Opioid Use for Abdominal Pain Rises

rom 1997 to 2008, opioid prescriptions for chronic abdominal pain more than doubled in the United States, according to a new study in Clinical Gastroenterology and Hepatology (2011;9:1078-1085). The investigators estimated the national prescribing trends and factors associated with prescribing opioids for chronic abdominal pain. They identified visits to outpatient clinics for this disorder using

reason-for-visit codes from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey from 1997 to 2008. Data were weighted to produce national estimates of opioid prescriptions over time. The researchers found that the number of outpatient visits for chronic abdominal pain consistently decreased over time from 14.8 million visits in 1997 to 1999 to 12.2 million visits in 2006 through

2008 (P=0.04). However, the adjusted prevalence of visits when an opioid was prescribed increased from 5.9% in 1997 through 1999 to 12.2% in 2006 through 2008 (P=0.03). Opioid prescriptions were most common among patients aged 25 to 40 years (odds ratio [OR], 4.6) and less common among uninsured (OR, 0.1) and black (OR, 0.3) patients. The investigators noted that this increase in opioid prescriptions has been problematic, in part, because no study has shown opioids to be effective for treating chronic abdominal pain. Addi-

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tionally, when used over long periods of time, opioids may worsen other gastrointestinal symptoms, such as constipation, nausea and vomiting. The growing use of opioids to treat “persistent abdominal pain highlights the growing challenges clinicians face trying to manage chronic illness without the time, infrastructure and incentives needed to take the integrated approach that experts suggest,” according to investigator Spencer D. Dorn, MD, MPH, assistant professor of medicine at the University of North Carolina, Chapel Hill.

26 Spotlight on Medication Safety

Pharmacy Practice News • April 2012

Fine-Tuning ADE Alerts Helps Avoid Drug Errors ‘It’s one thing to say you’re making interventions that R help patients, but’s it’s another to keep track of the

esearchers based in St. Louis are harnessing technology to transition from monitoring adverse drug events (ADEs) to actively preventing them. In July 2009, researchers at BJC HealthCare, a network consisting of 13 medical centers in the greater St. Louis area including Barnes-Jewish Hospital, modified the clinical decision support application at 11 of its hospitals to generate alerts indicating potential adverse

interventions, the metrics and the services you’re providing ….’ events related to 10 ADE triggers. Local hospital reviewers (mostly pharmacists) and a central BJC reviewer indepen-

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—Joy Alonzo, PharmD dently investigated the validity of each alert using a Web-based tool. From July to December 2009, the

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group identified 1,183 significant ADEs across the BJC system, 81% of which were hypoglycemia events. Then the investigators set out to address the problem. In May 2010, an ADE preventable harm team created a multidisciplinary task force including registered dietitians, certified diabetes educators, clinical nurse specialists and pharmacists, as well as an analyst, an informatics specialist and a project manager. The group identified national and local best practices and created a hypoglycemia “dashboard” to identify the current ADE rates and trends at each system hospital. To find the most common causes of hypoglycemia, the task force developed a Hypoglycemic Event Analysis Tool (HEAT), through which nurses and others investigating the events record their results electronically. Through HEAT, researchers have found a number of factors contributing to hypoglycemia, including patients’ home regimens being continued in the hospital; timing issues around insulin administration, food intake and when labs are drawn; and not noticing trends like dropping blood glucose over a series of mornings. At home, patients with diabetes take their insulin with a meal, Paul Milligan, PharmD, clinical lead at BJC’s Center for Clinical Excellence, told Pharmacy Practice News. At the hospital, three people can be involved in the transaction: a dietary staffer who brings the meal, a patient care tech who sticks a patient’s finger and a nurse who gives the insulin. Instead of everything happening within 30 minutes, the time can spread to 90 minutes. One BJC hospital changed its procedure so when the meal arrives, a nurse and patient care tech enter the patient’s room together to get a glucose reading and immediately give insulin if needed, cutting the time gap by more than half. The team also created an intervention tracking tool called Facility Strategy Tracker (FaST), which lists causative factors and their frequency at each network hospital, best practices or solutions identified by the team and a list of interventions either completed or in process at each hospital—allowing hospitals to identify their most common causative factors and prioritized solutions all in one place. Task force members continue to meet monthly and update their interventions on FaST. “Once hospitals identify their top causative factors, they click an area link and have access to interventions with the highest likelihood of success, the rationale and what other hospitals are doing,” Dr. Milligan said. “It’s a pretty cool tool. Our team is now adopting the same procedure and strategy for reducing oversedation.”

Spotlight on Medication Safety 27

Pharmacy Practice News • April 2012

As a whole, Dr. Milligan said, “Initially we spent a lot of time identifying harm and not a lot fixing it.” High costs and unknown outcomes often prevent hospitals from trying out interventions. “Now that we spend time identifying causes of harm, I can go to a hospital and say, ‘Thirty percent of your adverse events are caused by this.’ It’s easier to get buy-in from stakeholders when I can pinpoint the causes and solutions.” The task force’s “roadmap” for transition from surveillance to prevention, presented in October 2011 at the Ameri-

Ambulatory ADE Triggers

nformation technology also can be used to track adverse drug event (ADE) triggers in ambulatory settings, one recent study suggests. Researchers from the Veterans Health Administration’s Health Services Research and Development Service in Salt Lake City, working with colleagues at Boston University and Intermountain HealthCare, created a simulated electronic health record that merged data from three health care systems. They set up their database to flag all charts mentioning creatinine (to catch decreased renal function), white blood cell or platelet counts (to catch myelosuppression), warfarin (to catch rapid or excessive anticoagulation), hypokalemia, hyperkalemia and delirium. Research pharmacists then reviewed the 361 trigger-identified charts to determine the presence of harm due to an ADE and the potential for significantly changing therapy if the system had fired a trigger in real time. The hypokalemia trigger performed best in identifying harm, correctly identifying harm-causing ADEs in 17% of cases; the triggers for warfarin and delirium correctly identified harm-causing ADEs in 13% and 10% of cases, respectively. The creatinine trigger was found to have the best “clinical usefulness,” i.e., potentially preventing the most harm. In 60% of cases, there was an ADE resulting in harm to the patient that could potentially have been prevented if that trigger had fired in real time. Researchers predicted the platelet and hypokalemia triggers could have helped in 53% and 42% of cases, respectively. “It looks like they would work to change clinical care before harm was done,” Brenna Long, a research manager and study author, told Pharmacy Practice News. The work, funded by the Agency for Healthcare Research and Quality, was presented last fall at the American Medical Informatics Association’s annual meeting in Washington. —K.B.

can Medical Informatics Association’s annual meeting in Washington, D.C., consists of the following steps: identifying causative factors, reporting events to hospital safety teams, creating a systemwide multidisciplinary task force, selecting hospital and system interventions and distributing progress notes.

Kudos for Multidisciplinary Team Approach Joy Alonzo, PharmD, assistant professor of pharmacy practice at Texas A&M Health Science Center in Corpus

Christi, told Pharmacy Practice News she thought the BJC team did a great job of quantifying the problem, following Joint Commission recommendations of identifying best practices, picking one, implementing it and measuring the results. “The multidisciplinary team was the exact perfect thing to do … it was a classic systems engineering approach to quality improvement.” The increase in electronic health records is making implementation of programs like these easier, Dr. Alonzo said, allowing insight into critical data

so that hospital staff can more accurately determine if they are following protocols or if their interventions are effective. Otherwise, they’re left to anecdotal or empirical evidence. “It’s one thing to say you’re making interventions that help patients,” Dr. Alonzo said, “but it’s another to keep track of the interventions, the metrics and the services you’re providing to patients to prove you have utility and to continuously evaluate these metrics to ensure process improvement.” —Karen Blum

LEVETERACITAM INJECTION, USP

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INDICATIONS AND USAGE-Levetiracetam injection is an antiepileptic drug indicated for adjunct therapy in adult patients (16 years and older) when oral administration is temporarily not feasible. Partial Onset Seizures-Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures in adults with epilepsy. Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy-Levetiracetam is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults with juvenile myoclonic epilepsy. Primary Generalized Tonic-Clonic Seizures-Levetiracetam is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults with idiopathic generalized epilepsy. CONTRAINDICATIONS-None WARNINGS AND PRECAUTIONS Neuropsychiatric Adverse Reactions Partial Onset Seizures - In some adults experiencing partial onset seizures, levetiracetam causes the occurrence of central nervous system adverse reactions that can be classified into the following categories: 1) somnolence and fatigue, 2) coordination difficulties, and 3) behavioral abnormalities. In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of levetiracetam-treated patients reported somnolence, compared to 8.4% of placebo patients. There was no clear dose response up to 3000 mg/day. In a study where there was no titration, about 45% of patients receiving 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of the treated patients, compared to 0% in the placebo group. About 3% of levetiracetam-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo patients. In 1.4% of treated patients and in 0.9% of placebo patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence. In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of treated patients reported asthenia, compared to 9.1% of placebo patients. Treatment was discontinued in 0.8% of treated patients as compared to 0.5% of placebo patients. In 0.5% of treated patients and in 0.2% of placebo patients the dose was reduced. A total of 3.4% of levetiracetam-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients. A total of 0.4% of patients in controlled trials discontinued levetiracetam treatment due to ataxia, compared to 0% of placebo patients. In 0.7% of treated patients and in 0.2% of placebo patients the dose was reduced due to coordination difficulties, while one of the treated patients was hospitalized due to worsening of pre-existing ataxia. Somnolence, asthenia and coordination difficulties occurred most frequently within the first 4 weeks of treatment. In controlled trials of patients with epilepsy experiencing partial onset seizures, 5 (0.7%) of levetiracetam-treated patients experienced psychotic symptoms compared to 1 (0.2%) placebo patient. Two (0.3%) levetiracetam-treated patients were hospitalized and their treatment was discontinued. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. Two other events, reported as hallucinations, occurred after 1 to 5 months and resolved within 2 to 7 days while the patients remained on treatment. In one patient experiencing psychotic depression occurring within a month, symptoms resolved within 45 days while the patient continued treatment. A total of 13.3% of levetiracetam patients experienced other behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.) compared to 6.2% of placebo patients. Approximately half of these patients reported these events within the first 4 weeks. A total of 1.7% of treated patients discontinued treatment due to these events, compared to 0.2% of placebo patients. The treatment dose was reduced in 0.8% of treated patients and in 0.5% of placebo patients. A total of 0.8% of treated patients had a serious behavioral event (compared to 0.2% of placebo patients) and were hospitalized. In addition, 4 (0.5%) of treated patients attempted suicide compared to 0% of placebo patients. One of these patients completed suicide. In the other 3 patients, the events did not lead to discontinuation or dose reduction. The events occurred after patients had been treated for between 4 weeks and 6 months.

Myoclonic Seizures -During clinical development, the number of patients with myoclonic seizures exposed to levetiracetam was considerably smaller than the number with partial seizures. Therefore, under-reporting of certain adverse reactions was more likely to occur in the myoclonic seizure population. In some patients experiencing myoclonic seizures, levetiracetam causes somnolence and behavioral abnormalities. It is expected that the events seen in partial seizure patients would occur in patients with JME. In the double-blind, controlled trial in patients with juvenile myoclonic epilepsy experiencing myoclonic seizures, 11.7% of levetiracetam-treated patients experienced somnolence compared to 1.7% of placebo patients. No patient discontinued treatment as a result of somnolence. In 1.7% of levetiracetam-treated patients and in 0% of placebo patients the dose was reduced as a result of somnolence. Non-psychotic behavioral disorders (reported as aggression and irritability) occurred in 5% of the levetiracetam-treated patients compared to 0% of placebo patients. Non-psychotic mood disorders (reported as depressed mood, depression, and mood swings) occurred in 6.7% of levetiracetam-treated patients compared to 3.3% of placebo patients. A total of 5.0% of levetiracetam-treated patients had a reduction in dose or discontinued treatment due to behavioral or psychiatric events (reported as anxiety, depressed mood, depression, irritability, and nervousness), compared to 1.7% of placebo patients. Primary Generalized Tonic-Clonic Seizures During clinical development, the number of patients with primary generalized tonic-clonic epilepsy exposed to levetiracetam was considerably smaller than the number with partial epilepsy, described above. As in the partial seizure patients, behavioral symptoms appeared to be associated with levetiracetam treatment. Gait disorders and somnolence were also described in the study in primary generalized seizures, but with no difference between placebo and levetiracetam treatment groups and no appreciable discontinuations. Although it may be expected that drug related events seen in partial seizure patients would be seen in primary generalized epilepsy patients (e.g., somnolence and gait disturbance), these events may not have been observed because of the smaller sample size.In some patients experiencing primary generalized tonic-clonic seizures, levetiracetam causes behavioral abnormalities. In the double-blind, controlled trial in patients with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic seizures, irritability was the most frequently reported psychiatric adverse event occurring in 6.3% of levetiracetam-treated patients compared to 2.4% of placebo patients. Additionally, non-psychotic behavioral disorders (reported as abnormal behavior, aggression, conduct disorder, and irritability) occurred in 11.4% of the levetiracetam-treated patients compared to 3.6% of placebo patients. Of the levetiracetam-treated patients experiencing non-psychotic behavioral disorders, one patient discontinued treatment due to aggression. Non-psychotic mood disorders (reported as anger, apathy, depression, mood altered, mood swings, negativism, suicidal ideation, and tearfulness) occurred in 12.7% of levetiracetam-treated patients compared to 8.3% of placebo patients. No levetiracetam-treated patients discontinued or had a dose reduction as a result of these events. One levetiracetam-treated patient experienced suicidal ideation. One patient experienced delusional behavior that required the lowering of the dose of levetiracetam. In a long-term open label study that examined patients with various forms of primary generalized epilepsy, along with the non-psychotic behavioral disorders, 2 of 192 patients studied exhibited psychotic-like behavior. Behavior in one case was characterized by auditory hallucinations and suicidal thoughts and led to levetiracetam discontinuation. The other case was described as worsening of pre-existent schizophrenia and did not lead to drug discontinuation. Withdrawal Seizures-Antiepileptic drugs, including levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency. Hematologic Abnormalities -Partial Onset Seizures -Minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in levetiracetam-treated patients in controlled trials. A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant ()2.8 x 109/L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant ()1.0 x 109/L) decreased neutrophil count. Of the treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts. Juvenile Myoclonic Epilepsy -Although there were no obvious hematologic abnormalities observed in patients with JME, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients should be considered to be relevant for JME patients. Hepatic Abnormalities-There were no meaningful changes in mean liver function tests (LFT) in controlled trials in adult patients; lesser LFT abnormalities were similar in drug and placebo treated patients in controlled trials (1.4%). No patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment. ADVERSE REACTIONS Clinical Studies Experience-Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reactions that result from levetiracetam injection use include all of those reported for levetiracetam tablets and oral solution. Equivalent doses of intravenous (IV) levetiracetam and oral levetiracetam result in equivalent Cmax, Cmin, and total systemic exposure to levetiracetam when the IV levetiracetam is administered as a 15 minute infusion. The prescriber should be aware that the adverse reaction incidence figures in the following tables, obtained when levetiracetam was added to concurrent AED therapy, cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the adverse reaction incidences in the population studied. Partial Onset Seizures Table 3 lists treatment-emergent adverse reactions that occurred in at least 1% of adult epilepsy patients treated with levetiracetam tablets participating in placebocontrolled studies and were numerically more common than in patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 3: Incidence (%) of Treatment-Emergent Adverse Reactions in Placebo-Controlled, Add-On Studies in Adults Experiencing Partial Onset Seizures by Body System (Adverse Reactions Occurred in at Least 1% of Levetiracetam-Treated Patients and Occurred More Frequently than Placebo-Treated Patients) Body System/Adverse Reaction Levetiracetam Placebo (N=769)% (N=439)% Body as a Whole Asthenia Headache Infection Pain Digestive System

