Dr. Vanderveen: Ten years after the Institute of Medicine(IOM) report, To Err Is Human, do quality and especiallysafety still have traction within our healthcare system?

Dr.Wachter: I think what we’re seeing is a revolution. There areno signs of anything but continued acceleration and pressure toimprove quality and safety. Prior to 1999 there was no incentiveto work to improve safety other than professionalism and ethics.Those are powerful incentives, but not powerful enough tochange the system the way it needed to be changed.

In the last nine years, we’ve seen tremendous pressure comingfrom many fronts, whether it’s accreditation, information tech-nology, the regulatory environment, or transparency. It’s working

22 Patient Safety & Qual i ty Healthcare ■ July/August 2009 w w w . p s q h . c o m

What Is and Is Not Working

By David W. Bates, MD, MSc; Robert M. Wachter, MD;

and Tim Vanderveen, PharmD, MS

MEDICATION SAFETY TECHNOLOGIES:

lmost ten years ago, the Insti-tute of Medicine report, To Err IsHuman (2000), galvanizedhealthcare, patients, Congress,

and the media to pay attention to the prob-lems of patient and medication safety. Inthe years that followed, hospitals madeenormous investments to improve prac-tice and implement safety technologies.How far have we come? Where are wenow? Is there any way to anticipate whathappens next?

To help hospital leaders and clinicians answer criticalquestions about safety, on September 26, 2008, Drs. Batesand Wachter, two of the world’s leading experts on medi-cation safety, shared their perspectives in a nation-wide,interactive audio conference that drew listeners from morethan 1,100 sites across the United States. The 90-minuteprogram and Q&A was made possible by an unrestrictededucational grant from the Center for Safety and ClinicalExcellence. Tim Vanderveen, PharmD, vice president of theCenter, posed key questions and served as moderator. Thefollowing interview is taken from that presentation.

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The difficult question is who will pay for it? I think it’s goingto end up mostly being the hospitals. The payers have notshown much appetite for paying hospitals to make thesechanges, with some