15 14 13 7

9 13 8 6

Anorexia Nervous System Somnolence Dizziness Depression Nervousness Ataxia Vertigo Amnesia Anxiety Hostility Paresthesia Emotional Lability Respiratory System

15 9 4 4 3 3 2 2 2 2 2

8 4 2 2 1 1 1 1 1 1 0

Pharyngitis Rhinitis Cough Increased Sinusitis Special Senses

6 4 2 2

4 3 1 1

Diplopia

Myoclonic Seizures Table 4 lists treatment-emergent adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with levetiracetam tablets and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 4: Incidence (%) of Treatment-Emergent Adverse Reactions in a Placebo-Controlled, Add-On Study in Patients with Myoclonic Seizures by Body System (Adverse Reactions Occurred in at Least 5% of Levetiracetam-Treated Patients and Occurred More Frequently than Placebo-Treated Patients) Body System/Adverse Reaction Levetiracetam Placebo (N=60)% (N=60)% Ear and labyrinth disorders Vertigo Infections and infestations

Pharyngitis Inﬂuenza

7 5

0 2

Neck pain Nervous system disorders

Somnolence Psychiatric disorders

Depression

Musculoskeletal and connective tissue disorders

Primary Generalized Tonic-Clonic Seizure Table 5 lists treatment-emergent adverse reactions that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 5: Incidence (%) of Treatment-Emergent Adverse Reactions in a Placebo-Controlled, Add-On Study in Patients 4 Years of Age and Older with PGTC Seizures by MedDRA System Organ Class (Adverse Reactions Occurred in at Least 5% of Levetiracetam-Treated Patients and Occurred More Frequently than Placebo-Treated Patients) Body System/Adverse Reaction Levetiracetam Placebo (N=79)% (N=84)% Gastrointestinal disorders Diarrhea

Fatigue Infections and infestations

Nasopharyngitis Psychiatric disorders

Irritability Mood swings

6 5

2 1

General disorders and administration site conditions

DRUG INTERACTIONS In vitro data on metabolic interactions indicate that levetiracetam is unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above Cmax levels achieved within the therapeutic dose range, are neither inhibitors of nor high affinity substrates for human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid. Levetiracetam circulates largely unbound (<10% bound) to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely. Potential pharmacokinetic interactions were assessed in clinical pharmacokinetic studies (phenytoin, valproate, oral contraceptive, digoxin, warfarin, probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in epilepsy patients. USE IN SPECIFIC POPULATIONS Pregnancy-Pregnancy Category C-There are no adequate and well-controlled studies in pregnant women. In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. Levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration to female rats throughout pregnancy and lactation led to increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses *350 mg/kg/day (approximately equivalent to the maximum recommended human dose of 3000 mg [MRHD] on a mg/m2 basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/m2 basis). The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m2 basis). There was no overt maternal toxicity at the doses used in this study. Treatment of pregnant rabbits during the period of organogenesis resulted in increased embryo fetal mortality and increased incidences of minor fetal skeletal abnormalities at doses *600 mg/kg/day (approximately 4 times MRHD on a mg/m2 basis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1800 mg/kg/day (12 times the MRHD on a mg/m2 basis). The developmental no effect dose was 200 mg/kg/day (1.3 times the MRHD on a mg/m2 basis). Maternal toxicity was also observed at 1800 mg/kg/day. When pregnant rats were treated during the period of organogenesis, fetal weights were decreased and the incidence of fetal skeletal variations was increased at a dose of 3600 mg/kg/day (12 times the MRHD). 1200 mg/kg/day (4 times the MRHD) was a developmental no effect dose. There was no evidence of maternal toxicity in this study. Treatment of rats during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m2 basis). Patients may enroll in the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-2334 (toll free). Labor and Delivery-The effect of levetiracetam on labor and delivery in humans is unknown. Nursing Mothers-Levetiracetam is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants from levetiracetam, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use-Safety and effectiveness of levetiracetam injection in patients below the age of 16 years have not been established. Geriatric Use-Of the total number of subjects in clinical studies of levetiracetam, 347 were 65 and over. No overall differences in safety were observed between these subjects and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam in these patients. A study in 16 elderly subjects (age 61 to 88 years) with oral administration of single dose and multiple twice-daily doses for 10 days showed no pharmacokinetic differences related to age alone. Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Use in Patients with Impaired Renal Function-Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing hemodialysis. The dosage should be reduced in patients with impaired renal function receiving levetiracetam and supplemental doses should be given to patients after dialysis. OVERDOSAGE Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans The highest known dose of oral levetiracetam received in the clinical development program was 6000 mg/day. Other than drowsiness, there were no adverse reactions in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with levetiracetam overdoses in postmarketing use. Treatment or Management of Overdose - There is no specific antidote for overdose with levetiracetam. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient’s clinical status. A Certified Poison Control Center should be contacted for up to date information on the management of overdose with levetiracetam. Hemodialysis- Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment. Storage-Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (See USP Controlled Room Temperature). How Supplied-Levetiracetam injection 500 mg/5 mL is a clear, colorless, sterile solution. It is supplied in single-use 5 mL vials, available in cartons of 25 vials (NDC 0517-3605-25).

AR126 Iss. Date 1/2012

Spotlight on Medication Safety 29

Pharmacy Practice News • April 2012

ASSESSMENT TOOL continued from page 1

spoke during the webinar. “In addition, there can be a wide range of doses for the same drug.” As examples, she noted that methotrexate is administered in doses as small as 10 mg or as large as 20 g and that bevacizumab (Avastin, Genentech) is used at a dose of 5 mg/ kg every two weeks with a FOLFIRI (irinotecan, 5-fluorouracil [5-FU], leucovorin) regimen and 10 mg/kg every two weeks with a FOLFOX (oxaliplatin, 5-FU, leucovorin) regimen. Adding to the complexity are supportive-care therapies that require altered treatment schedules and a fairly constant stream of newly approved anticancer agents. In developing the new assessment

es on information about a patient that guides the appropriate selection of medications, doses and routes of administration. An item listed under this element states that a structured process is in place to collect and verify the patient’s first and last name, age or date of birth and medical record number or other unique identifier. Highlighting a potential error that can happen in this category, Ms. Shastay discussed an incident in which a patient responded to a name that was called in a waiting room for chemotherapy because he was “just tired of waiting” (ISMP Medication Safety Alert! 1997;2:1-2). This error was caught when the patient’s wife spoke up, but errors such as these can be avoided if a patient’s identity is verified in a variety of ways, including using birthday or address.

‘I would encourage every oncology department to use this tool, no matter its perceived level of [safety] expertise. You may well find holes in your system that could lead to devastating errors.’ —Phil Johnson, MS, RPh Table 1. Key Elements of ISMP Self-Assessment Tool 1. Patient information 2. Drug information 3. Communication of drug orders and other drug information 4. Drug labeling, packaging and nomenclature 5. Drug standardization, storage and distribution 6. Medication device acquisition, use and monitoring 7. Environmental factors, workflow and staffing patterns 8. Staff competency and education 9. Patient education 10. Quality processes and risk management

tool, an international group of oncology and medication safety experts reviewed the literature, practice guidelines and the ISMP database of chemotherapy errors. The first section of the assessment asks for basic demographic data, but this information is de-identified so users remain anonymous. The assessment itself is divided into 10 key elements that significantly influence safe medication use (Table 1). Each element is defined by one or more core characteristics that further define a safe medicationuse system, and each core characteristic contains individual assessment items to help institutions evaluate success. The tool includes 175 assessment items. “To complete the assessment, each organization should engage a multidisciplinary team to review each item and come to a consensus on how to score each item,” said Ms. Shastay (Table 2). The first element, for example, focus-

The second element focuses on drug information. To minimize the risk for error, the tool emphasizes that essential drug information must be readily available in a useful form to health care providers who order, dispense or administer medications. “These include drug references, textbooks or software programs that are current,” Ms. Shastay said. “You should also have a controlled drug formulary, and updated protocols and order sets. The pharmacy computer systems should be integrated with other systems to help obtain appropriate medication information, and having pharmacists available as a resource to other health care providers and patients in patient care areas is a must.” An item listed under the second element states that a structured process is in place to identify emerging internal and external information and re-evaluate the status of drugs on the formulary. This

Table 2. Scoring System A = There has been no activity B = Has been formally discussed/ considered C = Partially implemented D = Fully implemented in some areas E = Fully implemented through the organization N/A = Not applicable (for selected items)

is essential for many areas of medicine but particularly true for oncology, which is in a constant state of flux. Roughly a year ago, for example, Sanofi, which manufactures Taxotere, the brand name of docetaxel, changed its product so that it was distributed in one bottle instead of two, and the drug changed from a 10 mg/mL to a 20 mg/mL concentration. “We received a report from a hospital about a patient who received a twofold overdose of docetaxel during transition from one product to another,” as a result of confusion over the product change, Ms. Shastay said. Around the same time, a generic version of docetaxel came on the market in the original concentration of 10 mg/mL, adding another potential layer of confusion. As another example, element 7 of the self-assessment tool focuses on environmental factors. An item listed under this element states that oral chemotherapy/ biotherapy that needs to be manipulated from its original form must be first checked against a published reference. According to Ms. Shastay, the assessment includes some items that many institutions may not have implemented. “We realize that these items are actually stretch goals,” she said. But, using the tool and reviewing the items should highlight areas that institutions need to work on.

A Multipronged Approach The assessment tool has several goals, including identifying a baseline of oncology practices around the world, comparing experiences over time with similar organizations, using aggregate results to plan curricula and other educational itinerary and identifying opportunities for improvement. It is clear that improvements in oncology medication safety are needed. A 2008 Oncology Medication Safety Survey (J Oncol Pharm Pract 2008;14:169180) showed that less than 40% of pharmacists prepared IV vincristine via a minibag, a recommendation made by the World Health Organization to help avoid a devastating fatal chemotherapy error. (Minibag preparation is preferable because it results in a

small-volume dilution of vincristine, as opposed to drawing up higher concentrations of the drug in a syringe. The latter approach has led to numerous fatalities when the syringe was used to inject the drug via the intrathecal route.) This was just one of many shortcomings the survey identified. The ISMP said it hopes that the new assessment tool will help hospitals and clinics identify and bridge medication safety gaps in oncology.

Widespread Adoption Urged Phil Johnson, MS, RPh, who chaired the ISMP committee that developed the self-assessment tool while he was director of pharmacy at H. Lee Moffitt Cancer Center, in Tampa, Fla., said that he “sincerely hopes” all hospitals use the tool to assess the way they handle oncology drugs—even those facilities that have already implemented systems for improving the safety of chemotherapy administration. Although it may be tempting for such facilities to conclude that the self-assessment tool is not for them, “I would caution against measuring your expertise in this area based only on your own benchmarks,” he said. “Remember, this tool is a compilation of the world’s best chemotherapy standards; it offers a very broad, comprehensive assessment. So I would encourage every oncology department to use this tool, no matter its perceived level of expertise. You may well find holes in your system that could lead to devastating errors.” Mr. Johnson added an important legal consideration. “ISMP will promote this worldwide, so it will rapidly become a global standard,” he said. “If your hospital hasn’t met that standard, and medication errors happen that are addressed by this tool, then you may be legally liable.” For hospitals still on the fence, Mr. Johnson stressed that during his many years as a director of pharmacy at Moffitt, “having an outside objective opinion on what we were doing was always valuable.” In this case, the alternative—going it alone based on home-grown assessments—reminds Mr. Johnson of an oft-quoted aphorism: A lawyer who represents himself “has a fool for a client.” The smarter approach? “Use the ISMP self-assessment tool. I can’t imagine a hospital that would not find at least some operational areas in need of improvement. And for some facilities, it could truly be a life-saver.” —Kate O’Rourke, with additional reporting by David Bronstein

Ms. Shastay, Ms. Bartel and Mr. Johnson reported no relevant financial conflicts of interest.

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Medication Errors: A Year in Review

Horsham, Pennsylvania

he prevention of medication errors is an essential component of pharmaceutical care and must be a core mission of every pharmacy. For medication error

prevention efforts to be effective, they must become a priority. The first step in setting up an error-reduction program is to establish a multidisciplinary team to improve medication use. The team must be given reasonable time and resources to assess medication safety and implement system-wide changes that make it difficult or impossible for practitioners to make mistakes that reach the patient. This multidisciplinary team should accept ownership of the medication-use process and enthusiastically embrace the opportunity

to improve medication safety. The goals of the team should include the following: • Promote a culture of safety to lower medication errors; • Increase detection and reporting of medication errors and potential hazardous drug-use situations; • Explore and understand the root causes of medication errors; • Educate practitioners about the system-based causes of errors and their prevention;

KEY TO TABLES 1-4

Computerized prescriber order entry (CPOE)—A fully integrated CPOE system includes the capability to build medication safety alerts (eg, lookalike names) and clinical decision rules. Additionally, the CPOE system should

directly interface with the laboratory system and pharmacy, list drug–drug and drug–disease interactions, and offer clinical order-screening capability.

Bar code–enabled point-of-care (BPOC) systems—These systems are designed to prevent medication errors at the point of medication administration. BPOC systems verify and record all medications administered to

the patient through the use of a bar-code scanner that matches the medication to the patient by scanning a bar code on the medication and a bar code on the patient’s wristband.

“Smart” infusion pumps—These infusion systems allow users to enter various drug infusion protocols into a drug library with predefined dose limits. If a dose is programmed outside of established limits or clinical parameters, the pump halts or sounds an alarm, informing the clinician

that the dose is outside the recommended range. Some pumps can integrate patient monitoring and other patient parameters, such as age or clinical condition.

Automated dispensing cabinets (ADCs)—These are robust, point-ofuse dispensing systems. ADCs should be integrated with the health care facility’s information system and directly interface with the pharmacy

system. Additionally, ADCs must be able to use bar-coding technology for the restocking process to prevent medication errors.

Additionally, this system must be used to generate a computerized medication administration record (MAR) to be used by the nursing staff while administering medications.

“Robust” pharmacy order entry system—This order entry system is fully interfaced with a CPOE system. The pharmacy system must be able to produce medication safety alerts as well as directly interface with a health care facility’s information systems, such as the laboratory system.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

P H A R M AC Y P R AC I C E N E WS • A P R I L 2 0 1 2

Table 1. Safety Issues Related to Labeling, Packaging, and Nomenclature Title

Problem/Discussion Point

Recommendations

CLINIMIX (amino acids and dextrose, Baxter) and CLINIMIX E (amino acids and dextrose with electrolytes, Baxter)

• There have been several reports of nurses failing to break the seal that separates the 2 chambers, a key step for properly mixing the contents of both chambers prior to dispensing and administration.

• Start the initial infusion when the pharmacy is open, if possible, and dispense for each patient after proper mixing and labeling. • If the product is available in its overwrap in automated dispensing cabinets (ADCs) or other areas outside the pharmacy, teach nurses how to activate it using educational resources available at: www.clinimix.com/popups/video.jsp.

Concentrated sodium chloride 23.4% minibags

• Due to a shortage of sodium chloride (NaCl) concentrate (23.4% and 14.6%) in vials, compounding pharmacies are supplying these products to some hospitals. One compounder provides the concentrated sodium chloride 23.4% solution in a minibag. • Packaging the product in a minibag—as opposed to a vial—may lead to the mistaken belief that the product can be administered as is, despite labeling that indicates that it must be diluted for IV use.

• Perform a failure mode and effects analysis (FMEA) and address potential risks before the product is obtained and placed into use. • Consider implementing pharmacist double-checks and segregating the storage of these products away from other minibag infusions.

DAKIN’S Solution (diluted sodium hypochlorite)

• Century Pharmaceuticals lists the strengths on bottles of Dakin’s solution (diluted sodium hypochlorite) as full strength, half strength, and quarter strength. • Full-strength Dakin’s solution is a 0.5% solution; half-strength Dakin’s solution is a 0.25% solution; and quarter-strength Dakin’s solution is a 0.125% solution. • Other Dakin’s solution manufacturers primarily label only by percent concentration.

• If Dakin’s solution is being used in your institution, alert staff to the risk for confusing the terminology used to communicate strength. • Also be aware that using Dakin’s solution in 0.5%, 0.25%, and 0.125% concentrations may be toxic. Most hospitals use a modified Dakin’s solution of 0.025%.

DOCEtaxel (TAXOTERE, Sanofi-aventis) and DOCEtaxel (Hospira)

• A patient on Taxotere received 100 mg/m2 instead of a reduced dose of 50 mg/m2 soon after an ambulatory cancer center pharmacy began using the new 20 mg/mL one-vial product instead of the previously used 2-vial 10 mg/mL preparation. • A generic DOCEtaxel product (Hospira) also now is available as a single 10 mg/mL vial.

• Alert pharmacy staff and oncology nurses to the new 20 mg/mL Taxotere and 10 mg/mL generic DOCEtaxel (both one-vial products). • Update databases and internal drug resources to ensure proper mixing. • If your computer system allows for order replication from past admissions, work with your IT department to intercept orders in which the strength of the medication has changed. • For details, visit: http://www.ismp.org/ newsletters/acutecare/articles/20110321_ HospiraDocetaxelLetter.pdf

Epidural analgesic spikes with IV tubing

• While one nurse was starting a patient’s IV, another nurse scanned the patient’s wristband and bar codes on bags of epidural analgesia containing bupivacaine and an IV antibiotic. • The second nurse accidentally spiked the epidural analgesia bag instead of the antibiotic with a secondary IV tubing set and primed the tubing. • When the first nurse went to connect the tubing to the patient’s IV access port, she noticed that the wrong bag had been spiked.

• Distinguish epidural solutions from IV solutions by applying boldly colored “Epidural Use Only” warning stickers to both sides of the bag. • If possible, have pharmacy spike epidural bags with special epidural (or yellow streaked) tubing before dispensing. • Make the setup of epidural analgesia a separate, dedicated “time-out” process conducted immediately before the infusion is started. • Require anesthesia staff to gather or bring to the unit all epidural agents they plan to administer to the patient. • Establish a protocol to help recognize and treat bupivacaine toxicity.

EpiPen training pen (Dey Pharma)

• EpiPens are only available in a 2-Pak that includes 2 EpiPens plus a nonfunctioning training pen. • The training pen looks similar to, and could be confused with, a real EpiPen in an emergency.

• If hospitals store EpiPens on units for hypersensitivity reactions, remove the pens from their carton and only store active pens on units, including in ADCs.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Technology

2, 4

Table 1. Safety Issues Related to Labeling, Packaging, and Nomenclature Title

Problem/Discussion Point

Recommendations

Technology

Mix-ups between B. Braun’s heparin and HESPAN products

• There have been numerous reports of mix-ups between B. Braun’s heparin and HESPAN products • Both have red and blue lettering, and they share several letter characters in the same sequence (“H-E,” “P-A,” and “N”).

• Consider using a generic alternative to HESPAN, and refer to hetastarch products by the generic name. • Use bar-coding technology to help prevent packaging or container mix-ups.

2, 4

New infant acetaminophen concentration

• The new 160 mg/5 mL infant acetaminophen concentration has been arriving in hospitals, although manufacturers may not be providing notification about the change. • Supplies of the former 80 mg/0.8 mL product have been available until now, and hospitals may still have the older concentration in stock. • Some acetaminophen products do not have the new strength listed on the front panel of the carton.

• Exhaust or remove all supplies of the 80 mg/0.8 mL product before circulating the new one. • Alert all clinical staff, especially pediatricians and pediatric nurses, to create awareness of the concentration change and establish a release date for transition from the older product to the newer one. • Be sure parents understand how many milligrams to give their child and that they have the product that matches the instructions from the prescriber.

2, 5

Nuclear medicine vials still don’t have bar codes

• A radiopharmaceutical vial of DraxImage DTPA (Kit for the Preparation of Technetium Tc 99m Pentetate Injection, Jubilant DraxImage) was inadvertently placed in a leaded vial shield instead of MDP-Bracco (Kit for the Preparation of Technetium Tc 99m Medronate, Bracco Diagnostics). • Both vials have green caps with green and white labels. • Unit doses in varying amounts were dispensed from the vial to 6 hospitals/clinics, which resulted in nondiagnostic images for 12 patients. • Bar codes still are not required on radiopharmaceutical vials.

• Before activation, the products are not radioactive and should be stored in segregated areas to help prevent mix-ups between the look-alike vials. • Special precautions such as preactivation independent double-checks are needed, particularly because the products’ labels cannot be viewed easily once they are inside the vial shield. • It is not known whether manufacturers will be required to provide a bar code on radiopharmaceuticals.

• Recommend methods to facilitate the implementation of organization-wide, system-based changes to prevent medication errors; • Respond to potentially hazardous situations before errors occur; and • Learn from errors occurring in other organizations through the ISMP Medication Safety Alert! and other published accounts of medication errors, and proactively take measures to prevent similar errors. Effective results depend on understanding the entire medication-use process through varied perspectives and disciplines. ISMP is a nonprofit organization that works closely with health care practitioners and institutions, regulatory agencies, professional organizations, and the pharmaceutical industry to provide education about medication errors and their prevention. ISMP independently reviews medication errors that practitioners and patients have voluntarily submitted to the ISMP Medication Error Reporting Program. ISMP is an accessible resource for any pharmacist or organization interested in implementing the actions recommended herein. Among the many products and services that ISMP offers is the ISMP Medication Safety Alert! Acute Care Edition, a biweekly newsletter that provides timely information related to error prevention. It identifies errors that have been reported by other organizations and offers recommendations to prevent those

errors from occurring in the pharmacy. The information in Tables 1 to 4 of this review summarizes many of the significant error-prevention strategies that were recommended in the ISMP Medication Safety Alert! Acute Care Edition during 2011. The errors presented in the tables are actual or potential errors reported to ISMP. Each table consists of 4 columns. The first column lists the medications, devices, or other problematic issues involved. The second column describes the specific error or problem involved. The third column contains ISMP’s recommendations to proactively address and prevent errors from occurring. The fourth column lists technology that may help prevent these errors. Technology can be a powerful tool in the fight against medication errors but only when it is used appropriately within a well-designed medication-use system. The key summarizes the technology addressed in the tables, along with specific criteria that ISMP feels should be included.

Suggested Reading 1.

Cohen MR, ed. Medication Errors. 2nd ed. Washington, DC: American Pharmacists Association; 2007.

2. Institute for Safe Medication Practices Web site: www.ismp.org. 3. Institute for Safe Medication Practices. ISMP Medication Safety Alert! Acute Care Edition newsletters 2011. www.ismp.org/ newsletters/default.asp. Accessed March 19, 2012.

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Table 2. Problems Involving Drug Information, Patient Information, and Staff Education Title

Problem/Discussion Point

Recommendation

Technology

Patient verification process

• “Wrong patient” medication errors can occur for a variety of reasons at any phase of the medication-use process. • Prescribers have entered orders into the wrong patients’ records, or prescribed therapy based on misfiled lab results for another patient. • Telephone orders have been transcribed incorrectly onto the wrong patients’ records. • Patient labels have been applied to the wrong patients’ order forms. • Pharmacists have entered orders into the wrong patients’ profiles.

• All staff (not just nurses) should use 2 identifiers to identify/verify patients during all patient-associated tasks in the medication-use process when: -physicians prescribe medications; -pharmacy staff enter orders and dispense medications; -unit staff and nurses transcribe orders; -staff files test results; and -nurses administer medications. • Design technology systems to limit access to an applicable set of patients, not all patients within the facility.

1, 2, 5

PRADAXA (dabigatran, Boehringer Ingelheim) dosing in renal impairment

• A cardiologist prescribed Pradaxa for an outpatient with stage IV chronic kidney disease without adjustment for renal impairment. • After a follow-up office visit during which tarry stools and a low hemoglobin and hematocrit were identified, the patient was admitted to a critical care unit with a massive GI bleed.

• Ensure that your computer system(s) is/are updated with Pradaxa drug interactions and renal dosing recommendations.

1, 5

Preventing medication errors during codes

• Cardiac and/or respiratory resuscitation is a critical situation during which health care practitioners have little time for discussion and verification of the patient’s treatment plan, including medications. • During these medical emergencies, every second counts and every errant action or inaction can result in patient harm or death. • Observation-based simulations of codes have a documented medication error rate of up to 15%.

• Use separate adult and pediatric code carts. • Supply a neonatal emergency drug box/tray on code carts with neonatal-specific formulations in standard concentrations. • Provide drug reference sheets and IV titration dosing guides for all drugs in the cart (in the concentrations available), including admixture information, dosing instructions, maximum dose limits, and infusion rates.

Standard neonatal intensive care units (NICUs) drug concentrations

• ISMP and the Vermont Oxford Network developed a standard drug concentration list for NICUs

• All NICUs are urged to review and consider adopting this list of standard concentrations. • For the complete list, visit: www.ismp.org/ Tools/PediatricConcentrations.pdf

1, 3, 5

Use of 2 pumps to bypass the drug library

• A nurse used 2 smart infusion pumps to deliver propofol IV at a rate of 225 mcg/kg/min because the pumps’ drug library was set with a hard stop at 130 mcg/kg/min. • Propofol was prescribed for an off-label use (refractory status epilepticus), which required higher than recommended doses. • The patient exhibited propofol-related infusion syndrome. • Using 2 infusion pumps to exceed a hard stop has been observed in other inappropriate situations.

• Employing a technology workaround like this in an unintended manner should prompt an immediate peer review of the conditions that led to the workarounds. • Make staff aware that the need for a workaround is a clear signal that a potentially serious medication error might occur.

4, 5

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Table 3. Safety Issues Associated With Order Communication Title

Problem/Discussion Point

Recommendation

Technology

Confusion with “ketofol” (ketamine and propofol)

• Although studies show that “ketofol” may be effective and safe for procedural sedation, some concerns linger. • Admixture often occurs on units where sterility may be difficult to maintain. • Practitioners may be unfamiliar with the contrived name and not find it in any reference. • Ratios for combining the 2 drugs vary. • A syringe containing “ketofol” looks like a syringe containing just propofol.

• Conduct a failure mode and effects analysis to assess risks before using this combination product. • Take steps to promote sterility during admixture. • Establish a standard ratio to guide the mixing process. • Refer to the product using each drug’s official name, not “ketofol.” • Include both drug names and an expiration date on syringes of the product.

Dosing confusion for colistimethate for injection

• ISMP and the American Society for HealthSystem Pharmacists sent a warning through the National Alert Network (NAN) about dosing errors involving colistimethate sodium for injection, a prodrug of colistin with a high potential to induce nephrotoxicity and neurotoxicity. • The strength of colistimethate sodium is labeled in terms of the colistin base, not the prodrug. • Recently, a physician ordered the dose as the prodrug, but the dose was dispensed as colistin base, which resulted in an overdose. The patient developed complications, including acute renal failure, and later died.

• Dose colistimethate sodium ONLY as colistin base, with a dosage reduction for renal insufficiency. • Consider restricting ordering to infectious disease specialists or intensivists. • Use preapproved guidelines or order sets with colistin-base dosing only. • Dose limits should be established, with immediate investigation required for doses outside hospital guidelines. • For the full NAN alert, visit: www.ismp.org/ sc?k=nanalerts.

1, 5

Drug names that end with the letter “L”

• Drug names that end with the letter “L” have contributed to overdoses. • The lower case “l” has been misread as the numeral “1” and misread as part of the dose. • For example, lisinopril 2.5 mg can be misread as lisinopril 12.5 mg if there is inadequate space between the last letter of the drug name and the numerical dose (ie, lisinopril 2.5 mg).

• Advise prescribers, pharmacists, and nurses to leave sufficient space between the numeric dose and the drug name. • This recommendation also applies to electronic prescribing and standard order sets because typed drug names and doses also can result in errors if sufficient space is not provided between the drug name and dose/strength.

LUGOL’s Solution (strong iodine solution)

• Dosing errors associated with prescribing, dispensing, or administering milliliter doses of Lugol’s solution have occurred when just a few drops were indicated. • Contributing factors include unfamiliarity with the drug, which is infrequently prescribed, and unexpected dosing units because adult doses are typically expressed in milliliters, not drops.

• Provide protocols for managing acute hyperthyroidism, protecting the thyroid during exposure to radioactive iodine, and preoperative use of iodine solutions. • Include iodine solution dosing information in protocols and order-entry systems. • Dispense each dose of iodine solution in a prefilled syringe. • If a bulk bottle must be dispensed, affix a warning: “The total volume in the container would be toxic if taken as a single dose.”

Mix-up between PCN-200 and penicillin

• A nurse typed “PCN” for a penicillin-allergic patient into the allergy pick-list section and inadvertently selected “PCN-200.” • PCN-200 was a grapefruit seed extract product that was discontinued several years ago.

• If PCN-200 is still listed as an option (type “PCN” in your allergy pick list to find out), either remove it manually or work with your computer system vendor to remove it.

Mix-up between penicillamine (CUPRIMINE, Valeant; DEPEN TITRATABS, Meda Pharmaceuticals) and penicillin

• An electronic prescription for penicillamine was ordered for a 9-year-old patient who tested positive for Streptococcus. • The nurse practitioner intended to order penicillin, not the chelating agent.

• Consider the use of tall man lettering for penicillAMINE. • Incorporate the brand name and the purpose of the medication on the prescription. • Create an alert that will inform the practitioner that penicillAMINE is a look-alike/sound-alike (LASA) medication.

1, 5

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Table 3. Safety Issues Associated With Order Communication

(continued)

Title

Problem/Discussion Point

Recommendation

Technology

Mix-up between pyridoxine and PYRIDIUM

• Pyridoxine (vitamin B6) was prescribed and pyridium (phenazopyridine) was dispensed and administered. • The drug names look alike, and the products are both available as 100 mg tablets. • Typing “PYR…,” into computerized drug order systems calls up pyridium, pyridoxine, and other products that begin with PYR, making selection errors more likely.

• Medication listings for pyridoxine in computer systems should be modified to help distinguish it from pyridium and other medications. • An example modification is “vitamin B-6 pyridOXINE” on the screen, and pyridium can be listed as phenazopyridine.

1, 5

Mix-ups between TEAspoons and mL

• Dangerous mix-ups between TEAspoon and milliliter dosages are common and have been happening for many years, particularly in outpatient pharmacies. • ISMP received a report in which a pharmacist accidentally provided instructions on the prescription label for a child to receive 3.5 TEAspoonfuls of a liquid antibiotic for 10 days instead of 3.5 mL per dose.

• ISMP would like to see the complete elimination of TEAspoonful, TABLEspoonful, and other non-metric dosing, as well as the elimination of the abbreviations “tsp” and “tbsp,” which are easy to confuse. • Doses expressed using mL are recommended to eliminate the risk for confusion.

1, 5

Revised HYDROmorphone dosing recommendations

• FDA, ISMP, and the Pennsylvania Patient Safety Authority have received reports of harmful errors involving HYDROmorphone injection. • Many errors have been associated with dose conversions from morphine to HYDROmorphone, packaging confusion, and high starting doses for opioid-naive patients.

• FDA approved revisions to the Prescribing Information (www.purduepharma.com/PI/ prescription/DilaudidInjectionsPI.pdf), container labels, and carton labeling for DILAUDID and DILAUDID-HP (Purdue Pharma), which will also affect generic parenteral HYDROmorphone. • Alert prescribers that the IV starting dose has been reduced to 0.2-1 mg (previously 1-2 mg), and that a dose-conversion table is in the Prescribing Information to help convert from other opioids to HYDROmorphone.

1, 5

Table 4. Medical Devices and Other Discussion Items Title

Problem/Discussion Point

Recommendation

ActHIB component of 2-vial PENTACEL vaccine error

• Numerous infants did not receive the Haemophilus influenzae type b component of PENTACEL, a 2-part vaccine packaged in cartons containing vials of liquid DTaP-IPV (diphtheria, tetanus, pertussis-inactivated polio virus) and vials of lyophilized Haemophilus influenzae (ActHIB). • Nurses administering the 2-part vaccine failed to use the DTaP-IPV component to dilute and mix with the lyophilized ActHIB powder component of the vaccine.

• Pharmacies should dispense the 2 vials together using a rubber band or by placing the 2 vials in a ziplock bag. • Affix an auxiliary label to the carton to remind staff to use both vials. • To confirm administration of both of the components, staff should document the National Drug Code number for each vial in the vaccine log before administration. • Documenting the actual administration of the vaccine should always occur after it is given.

Bar-code scanning after drug administration has occurred

• The purpose of bar-code scanning is defeated when it occurs after drug administration— a practice called back scanning, which is one of the observed workarounds used to reduce workload during the drug administration process. • Employing this workaround increases the risk for wrong drug, wrong dose, wrong time, wrong route, and wrong patient errors.

• Hospitals should monitor for back scanning practices, identify the causes if it occurs, and make the necessary system changes to prevent this practice, including but not limited to educating nurses about the risks associated with this practice. • If a drug must be given under urgent conditions, the safest method is to scan the patient and medication bar codes, and create a new task on the electronic medication administration record (eMAR) to trigger later documentation of drug administration.

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Technology

Table 4. Medical Devices and Other Discussion Items Title

Problem/Discussion Point

Recommendation

Technology

Electrolyte shortages

• The national drug shortage of common electrolyte solutions in certain strengths and sizes has forced many pharmacists to replace their standard injectable solutions with different products.

• Follow a formal verification process for purchasing alternative products. • Ensure that necessary changes are made within computer software that drives various medication-use systems, such as IV compounders and robots, automated dispensing cabinets, computerized orderentry systems, smart pumps, and any other affected technology.

1, 2, 3, 4, 5

Ingested or aspirated foreign object

• A hospitalized surgical patient developed a postoperative cough that continued for a couple of weeks after discharge. • During a strong coughing spell, the patient coughed up a small white cap. • The patient had accidentally ingested or aspirated a 0.9% sodium chloride syringe cap, which the hospital used for IV flushes.

• Staff who enter patient care areas need to keep the patient’s room and/or immediate care area free of clutter that could result in accidental ingestion or inhalation of unintended products—even when patients are fully alert and oriented. • Never leave syringe caps, fixatives, developer solutions, cleaning agents, topical antiseptics, or other topical liquid products at the bedside.

Infusion reconnected to the wrong patient

• Both patients in a semi-private room had been disconnected from their primary IV solutions so they could take showers. • Each patient’s primary solution was hung on a separate mobile IV pole, but both poles were right next to each other between the 2 patient beds. • Afterward, a nurse went to start a piggyback antibiotic for one of the patients but realized she had not restarted the patient’s primary infusion. • After reconnecting the primary infusion, the nurse attached the piggyback antibiotic solution to a port in the primary infusion tubing. • She then realized she had connected the wrong primary line to the patient.

• When connecting or reconnecting any infusion, always verify the actual solution in the container, and then trace the line from the solution to the patient’s correct access point (route) before making any attachments. • You may also trace the line from the patient’s access point outward to the solution, and then conduct a second trace from the solution to the patient. • Either way, be sure to verify all line attachments before making them.

Insulin pen teaching device used in error

• Several days after receiving Lilly Humalog insulin cartridges and pen device in a clinic, a patient presented to the emergency department with elevated blood sugar. • After opening the pen to determine if the insulin cartridge was empty or defective, staff found that the pen contained a teaching cartridge filled with saline. • When a teaching cartridge is put in the pen device, you cannot see the drug name or banded colors that differentiate the teaching cartridges from actual insulin cartridges.

• Visually inspect each pen and insulin cartridge before dispensing it to the patient. • Verify that the locations of teaching cartridges and insulin cartridges are separated to avoid dispensing errors. • Suggestions have been presented to Lilly pertaining to the color of the teaching pens and cartridges to help distinguish them.

Misadministration of insulin

• In several instances, practitioners did not understand that “U-100” refers to the concentration; they also did not realize there was a difference between insulin and parenteral syringes, and they were unaware of the role insulin plays in treating hyperkalemia. • In one case, 4 mL of regular insulin was administered instead of 4 units. • In another case, 50 units of regular insulin, rather than 5 units, was added to an existing IV infusion. • In a third case, a patient with hyperkalemia received only the insulin portion of the treatment but did not receive the 50% dextrose injection.

• Educate staff regarding insulin concentration, the differences between insulin and parenteral syringes, and how to measure doses. • Restrict insulin preparation and administration to those who have shown competency. • Ensure insulin syringes are readily available in all patient care units. • Pharmacy should prepare, label, and dispense insulin in minibags for hyperkalemia treatment and in a standard concentration for infusions. • An independent double-check should be conducted before dispensing and administering IV insulin. • Monitor patient’s response to insulin by obtaining blood glucose levels.

Table continues on next page

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Table 4. Medical Devices and Other Discussion Items

(continued)

Title

Problem/Discussion Point

Recommendation

Oral syringe adapters

• When a child went to the refrigerator to get a juice bottle, he picked up his medicine bottle containing TAMBOCOR (flecainide, Medicis) and was able to access the suspension and drink most of it because the child-resistant cap was not on the bottle. • Errors like this could happen with any oral liquid medication prescribed to children or adults.

• Dispense oral liquid medications with an oral syringe adapter that allows the child-resistant bottle cap to be replaced without removing the adapter. • Even with adult liquid medications, this precaution is critical to prevent a child from accessing adult medications. • Join the Up and Away and Out of Sight Campaign (www.upandaway.org/), and help remind consumers about safe medication storage.

Parenteral nutrition compounding error – sodium chloride

• A 6-week-old infant died in late 2010 after receiving a parenteral nutrition (PN) solution that contained 60 times more sodium than prescribed. • The PN that was prescribed included 14.7 mEq of sodium chloride and 982 mg of calcium. • The order was faxed to the pharmacy after midnight and a pharmacy technician entered it into the automated compounder software. • The technician accidentally entered the prescribed dose of calcium (“982” mg) into the mEq field for sodium. • The technician then prepared the PN using the automated IV compounder and placed the label with the erroneous sodium content onto the PN. • Unfortunately, the pharmacist did not detect the error when checking the final product. • A different label with the sodium content listed as 14.7 mEq was placed over the label produced by the compounder software that listed the actual amount of sodium (982 mEq) in the solution. • The nurse who eventually started the PN solution was unable to detect the error.

• Establish policies that require pharmacists to compound PN during the day shift to maximize the safety with which these solutions are prepared and dispensed. • Synchronize the order and format of listing ingredients in PN order sets, the pharmacy computer system, the compounder software, and the PN label to help prevent errors caused by jumping back and forth. • Install, test, and maximize automated dose limit warnings in the pharmacy computer system and automated compounder order-entry system. • If your PN software supports warning limits, fully implement them. Produce product labels and associated work labels for compounded solutions that include the actual dose/strength of the base solution and each additive, not just the volume amounts needed to prepare the products. • Perform several verification processes of the PN order in the pharmacy; verify the PN product, additives, and expected versus actual weight of the final PN product.

Scanner beep only means the bar code has been scanned

• Regardless of whether a correct or incorrect product or patient has been scanned, audible bar-code scanners produce the same beeping sound. • The nurse must confirm whether he or she scanned the correct patient/medication by reading the actions on the eMAR or hand-held scanner screen. • Some nurses have mistakenly relied on the sound of the beep alone to signal verification of the patient and medication.

• Identify and remedy conditions that may result in absent or poor visibility of the full eMAR during the entire medication administration process, including the scanning process. • Scanners that incorporate their own selfcontained internal logic may be employed so nurses can view alerts associated with scanning. • Educate users not to rely on the audible beep to verify the patient/medication.

“Second victims” of medical errors

• Patient tragedies caused by medical errors can shake involved practitioners to their very core. • The impact is felt in their private lives, in interactions with professional colleagues, and in the context of their social life. • These second victims of errors suffer a medical emergency equivalent to post-traumatic stress disorder. • The instant patient harm occurs, involved practitioners also become patients of the organization—patients who often suffer in silence.

• Develop a crisis management plan that includes a formal infrastructure for second victim support before it is needed. • Second victims have the right to be treated with respect, to participate in the process of learning from the error, to be held accountable in a just culture, to not be abandoned by the organization, and to be supported by their peers and leaders. • For details regarding the deployment of a second victim rapid-response team and other resources, visit: http://www.ismp.org/ newsletters/acutecare/articles/20110714.asp.

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Technology

Spotlight on Medication Safety 31

Pharmacy Practice News • April 2012

Practical Med Safety Tips Offered at ASHP Pearls Session New Orleans—Intrathecal agents, IV oxytocin and investigational drugs were among the targets of recent medication safety efforts presented during the Safety and Quality Pearls session at the 2011 American Society of Health-System Pharmacists (ASHP) Midyear Clinical Meeting.

Duke Team Responds To Labeling Event For Intrathecal MTX When an intrathecal methotrexate (MTX) syringe was labeled with a “not for intrathecal use” auxiliary label and delivered to a designated procedure area, pharmacists at Duke University Hospital, in Durham, N.C., who learned about this near miss decided to review the event and take steps to improve patient safety at the hospital. The pharmacy department (pharmacists and pharmacy technicians) “embraced this near miss as an opportunity to be introspective and to use a guided process to critically review this event and take actions that were within our sphere of influence,” according to presenter Melissa W. King, PharmD, Duke Hospital’s medication safety manager. Dr. King described how medicationsafety pharmacists, in collaboration with pharmacy senior management, developed a process to bring together front-line staff, managers and other content experts to review pharmacy-related events that were “worthy of attention” but not associated with patient impact or serious enough to be considered for formal root cause analysis. Dr. King noted that the process that they use stresses confidentiality and has a nonpunitive approach. In reviewing the intrathecal MTX incident, the Duke team discussed what happened, why it happened and what should have happened, and then “determined actions that should be taken to address the systems that failed,” said Dr. King. The goal was to make this a “never event” by developing actions that eliminated the risk for the labeling error. They developed a rolling action item list (RAIL) that outlined the specific problems identified, the proposed actions that would be taken to address those problems, the individuals responsible for the particular actions and a tentative date for completion of the actions. Lessons learned during the analysis included the recognition that the hospital had processes for preparing chemotherapy but no processes specific to preparing intrathecal doses. Dr. King and her colleagues also uncovered practice discrepancies between the night and day shifts, use of confusing lingo when referencing “not for intrathecal use” auxiliary labels and lack of auxiliary labels to indicate that the medications were for intrathecal administration. Dr. King noted that the “success of

this process lies in the involvement and creativity of the front-line staff, the investment of the leaders and a desire to pave the way for change.” She added, “There is affirmation that comes from seeing solutions implemented as a result of a single event being reported.”

North Carolina VAMC Targets Investigational Drugs To Prevent Errors A team at the Durham Veterans Administration Medical Center uncovered some common practices of their investigational drug service that could lead to medication errors and developed strategies to address those practices to increase patient safety.

Figure. An example of poorly labeled, large quantities of investigational drugs.

In the safety pearl session, Jamie Brown, PharmD, BCPS, PGY-1 residency program director and drug information and investigational drug specialist at the medical center, noted that he and his colleagues uncovered numerous safety concerns associated with the investigational drug service. These issues included problematic drug names; drug name changes, especially when a clinical trial was conducted over a long period of time; and abbreviations. He noted that the names used were often “complex and not very intuitive,” and that there were cases in which people were “using different names for the same drug.” Labels also presented a problem. The font often was too small, and there was inadequate information, dangerous abbreviations and/or multiple languages. The team also found that multiple strengths of the same drug raised an issue. “We want the active drug and placebo to look the same—that’s the whole point—but there might be 10 mg, 20 mg, 30 mg and 40 mg tablets, and the more tablets that look the same, the more likely you might use the wrong one,” said Dr. Brown.

Expiration dates were another area causing potential errors, he said, noting that often expiration dates were not listed or documented or were inaccurate. Because of the large volumes of drugs often required for a trial, storage also presented a safety concern (Figure). To promote safety in the investigational drug setting, the VA team developed a program that included a risk assessment for each protocol that evaluated the labeling and storage of the drug, dispensing instructions with order templates and dosing nomograms for a step-by-step process for drug filling, and shared information about the study protocol with all staff who might need to fill protocol orders. “We want to make sure everyone’s on the same page from day 1, that they know how to fill these medications.” They also shared any concerns with pharmaceutical company sponsors, so that safer products could be developed in the future. In addition to the educational program, Dr. Brown and his colleagues made labeling enhancements with auxiliary labels, repackaging products when necessary, and including necessary information on prescription labels created in the pharmacy. They took steps to promote safer storage of investigational agents by dedicating adequate space to these products, in labeled bins away from other medications. They also separated sound-alike, lookalike products and removed excess supplies. Lastly, they incorporated a reporting component in their program, so that if an error occurred with an investigational drug, personnel involved would include a note in the file, describing the incident and providing a corrective action plan. They also would notify the institutional review board, which then would review the protocol to assess risk versus benefit, as well as the study’s sponsor and the Institute for Safe Medication Practices.

Intranet Site Improves Communication To Manage Drug Shortages As the management of drug shortages became increasingly difficult over the past several years, with shortages affecting increasing numbers of drugs for longer periods of time, pharmacists at a hospital in Wisconsin established a comprehensive intranet site to better manage these shortages. “The communication piece really is so critical” when dealing with drug shortages, said presenter Julie Phillips Karpinski, PharmD, BCPS, drug information

pharmacist in the Department of Pharmacy at Froedtert Hospital, in Milwaukee. “But,” she added, “it’s also so difficult” because if you bombard physicians with information, it can lead to false alarms or a version of alert fatigue. To address problems they encountered in communicating shortage information effectively, Dr. Karpinski and her colleagues set up internal Web portals to enable sharing of shortage-related documents, recommendations, management strategies, and other information. Initially, the intranet tool was just a list of the drug shortages that was managed and used by staff involved in purchasing and drug policy, but it has grown to provide details to health care providers throughout the facility to help them manage drug shortages. “It has expanded into a dynamic communication tool” for pharmacists, pharmacy technicians, physicians and nurses,” said Dr. Karpinski. The portal allows shortages to be sorted either alphabetically or by severity level, displays the vial sizes affected and includes a comments section, as well as a link to the ASHP Web site, which offers more details on specific drug shortages. The comments section increases communication among the staff regarding stock allocation and conservation plans, recommendations for alternative agents, and messages regarding current and anticipated supplies. This allows pharmacists to “keep track of stock and determine when we need to seek alternatives,” said Dr. Karpinski. They also include a list of oncology patients who have upcoming doses scheduled so they can plan ahead. Dr. Karpinski noted that the shortage portal, which has helped the hospital manage more than 500 drug shortages since it was created in 2006, is the second most used intranet site after the hospital’s formulary.

Johns Hopkins Sets Up Strategies for Safer Use Of Intravenous Oxytocin Pharmacists at Johns Hopkins Hospital, in Baltimore, conducted a prospective review that uncovered safety issues related to the use of the high-alert medication oxytocin and implemented risk reduction strategies to address those issues. Their review was based on an article published in ISMP Medication Safety Alert! that shed light on the potential safety risk of adding drugs to hanging IV bags. While the issue had occurred at another hospital, because this could occur anywhere, the team at Johns Hopkins decided to proactively address this issue at their institution. The pharmacists “identified many

•

see PEARLS, page 32

32 Spotlight on Medication Safety

PEARLS continued from page 31

safety issues,” said Ambra King, PharmD, currently a medication safety officer at Northeast Georgia Medical Center, in Gainesville, who conducted the review with her colleagues while she was a postgraduate year 2 medication use safety resident at Johns Hopkins. The team consisted of their OB/GYN pointof-care pharmacist, medication safety officers, an obstetrician and other key staff. The group found that when oxy-

Pharmacy Practice News • April 2012

tocin was added to a hanging bag, there was “incomplete diffusion of the drug throughout the bag.” They conducted an experiment that showed that oxytocin pooled at the top of the bag, which uncovered the need to invert the bag to ensure proper mixing. The team viewed that as a safety issue in that “as additional oxytocin was added to the bag, it was then unknown what the true concentration was in the bag,” noted Dr. King. They also saw variation in the administration rates, she said. “Some of these drugs were being administered wide

open or stopped too early for our postpartum hemorrhaging patients.” Based on their findings, they developed some risk reduction strategies to mitigate harm related to the use of oxytocin. They promoted the use of pharmacy-prepared oxytocin infusion bags. Also, previously, they had a number of predefined oxytocin concentrations, so they standardized to a single concentration (20 units/500 mL sodium chloride 0.9%) as well as the infusion rate (100 mL/h over five hours) for postpartum hemorrhaging. In cases where oxytocin was not effective, they

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used alternative agents, and they educated the staff about “the importance of implementing these risk reduction strategies.” Several positive outcomes resulted from the initiative, Dr. King noted. They learned that the standard concentration and standard infusion rate resulted in longer drug availability in the body. “There was increased staff satisfaction in that the nurses were no longer having to manipulate the oxytocin bag at the bedside,” she said. Some prescribers initially were inconsistent despite the standard concentration and rate. So, the team revised the standard order forms to simplify appropriate ordering. Since the presentation, additional changes have been put in place, Dr. King noted. Several predefined infusions have been removed from use. The postpartum dosing protocol had been redefined as 30 units in 500 mL of sodium chloride 0.9%, with rate changes dependent on the patient’s condition and response to oxytocin. Additionally, the team educated the medical and nursing staffs on the pharmacokinetics of oxytocin so they could better understand the preferred dosing scheme. —Sarah Tilyou

New Product Advertisement CutisPharma, Inc. Introduces New Compounding Kits

utisPharma, Inc. announced the introduction of its FIRST® Mouthwash BLM 4oz and 6oz compounding kits. These products expand the FIRST® Magic Mouthwash line for the company. “Pharmacies have told CutisPharma, and our research has indicated, that there are just as many 4 oz and 6 oz prescriptions for “Magic Mouthwash” containing Benadryl®, lidocaine and Maalox® as there are 8 oz prescriptions. Pharmacists now have greater flexibility in filling FIRST® “Magic Mouthwash” prescriptions,” said Dr. Indu Muni, founder, chairman and CEO of CutisPharma, Inc. CutisPharma, Inc. also announced the introduction of FIRST®- Omeprazole and FIRST®- Lansoprazole Unitof-Use oral suspension compounding kits. These new kits will help pharmacists dispense these compounded prescriptions containing widely used proton pump inhibitors (PPIs). Traditionally, compounded omeprazole and lansoprazole oral suspensions can take up to several hours to prepare and are quite unpleasant to the taste. With FIRST®- Omeprazole and FIRST®- Lansoprazole, pharmacists can just add the liquid suspension to the powder, shake and then, within minutes, dispense the product to the patient with the improved flavoring.

Spotlight on Medication Safety 33

Pharmacy Practice News • April 2012

HIV MIX continued from page 1

Most striking—and controversial— is the evidence that phenytoin may reduce lopinavir/ritonavir (Kaletra, Abbott) levels by approximately 30%. The panel recommended that a dosage increase of about 50% may be necessary to maintain serum concentrations of the HIV combination therapy. “That’s a huge increase,” said Betty Dong, PharmD, clinical professor in the Department of Family and Community Medicine and professor of clinical pharmacy at the University of California, San Francisco School of Pharmacy. “It differs from the guidelines by the Department of Health and Human Services, and [given the side effects], I don’t know if I would do that, to be truthful.” Gretchen Birbeck, MD, MPH, lead author of the report on the panel’s findings acknowledged Dr. Dong’s concerns. “I would want to run a test because you are risking toxicity [with such an increase],” she said. “The main message is that if you combine these two drugs, there is a likelihood that you will have a low antiretroviral level and need to test.” Dr. Birbeck, professor of neurology and epidemiology and director of the International Neurological and Psychiatric Epidemiology Program at Michigan State University in East Lansing, said that pharmacists are in an excellent position to make the risks known. “If I were a pharmacist and saw this combination of drugs ordered, it would be a big red flag. I wouldn’t just let it through,” she said. “There’s often an absence of communication between specialists who are prescribing different drugs, and the pharmacist is most likely to be the one who discovers the problem.”

A Case for More Research Despite the panel’s findings, there remains a dearth of information about drug–drug interactions involving antiseizure medications and HIV drugs, Dr. Birbeck stressed. “There is an abysmal lack of data to go on, especially as brandnew drugs are being used in conjunction with older agents,” she said. “No one has assessed the impact of phenobarbital, and there was not one paper about antiretrovirals and gabapentin.” Dr. Dong agreed that there needs to be further research. “That there were only

a few recommendations in the panel’s conclusion speaks to the lack of hardcore randomized [controlled trial] data,” she said. “Their conclusions are based on evidence, but what evidence there is isn’t very strong.” Without the last word in research on these interactions, Dr. Birbeck noted, pharmacists need to take more of an empirical approach to protecting patients on HIV and anti-seizure medications. When an adverse reaction is suspected, she noted, pharmacists should approach the specialist who

prescribed the anti-seizure medication, usually a neurologist. “The neurologist will have more leeway in options. There are some patients who respond extremely well to phenytoin and not other drugs, but more often, patients taking phenytoin can be switched to other medications,” she said. “The physician treating the HIV doesn’t have the same breadth of options. It’s pretty much protease inhibitors or some type of reverse transcriptase inhibitor.” —Terri D’Arrigo

Other Interactions Found Based on the rest of the panel’s findings, there are several potential HIV–anti-seizure drug interactions for pharmacists to keep in mind. The panel found that valproic acid may increase zidovudine exposure, which they said could be offset by a reduction in zidovudine dosage. The analysis revealed that ritonavir/atazanavir (Norvir, Abbott; Reyataz, BristolMyers Squibb) may reduce lamotrigine (Lamictal, GlaxoSmithKline) exposure by roughly 30%, and the panel noted that a lamotrigine dosage increase of approximately 50% may be needed to maintain lamotrigine serum concentrations. The analysis also suggested that certain combinations of drugs will not result in interactions that require dosage adjustments. These combinations are atazanavir or raltegravir (Isentress, Merck) with lamotrigine, raltegravir with midazolam, and valproic acid with efavirenz (Sustiva, Bristol-Myers Squibb).

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34 Spotlight on Medication Safety

Pharmacy Practice News • April 2012

Standard treatments urged

In Warfarin Reversal, Consistency Could Improve Care Houston—Bringing some standardization to the treatment of warfarin coagulopathies could have clinical benefits, according to studies presented at the 2012 Society of Critical Care Medicine (SCCM) Congress. During one of the studies, conducted at Maine Medical Center, in Portland, implementation of a standardized warfarin reversal protocol and an educational program resulted in faster international normalized ratio (INR) normalization and reduced mortality for patients with intracerebral hemorrhage (ICH). Jennifer Duprey, DO, a hospitalist at the medical center, and her colleagues compared their experience with warfarin-associated ICH before and after implementing a prothrombin complex concentrates (PCC)-based warfarin reversal protocol (abstract 518). Although ICH scores were similar between the patients admitted before (n=51) and after (n=33) the intervention, documented INR normalization occurred faster (≤12 hours in 16% vs. 61%; P<0.001) and in-hospital mortality declined post-intervention (45.1% vs. 18.2%; P=0.013). C. Michael White, PharmD, FCP, FCCP, professor and head of the Department of Pharmacy Practice at the University of Connecticut, in Storrs, said that the study was “a before-and-after evaluation” that is “prone to … timerelated biases.” He said it was not clear whether the benefits were provided by the addition of PCC or the educational process. “But the results are intriguing and suggest that, as in other diseases and disorders, using a more standardized approach yields better outcomes.” William E. Dager, PharmD, BCPS (AQ Cardiology), pharmacist specialist at UC Davis Medical Center, in Sacramento, Calif., agreed that the study suggests that “standardizing the process seems to have a benefit.”

Variation May Compromise Care In a second study, investigators from Henry Ford Hospital, in Detroit, found tremendous variability in methods used to reverse warfarin coagulopathy at their hospital, and developed a standardized protocol to try to address some of the problems associated with that variability. “Variability in health care leads to worse outcomes,” investigator Tamer Abdelhak, MD, the hospital’s Neurocritical Care Program director, told Pharmacy Practice News. Dr. Abdelhak and his colleagues conducted a retrospective review of their

‘The results are intriguing and suggest that, as in other diseases and disorders, using a more standardized approach yields better outcomes.’ —C. Michael White, PharmD, FCP, FCCP

Ideal Versus Actual Body Weight For Dosing of Prothrombin Complex Concentrates

lthough the literature supports the use of the international normalized ratio (INR) and weight for prothrombin complex concentrates (PCC) dosing to reverse warfarin-related bleeding, the measurement used to determine weight varies in clinical practice. Investigators from Indiana University Health Methodist Hospital, in Indianapolis, sought to determine whether there was a benefit to using actual body weight (ABW) over ideal body weight (IBW) for PCC dosing (abstract 281). Investigator Emily M. Hutchison, PharmD, BCPS, clinical pharmacy specialist, trauma/critical care, at the hospital, noted that PCC was added to the hospital’s formulary on June 1, 2010; it was dosed initially based on initial INR and IBW, but on March 1, 2011, the hospital changed the weight measurement to ABW, hypothesizing that it would lead to more rapid reversal of coagulopathy. Dr. Hutchison and her colleagues retrospectively evaluated the patients who were treated at the hospital between June 1, 2010 and July 5, 2011, and who had an initial INR ≥1.5 and needed urgent reversal of warfarin coagulopathy. Eightythree patients received PCC during the study period, 63 meeting inclusion criteria (45 with IBW, 18 with ABW). Median time to obtain an INR less than 1.5 was 190 minutes in the IBW group and 600 minutes in the ABW group (P=0.47). The researchers concluded that time to INR reversal with PCC was not significantly different when the dose was based on INR and ABW as opposed to IBW. There was no difference in the percentage of patients who received fresh frozen plasma (FFP) (P=0.20), amount of FFP administered (P=0.57) or INR at 24 hours (P=0.39). One patient dosed using IBW experienced a superficial clot and venous thromboembolism nine days after PCC was given. William E. Dager, PharmD, BCPS (AQ Cardiology), pharmacist specialist at UC Davis Medical Center, in Sacramento, Calif., said that the study shows “there may not be a benefit to ABW. Their results suggest that IBW per unit per kilogram dosing might be OK.” However, he noted that the timing of the INR draws in the study was not clear. If it was variable, that could have influenced the results. —G.O. Drs. Dager and Hutchison reported no relevant financial disclosures.

institution’s warfarin reversal methods in patients with ICH, with the aim of identifying areas that could be improved (abstract 824). Between 2001 and 2011, 2,971 patients were admitted to the institution with ICH. Of these patients, 41 were on warfarin. (Since then, said Dr. Abdelhak, the number of patients in the study has reached 120; the study is being prepared for submission to the journal Critical Care Medicine.) The investigators found that the mean time elapsed prior to a post-therapy repeat INR check was 155 minutes. Reversal agents used included vitamin K in 36 patients (87.8%), fresh frozen plasma in 34 (82.9%), activated factor VII in 19 (46.3%) and PCC in 20 (48.7%). Thirty patients (73%) received three reversal agents. Sixteen patients (39%) died. Commenting on the findings, Dr. Dager said that 155 minutes seemed long for the mean time before a post-therapy repeat INR. “One should do INR shortly after an intervention has been done,” he said. He also saw room for improvement in the center’s administration of vitamin K, which only was given to 87.8% of patients. “Why was vitamin K not given to 12% of the patients?” He said that he believes a three-drug regimen may be necessary in some settings, but that there is a risk for clotting complications from the use of PCC or recombinant factor VIIa.

‘Variability in health care leads to worse outcomes.’ —Tamer Abdelhak, MD To address such concerns raised by their findings, the investigators established a standardized protocol for reversal with strict follow-up of INR, and planned to study it prospectively. “It’s similar to what was done in sepsis and stroke, changing how a system practices,” in an effort to improve outcomes, said Dr. Abdelhak. Dr. White noted that the study “shows the extreme variability in care patterns” that can occur even “within a single health system when it comes to caring for ICH patients. This variability calls out for a more uniform approach.” —George Ochoa Drs. Duprey, Abdelhak, Dager, and White reported no relevant financial conflicts of interest.

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Pharmacy Practice News • April 2012

Educational Review

Medication Safety Systems in the ICU: Beware of the Humans Steven J. Martin, PharMD, BCPS, FCCP, FCCM Professor and Chairman

Shelley a. KloChan, PharMD Critical Care Resident Department of Pharmacy Practice College of Pharmacy and Pharmaceutical Sciences The University of Toledo Toledo, Ohio

edication safety systems are

a prominent aspect of any critical care setting today.

In addition to establishing methods and processes to enhance safety, institutions have created error-detection tools, encouraged medication error reporting, and refined methods of root-cause analysis to determine the causes of, and outcomes from, errors.

Technology continually is enhancing the druguse process, and improving safe medication practices throughout the health care system. Many institutions have implemented technologies to enhance safety, and incentives created by the 2010 Patient Protection and Affordable Care Act are designed to encourage health systems to further enhance their systems through 2014. In the critical care areas of most hospitals, these technologies include electronic medical records (EMRs), computerized prescriber order entry (CPOE), advanced infusion (smart) pumps, rule-based decision software, bar-code medication administration (BCMA), and automated dispensing machines. This interest in medication safety found its roots in the 1999 Institute of Medicine (IOM) report (To Err is Human) that estimated that more than 1 million injuries and nearly 100,000 deaths occur in the United States each year as a result of mistakes that are preventable.1 Despite the release and widespread dissemination of this report, current estimates suggest that medication errors may account for nearly 80% of all serious medical errors, and most of these errors occur during drug administration.2 The ICU, with an estimated medication error rate of approximately 12%,2 typically has the highest incidence of adverse drug events (ADEs) of any physical space in the hospital, often exceeding twice the number of any other area.3 This may be due to the complexity of care and fast-paced nature of critical care. ADEs in the ICU also typically are more severe due to the amount of high-risk medications used in that setting.2,4 Despite state-of-the-art technologies (Table 1), errors still occur. Many times, new technologies implemented to reduce errors themselves become

the cause of the errors. New technologies upset the processes that are familiar to the workforce. New technologies may not use similar workflows as manual systems, may require more time initially than manual systems, and frustration by the user can result in workarounds. New technologies often are added piecemeal, and may not be integrated with each other to provide a seamless system.

BCMA Systems Much has been written about workarounds to BCMA systems. BCMA is a point-of-care verification of the correct patient and medication. With a BCMA system, the nurse scans a bar-coded medication package prior to administration using a handheld bar-code scanning device. The nurse then scans the patient’s wristband, verifying that the drug to be administered is the correct medication for the correct patient. The nurse also scans his or her own bar-coded identification badge, which electronically records the medication administration in the patient’s electronic medication administration record.5 A report by Koppel et al highlights many of the challenges associated with BCMA technology in patient care settings. Koppel et al identified 15 types of BCMA workarounds, including affixing patient identification bar codes to computer carts, nurses’ belt rings, or other convenient stationary objects, and carrying prescanned medications for several patients on carts.6 They also uncovered 31 different causes of workarounds, such as unreadable medication bar codes, nonfunctioning scanners, unreadable or missing patient identification wristbands, medications without bar codes, scanners with dead batteries, and poor wireless service

in patient care areas. The causes were categorized as task-related, organizational, patient-related, and environmental.

Smart Infusion Pumps Workarounds related to the use of smart infusion pumps also have caused medication errors. Smart pumps are programmed with drug libraries, and they provide point-of-care decision support feedback for excessively high or low IV infusion rates and drug doses. Drug libraries may be specific to each ICU setting, with unique rules for individual clinical areas, such as medical, surgical, cardiothoracic, and pediatric ICUs. The role of the smart pump is to “remember” the large number of rules (hospital-defined dosing policies and other clinical pathways or restrictions) that are entered into the drug library, and to apply those rules during pump programming to warn clinicians about potentially unsafe drug therapies.7 These devices may be programmed to provide “soft” alert feedback, which allows overrides, and “hard” alerts that cannot be overridden. Rothschild et al identified common workarounds that were employed when the smart pumps with decision support software were in operation. These included bypassing the drug library and overriding alerts, including those related to the use of inappropriate boluses. During the intervention period when agents were preprogrammed in the smart pump library, users bypassed 24% of alerts.8 Common agents involved when drug libraries were bypassed were propofol (68.3%) and insulin (61.5%). Among the bypasses, 3 were associated with preventable ADEs, and 44 Text continues on page 36

36 Spotlight on Medication Safety

Text continued from page 35

with nonintercepted potential ADEs. Soft alerts that were overridden resulted in 1 preventable ADE and 24 nonintercepted potential ADEs. Grissinger reported on an institution that had a heparin infusion error despite the use of a smart pump.7 A nurse erroneously programmed a heparin infusion to be administered at 1,000 mL per hour, not 1,000 units per hour (20 mL per hour), as ordered. The nurse bypassed the dose-checking technology provided by the smart pump. The institution later determined that most nurses in the hospital routinely bypassed the dose-checking capability of the smart pumps. Reasons for this workaround included a low perception of risk when bypassing the technology, an institutional failure to make adjustments in the drug library when alerts were not credible, the extra time required to use the pump’s built-in features, limited nursing time and clinical emergencies, and a culture that supported at-risk behaviors, including technology workarounds. Grissinger likened smart pumps to the automobile seat belt.7 Seat belts, like dose-checking technology, can be bypassed despite a policy that requires their use. He suggested that institutions should create a culture of safety throughout the institution, as well as analyze pump logs and adjust drug libraries as needed, evaluating all overrides, and publicizing “good catches.” Workarounds are not the only concerns with smart pump technology. Older pumps do not integrate with CPOE, real-time vital sign alerts, or laboratory results.5 Most pumps do not allow for automated closed-loop drug titration integrated into CPOE systems.5 Smart pumps also cannot prevent administration of the wrong drug or the wrong concentration of a drug.5 Two prominent errors of this type reached the national spotlight in which the wrong concentration of IV heparin was administered. Both incidents resulted in 1,000-fold overdoses, one of which resulted in the deaths of 3 newborn infants at Methodist Hospital in Indianapolis in 2006, and the other which led to a life-threatening event involving actor Dennis Quaid’s premature twins at Cedars-Sinai Medical Center in Los Angeles in 2007.5

CPOE Systems The use of electronic prescribing through CPOE systems has increased since implementation of the 2010 Affordable Care Act. CPOE systems automate the prescribing process for medications and other types of

Pharmacy Practice News • April 2012

Table 1. Safety Systems Commonly Used in Critical Care Settings Intensive surveillance systems Advanced (“smart”) infusion pumps EMR systems Automated dispensing cabinets CPOE systems Rule-based decision software Telemedicine systems BCMA systems Electronic medication administration records BCMA, bar-code medication administration; CPOE, computerized prescriber order entry; EMR, electronic medical record

physician orders. The technology may be as simple as electronic lists of medications available from the institution’s formulary, to systems providing decision support, drug interaction screening, laboratory value screening, and a mechanism of alerts and reminders sent to the physician when problems are detected.9 CPOE systems were designed to improve the medication-use process and reduce medication errors. Most systems positively affect medication safety in several ways: reduced prescribing and transcription errors, reduced patient handoffs, directed prescribing that may improve medication selection and compliance with critical treatment pathways, improved access to patient data, and reduced medication delivery time from the pharmacy.9

Ammenworth et al performed a recent systematic review of the effect of CPOE systems on medication errors.9 They found that 23 of 25 studies showed a significant relative reduction in the risk for medication errors with CPOE, with a risk ratio between 0.01 and 0.87, indicating a relative risk reduction for medication errors between 13% to 99%. Interestingly, one study identified in the review reported an increase of 26% in medication-error risk, but the CPOE system at this institution did not communicate with the pharmacy system, leading to transcription errors when orders were entered into the pharmacy software.9 Four of 6 studies demonstrated a relative risk reduction for ADEs of 30% to 84%, and 6 of 9 studies reported a relative risk reduction of 35% to 98%

Table 2. Unintended Adverse Consequences From CPOE Implementation More or new work for clinicians Unfavorable workflow concerns Never-ending system demands Problems related to paper persistence (in which use was especially pronounced when paper interfaces substituted for lack of electronic CPOE system integration with other clinical systems [eg, medication administration recording, pharmacy dispensing, or laboratory ordering]) Untoward changes in communication patterns and practices, that promote reductions in face-to-face communication regarding patient care, and the belief that entry of an order into the system ensures that the proper people will see it and act on it Negative workplace attitudes Unexpected changes in the power structure, through loss of physician professional autonomy and enforcement of specific clinical practice patterns Overdependence on the technology Generation of new kinds of errors CPOE, computerized prescriber order entry Based on reference 10.

for potential ADEs. Despite these benefits, CPOE systems have been associated with new and different types of medication errors. Campbell et al reported unintended adverse clinical consequences resulting from CPOE implementation at 5 hospitals and found 9 types of major categories of adverse consequences including generation of new kinds of errors, overdependence on the technology, and negative workplace attitudes (Table 2).10 New CPOE–related errors result from the variety of different ways in which data were presented electronically; confusion with medication ordering options and their electronic presentation and selection methods; inappropriate text entries; poor communication that leads to misunderstanding of test, training, and production versions of systems; and workflow process mismatches.10 System designs (including poor data organization, data omissions, etc), and end-user confusion about system functionality also contributed to new forms of errors. The authors noted that clinical decision support features built into CPOE systems created more than 25% of these unintended consequences. Other studies have found that errors related to CPOE–entered orders are common due to the ease of the point-and-click nature of ordering.11 The ease of moving from patient to patient makes entering orders for the wrong patient more common.12 Medications with similar names listed close to each other or in drop-down boxes can result in the wrong medication being ordered.13 Multiple routes, doses, frequencies, and formulations all listed for a single drug increase the risk that a prescriber will enter the incorrect drug, dosage form, route, or schedule of administration without realizing it.13 Advanced CPOE systems can alert a physician and can prevent overdosing, duplicate orders, and allergic and drug–drug interactions. However, alert fatigue may result when there are too many alerts that cause physicians to override both important and unimportant alerts. Van der Sils et al found that physicians override drug safety alerts 49% to 96% of the time, with as many as 20% of physicians admitting that they override alerts without checking.14 Their data indicated that overriding alerts can result in ADEs in 2% to 6% of all overridden messages. Officials at institutions may feel pressured into turning off alerts without performing careful error management, which may lead to medication errors and reduced patient safety.14

Spotlight on Medication Safety 37

Pharmacy Practice News • April 2012

uncertainty about identifying an event, and uncertainty about the clinical significance of the event.16,18-21 The stigma of making or identifying an error also remains a barrier to reporting.19 Even when health care professionals are told the reporting is anonymous, many still fear it is not truly anonymous and will result in punishment.19 Reporting systems are designed to identify problems even if they do not reach the patient. Health care professionals often only report problems that lead to patient harm.20 Potential

errors that are caught before they can affect patients often are not reported because they may be viewed as trivial because they do not actually reach the patient.19 Health care professionals are more likely to report medication errors when patients receive the wrong medication but less likely to report when patients do not receive ordered medications, although both situations describe medication errors.18 Despite the nearly 20 years of focus on ADE and medication error Text continues on page 38

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Measuring and reporting medication errors is an important process in the promotion of medication safety in the ICU. In 1993, the Joint Commission wrote a report in which it hypothesized that developing medication error or ADE reporting systems could result in a reduction of medical and health care errors.15 This report, coupled with the IOM report in 1999, began the era of error reporting in hospitals and health care systems. The process for event reporting varies among institutions. Several mechanisms have been suggested. National surveillance data should be monitored so information can be shared across health care systems.16 Targeted analysis using administrative data such as International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) codes associated with ADEs (also known as E-codes) that are assigned at discharge, may identify drug misadventures.16 Morbidity and mortality conferences that are routinely conducted among medical disciplines could be made more widely available to engage all ICU practitioners.16 Incidents such as readmission to the hospital/ICU or death could trigger more intensive analysis to search for potential safety issues.16 Use of text word search and text mining in the medical record may quickly provide useful data if the process is automated through computerized screening; this could identify as much as 70% of the ADEs that a manual search would find.17 Traditional screening methods include manually identifying potential triggers such as antidotes or serum drug concentrations, and this process can be automated with computer software that could combine sets of orders or pieces of data (such as abnormal laboratory values with potential causal drugs [eg, hypoglycemia and concurrent insulin use]) to provide more precise analysis.16 Technology also could be used to generate reports from automated dispensing cabinets, smart pumps, ventilators, and other devices that are used when ADEs or medication errors occur.16 Despite these options, most institutions continue to rely on voluntary reporting as a primary means of capturing data on ADEs and medication errors,16 which has led to their being underreported.18 The Joint Commission found that as few as 5% of all ADEs are reported to appropriate authorities each year.15 Pharmacists provide the majority of medication error reports, but this activity often is a performance metric for pharmacist annual evaluations.3 Harper et al

conducted a survey of nurses and physicians and found that nearly 90% of those surveyed were aware of the Joint Commission’s mandatory reporting system, yet only 50% of the nurses and less than 20% of the physicians reported that they used the system.19 Reasons for underreporting of ADEs and medication errors include confusing reporting systems, substantial effort and time required to complete the report, fear of negative outcomes or blame, lack of action being taken to correct the problem,

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38 Spotlight on Medication Safety

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reporting, a disconnection still exists between the clinicians involved and the culture or systems used to collect and analyze the data.

Summary Medication safety systems have proliferated in the years since the landmark 1999 IOM report. In many institutions, the urgency to make changes in processes and systems has resulted in a neglect of cultural changes that inculcate a mission

of safety. Despite advances in technologies that have been proven to make the medication use safer in the critical care setting, workarounds and other cultural behaviors often mitigate the value of the technology. The lack of integration of medication safety systems defeats the goal of technologies and frustrates the workforce in the critical care setting. Institutions and individual clinicians in ICUs should be aware that technology-induced complacency about medication safety could be a

Pharmacy Practice News • April 2012

recipe for trouble, especially when the human element remains the vital component in the drug-use process.

References 1.

Kohn LT, Corrigan JM, Donaldson MS, eds. To Err is Human: Building a Safer Health System. A Report of the Committee on Quality of Health Care in America, Institute of Medicine. Washington, DC: National Academy Press; 2000.

2. Rothschild JM, Landrigan CP, Cronin JW, et al. The Critical Care Safety Study: the incidence and nature of adverse events and serious medical errors in intensive care. Crit Care Med. 2005;33(8):1694-1700.

3. Kaboli PJ, Glasgow JM, Jaipaul CK, et al. Identifying medication misadventures: poor agreement among medical record, physician, nurse, and patient reports. Pharmacotherapy. 2010;30(5):529-538. 4. Kane-Gill S, Weber RJ. Principles and practices of medication safety in the ICU. Crit Care Clin. 2006;22(2):273-290. 5. Rothschild JM, Keohane C. The role of bar coding and smart pumps in safety. Morbidity and Mortality Rounds on the Web. 2008; http://webmm.ahrq.gov/perspective.aspx? perspectiveID=64#ref7back. Accessed March 8, 2012. 6. Koppel R, Wetterneck T, Telles JL, Karsh BT. Workarounds to barcode medication administration systems: their occurrences, causes, and threats to patient safety. J Am Med Inform Assoc. 2008;15(4):408-423. 7.

Grissinger M. “Smart pumps” are not smart on their own. P T. 2010;35(9):489-529.

8. Rothschild JM, Keohane CA, Cook EF, et al. A controlled trial of smart infusion pumps to improve medication safety in critically ill patients. Crit Care Med. 2005;33(3):533-540. 9. Ammenwerth E, Schnell-Inderst P, Machan C, Siebert U. The effect of electronic prescribing on medication errors and adverse drug events: a systematic review. J Am Med Inform Assoc. 2008;15(5):585-600. 10. Campbell EM, Sittig DF, Ash JS, Guappone KP, Dykstra RH. Types of unintended consequences related to computerized provider order entry. J Am Med Inform Assoc. 2006;13(5):547-556. 11. Maslove DM, Rizk N, Lowe HJ. Computerized physician order entry in the critical care environment: a review of current literature. J Intensive Care Med. 2011;26(3):165-171. 12. Magrabi F, Li SYW, Day RO, Coiera E. Errors and electronic prescribing: a controlled laboratory study to examine task complexity and interruption effects. J Am Med Inform Assoc. 2010;17(5):575-583. 13. Bedouch P, Allenet B, Grass A, et al. Drugrelated problems in medical wards with a computerized physician order entry system. J Clin Pharm Ther. 2009;34(2):187-195. 14. van der Sijs H, Aarts J, Vulto A, Berg M. Overriding of drug safety alerts in computerized physician order entry. J Am Med Inform Assoc. 2006;13(2):138-147. 15. Joint Commission on the Accreditation of Healthcare Organizations. The Measurement Mandate. Oakbrook Terrace, IL: JCAHO; 1993. 16. Stockwell DC, Kane-Gill SL. Developing a patient safety surveillance system to identify adverse events in the intensive care unit. Crit Care Med. 2010; 38(6 suppl):s117-s125. 17. Jha AK, Kuperman GJ, Teich JM, et al. Identifying adverse drug events: development of a computer-based monitor and comparison with chart review and stimulated voluntary report. J Am Med Inform Assoc. 1998; 5(3):305-314. 18. Evans SM, Berry JG, Esterman A, et al. Attitudes and barriers to incident reporting: a collaborative hospital study. Qual Saf Health Care. 2006;15(1):39-43. 19. Henriksen K, Battles JB, Marks ES, et al, eds. Rockville (MD): Agency for Healthcare Research and Quality (US); 2005. 20. Wakefield DS, Wakefield BJ, Uden-Holman T, Borders T, Blegen M, Vaughn T. Under– standing why medication administration errors may not be reported. Am J Med Qual. 1999;14(2):81-88. 21. Etchegaray JM, Throckmorton T. Barriers to reporting medication errors: a measurements equivalence perspective. Qual Saf Health Care. 2010;19(6):e14.

Spotlight on Medication Safety 39

Pharmacy Practice News • April 2012

UW Health Wins ASHP Award for Anticoagulation Safety T he University of Wisconsin Health Systems (UW Health) in Madison recently won a $50,000 award for excellence in medication use safety from the American Society of HealthSystem Pharmacists (ASHP) Research and Education Foundation for their anticoagulation stewardship program (ASP). The award, sponsored by the Cardinal Health Foundation, is the only national honor that recognizes a pharmacist-led multidisciplinary team for implementing significant, institution-wide improvements in medication safety, according to the ASHP.

conditions, she noted. Yet, before the program was implemented, 20% of surgical inpatients and 24% of nonsurgical patients at UW Health did not receive blood clot prevention therapy—which is given in the form of a heparin-based medication. Now

those figures are down to 3% and 8%, respectively. The hospital’s data show a corresponding reduction in postoperative clots from 11.6 per 1,000 cases to 6.6 per 1,000 cases. “That’s the most significant thing we’ve done for patients. The number of blood

clots has gone down dramatically,” Dr. Rose said. UW Health’s bottom line also has benefited. The reduction in clots has saved an estimated $1 million in hospital costs, according to the ASP team. “It’s nice to know that our program is making a difference.” —Dana Hawkins-Simons

‘The number of blood clots has gone down dramatically.’ —Anne Rose, PharmD The goals of the ASP, launched in fall 2009, are to improve the safety, quality and regulatory compliance measures for clot prevention and use of bloodthinning medications throughout the entire UW Health system. “We focus on the whole health system, both inpatient and ambulatory settings. That makes us different from many other programs,” said Anne Rose, PharmD, ASP coordinator at UW Health. “The other unique aspect is that we give the entire frontline staff—physicians, pharmacists and nurses—the knowledge and tools they need to assess and treat patients around the clock. We didn’t want our ASP staff to just provide a consult service.” The stewardship team developed inpatient clinical tools, such as practice guidelines and order sets, which were configured into the UW Health’s electronic medical record system. These order sets include standardized physician orders for medications and other therapies to prevent and treat clots in hospital patients.

Warfarin Management And Blood Clot Prevention The ASP team developed clinical dosage guidelines, computerized documentation protocols and educational programs for the management of warfarin. Nurses in 39 primary care clinics across UW Health, covering more than 3,000 patients on warfarin, use the resources. An assessment of the initial pilot clinics found that the percentage of patients within target international normalized ratio (INR) range improved from 65% to 72% after implementation of the protocol. Blood clots are considered one of the most preventable hospital-acquired

40 Technology

Pharmacy Practice News • April 2012

Opinion

Stage 2 Proposal Offers Incentives for BCMA Release of new ‘meaningful use’ criteria an opportunity for pharmacist input Jamie Kelly President Entropy Research San Diego, California

n the landmark March 2001 report, Crossing the Quality Chasm, the Insti-

tute of Medicine argued that reimbursement methods of the U.S. health care system provide little financial reward for improvements in the quality of care and may even inadvertently pose barriers to innovation. In fact, the authors asserted, the system allows—and sometimes even rewards—defective care because it is unable to reward future benefit.

Nowhere does this logic apply more aptly than with the adoption of health care information technology (HIT). Until the introduction of the Health Information Technology for Economic and Clinical Health (HITECH) Act, established as part of the American Recovery and Reinvestment Act of 2009, the investment in electronic health record (EHR)

Presents

Bridging the gap between the hospital and post-discharge care

Volume 1 • Number 1 • Winter 2012 A Supplement to Pharmacy Practice News

In This Issue

Embracing Rather Than Fighting Specialty Pharmacy

Ask the Expert

nfusion centers and other community practice sites that manage patients post-discharge share a common lament: Why do so many of those patients often struggle with the basics of care after they leave the (usually) safe confines of the hospital? One glaring contributing factor is a lack of collaboration between hospitals and the community sites of care, according to Dennis Street, RPh, lead pharmacist at Mercy Home Infusion, which is affiliated with Mercy Hospital in St. Louis. “It’s a big enough transition to get patients out of the hospital, much less getting them out of the hospital and starting them on

Tips for partnering with managed care organizations, plus cost-saving strategies.

Q&A

Stephanie Holliday, PharmD, discusses REMS, self-administered oral chemotherapy and other hot topics in specialty pharmacy.

Opinion

N. Lois Adams, BPharm, on reining in the high cost of drug therapy.

Operations & Mgmt

Aetna Specialty Pharmacy, other providers offer drug adherence strategies.

Educational Review

Antimicrobial Efficacy

Policy

Patient assistance programs, plus a projection that specialty pharmacy drug spending will soar by 26.5% in 2012.

Building a Better Care Transition: What Works Now

•

Tips for Surviving The TPN Shortage

University of Illinois clinical staff pharmacist Nehrin Khamo, PharmD, educates a patient on self-injection techniques.

lthough many health-system pharmacists bristle at limited distribution networks and other restrictions placed on some specialty medications, more and more of them are deciding to embrace specialty pharmacy rather than fight it, and thus join the ranks of smaller and larger specialty operations providing that segment of care. To offer insights into this new source of competition, Specialty Pharmacy Continuum profiled three hospitals that are bolstering their presence in the market: The University of Illinois Hospital and Health Sciences System, Chicago; Fairview Pharmacy Services, Minneapolis; and Duke University Hospital, Durham, N.C. The health systems cite revenue loss as one reason for their recent efforts: they simply can’t afford to continue seeing patients siphoned off to specialty pharmacy providers. But finances aren’t the only motivation; another key driver is the need to provide for patients’ total health needs across transitions of care, as the era of accountable care organizations and payments based on quality standards gets under way. For Kyle Skiermont, PharmD, director of specialty infusion operations at Fairview Pharmacy Services, improving patient care is the No. 1 reason health systems enter or expand into the specialty pharmacy area. His operation, a part of Fairview Health Services, a large regional network of hospitals, already is well established as a

•

see EMBRACE, page 11

FDA Approvals Kalydeco approved for cystic fibrosis patients with CFR gene mutation. See page 26.

see CARE TRANSITION, page 8

hings have been heating up on the IV nutrition shortage front. Last fall, Baxter hosted the first-ever nutrition shortage safety summit, and the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), which put together a task force to address the supply shortages, has been issuing frequent updates and guidances to help its members prioritize, substitute and manage the limited supplies they have. But such regulatory and policy efforts only go so far in mitigating the effects of the shortage on patient care. Here are several practical strategies that home infusion centers are using right now to weather the storm.

•

see TPN SHORTAGE, page 10

The Book Page

A new quarterly publication from the editors and publisher of Pharmacy Practice News. Each issue will provide essential clinical and business information for stakeholders in specialty pharmacies, home infusion providers, insurers and managed care organizations. Our goal: to help foster high-quality, cost-effective treatment across the entire patientcare continuum. To subscribe, visit pharmacypractice news.com

MedInfoNow Subscription

See page 27.

Bridging the gap between the hospital and post-discharge care

systems was a financially unattainable goal for cash-strapped individual and institutional health care providers. But HITECH’s 2-pronged approach of incentive payments for adopting EHR systems and future penalties for not adopting them has dramatically changed the EHR landscape. Since the initiation of the program, nearly 2,000 hospitals and more than 41,000 doctors have received $3.1 billion in stage 1 incentive payments for ensuring meaningful use of EHR. On Feb. 23, the Centers for Medicare & Medicaid Services (CMS) took the next step and issued stage 2 meaningful use criteria in a 455-page notice of proposed rulemaking. For the most part, the proposed rule carries forward the pharmacy-related recommendations outlined last summer by the CMS HIT Policy Committee. One noteworthy change in the previous draft relates to the use of electronic medication administration records (eMAR). CMS originally called for 30% of medication orders to be automatically tracked via eMAR. The latest criterion reduced the orders threshold to 10% but introduced a new factor—the use of “assistive technology” to enter information into the eMAR. The proposed rule defines eMAR and assistive technology as “technology that automatically documents the administration of medication into certified EHR technology using electronic tracking sensors,” including radiofrequency identification or electronically readable tagging, such as bar coding.

Safety First The decision by the HIT Policy Committee to specify the use of assistive technologies was based on clinical evidence. The committee weighed the long-term experience of organizations such as Hospital Corporation of America (HCA) and Brigham and Women’s Hospital, which have adopted and studied the effect of bar coding on the safe dispensing and administration of medications. No doubt, the support of industry organizations such as the Institute for Safe Medication Practices (ISMP), the American Society of Health-System Pharmacists, the Joint Commission, and the University Hospitals Consortium also contributed to the CMS decision to include assistive technologies. Coupling bar-coding technology with eMAR helps achieve multiple goals, not the least of which is improved patient safety. Bar code medication administration (BCMA) facilitates compliance with the Joint Commission’s perennially No. 1 National Patient Safety Goal: to improve positive patient identification.

Technology 41

Pharmacy Practice News • April 2012

Opinion BCMA also eliminates the opportunity for human error in matching the patient to his or her prescribed orders and verifying the medication, dose, and time of administration. Automated matching overcomes inevitable human factors that prevent caregivers from intercepting errors at the point of care. “Hospitals can implement eMAR applications without incorporating bar-code verification—we’ve done it for years,” said Stu Levine, PharmD, informatics specialist with ISMP. “But by clarifying the definition of the eMAR to require auto-ID technology, the proposed rule significantly advances the ‘meaningfulness’ of the eMAR. With a scan at the bedside, the potential for administering the wrong medication to the patient is greatly reduced. Information on medication administration is captured in a much timelier manner than a manual documentation process can accomplish.”

hospitals are using bar-code scanning to verify medication administrations.” This represents more than 60% of total acute care beds, he noted. The majority of the early-adopter facilities have been larger academic medical centers and health system–affiliated hospitals. The next class of hospitals to implement primarily will be composed of community hospitals with fewer than 200 beds. Given the limited resources of the adopting market, industry experts predict that the minimum 10% of orders threshold set by CMS might have unintended

consequences. Dr. Levine explained that “modest requirement attempts to follow the original CPOE [computerized prescriber order entry] objective in allowing small pilot implementations to get the process started. However, in reality, it is extremely difficult to operate a bifurcated system with a bar code–enabled eMAR on some units and a paper-based system on others.” Mike Wisz, of Mike Wisz and Associates, a health care IT consulting firm, recalled that in the early 2000s, pioneering hospitals were forced to con-

tend with bifurcated systems still reliant on manual charting alongside their eMAR systems. “Due to the immaturity of the software at the time, many early hospitals piloted bar coding on just a small sample of nursing units,” noted Mr. Wisz. “These early sites were forced into bad practice by operating dual systems. Eventually, when the software matured, replacing the legacy processes and workarounds in the pilot units proved more difficult than expanding into new units. It would be a shame if hospitals rushed

•

see BCMA, page 42

Enhancing the Closed-Loop Medication Use Process The medication use process is not a linear path that begins with prescribing and concludes with administration. Rather, the process is cyclical. Administration data affect future prescribing decisions, making the quality of those data critically important to effective therapy. Closedloop safety is optimized when the ordering physician is presented with real-time, accurate documentation of medication administration. “Without the reinforcing practice of scanning the medication in its packaging immediately before administration, nurses often document retrospectively in some other location on the nursing unit. This practice leads to inaccuracies in the eMAR, which can ultimately create opportunities for error. The inaccuracy is then perpetuated when the physician uses the eMAR to make subsequent therapy decisions,” according to Dr. Levine. For instance, a prescriber might wish to increase a daily warfarin dose based on recent lab results. If a recent dose of warfarin has been administered but has not yet been documented on the eMAR, the prescriber might order the new higher total daily dose, resulting in duplicate dosing and the potential for associated toxicities. With real-time eMAR data, the physician would see the dose already administered and order a smaller “booster” dose for the current day and begin the increased daily dose the following day. Real-time visibility into an accurate eMAR likewise informs pharmacists during medication order review.

Unintended Consequence: Rushed Implementations Of Low-usage Pilots Mark Neuenschwander, co-founder of the unSUMMIT for Bedside Barcoding estimates that currently “over 46% of U.S.

Educate your Pharmacy Buyer on the ins and outs of pharmacy purchasing for hospitals, medical centers, & health systems. Lectures solely focused on Pharmacy Purchasing: Cost Savings & Revenue Generating Improving Productivity & Efficiency Buying Best Practices Attendees receive 8-10 ACPE-accredited CE’s for Pharmacy $25 off a NEW NPPA Membership with Conference Registration–use Discount Code: “New Member”

42 Technology

Pharmacy Practice News • April 2012

Opinion

BCMA continued from page 41

to pilot technology in just a couple of care areas to reach the 10% without considering the broader … picture.” Mr. Neuenschwander agreed, saying, “Using two systems for medication administration is not only dangerous but unnecessary.” From a practical standpoint, he suggested, “When done the right way, a hospital absorbs about 90% of the cost of implementation in order to reach the minimum threshold. Planning to go the full distance from day 1 sets a path to reach scan rates of more than FILE SLUG 90% of medications administered with CMEzoneaqtrpg.indd 1ST PROOF LAYOUT APPROVEd bar code throughout the hospital—not InITIALS And dATE counting the ED [emergency departMAX sign-off ment] and OR [operating room].” Senior Editor

Measurement Matters Copy Editor

Beyond the problems with pilots, Sales pharmacy leaders warn that another April 2, 2012 1:26 PM Production could be less unintended consequence than optimal implementation of houseCreative wide systems. Richard Malone, PharCOMMENTS: Half Vertical mD, from Vanderbilt University Medical 4C Center (VUMC), in Nashville, Tenn., postulated that “the way the criteria are proposed, hospitals may be incented to rush a housewide implementation. R2

Then, they rely on a handful of superusers to achieve 10% compliance, while failing to improve safety and possibly even causing new sources of harm.” Dr. Malone said that he envisioned that improperly implemented systems could cause hospitals to fall out of compliance with the Joint Commission’s continuity of care standards. Having participated in BCMA implementations within HCA, Vanguard Health, and now VUMC, Dr. Malone supports the use of pilot implementations, saying, “The intent should be to choose a unit or units that, with … compliance greater than 90%, will reach the 10% CMS threshold for total doses tracked PROOFeMAR.” 1 12/10 OK code–enabled via theFInALbar But InITIALS And dATE REV 1 12/17 he echoed Dr. Levine and Mr. NeuenREV 2 schwander’s comments, saying, “The iniREV 3 tial units should be part ofREVa4broader plan REV 5 according to and timeline to implement REV 6 best practices in all units housewide.” 7 The eMAR objective REValso presents REV 8 opportunity for highly variable methods REV 9 of measurement. The proposed rule calls for measurement of orders administered, but Dr. Malone suggested that doses, rather than orders, would be a more precise measuring denominator. BCMA applications commonly record scanning compliance as a percentage of admin-

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istration events relative to the number of doses. Because multiple doses often are given against one order, the rule’s measurement exposes uncertainty when an order is initiated for a patient on a nursing unit that uses eMAR and then transfers to another unit that does not. Dr. Malone stated, “I can tell you from experience, thresholds such as these can be easily manipulated. Hospitals will benefit from more direction surrounding who measures, how they measure, and when they measure.”

when it comes to learning the bar-code technology ropes, there is a resource that focuses solely on the topic”—the unSUMMIT. Through its annual meeting and virtual programs, the unSUMMIT facilitates networking among health care systems in various stages of bar-code technology use, uniting nursing, pharmacy, and IT around the topic. The next unSUMMIT annual meeting will be held May 2-4, in Anaheim, Calif.

Get Paid To Do the Right Thing, The Right Way

CMS is accepting comments on the proposed rule no later than 5 pm on May 7, 2012. You may submit comments electronically or by regular mail. To submit electronic comments, go to http://www. regulations.gov/#!submitComment;D=C MS-2012-0022-0001 and complete the form. You may also mail comments to: Centers for Medicare & Medicaid Services, Department of Health and Human Services, Attention: CMS-0044-P, P.O. Box 8013, Baltimore, MD 21244-8013. If your institution has seen positive results with BCMA, please take the time to comment on the proposed rule. The submission process is simple and only takes a few minutes. Be sure to share specific findings that demonstrate safety benefits that your institution has realized with BCMA. Your input will go a long way toward creating safer pointof-care systems.

Hospitals that attested to stage 1 meaningful use in 2011 have until fiscal year 2014 to meet stage 2 criteria— a 1-year extension beyond the previous timetable. All other hospitals are required to demonstrate 2 years of stage 1 meaningful use, then 2 years of stage 2 meaningful use. This schedule allows hospitals sufficient time to implement BCMA in such a way as to maximize the safety benefit with careful attention paid to caregiver workflow. “Bar coding at the point of care is the right thing [to do], but it must be done the right way,” said Mr. Neuenschwander, adding, “The body of literature on barcoding best practice is developing, and there are hundreds of hospitals willing to share their lessons learned.” Indeed, pharmacy informatics blogger, Jerry Fahrni, PharmD, stressed the importance of gathering tips from peer experience when planning a BCMA implementation. “Historically, the sad truth has been that hospitals reinvented IT wheels time and time again because forums for peer-topeer education have been limited to large one-size-fits-all industry events. But,

Don’t Miss the Opportunity To Comment

Jamie Kelly is the president of Entropy Research, Inc, a marketing firm serving the life science industry. Ms. Kelly is the co-founder of the annual unSUMMIT for Bedside Barcoding educational conference (www.unsummit.com). She may be contacted at jkelly@entropyresearch.net.

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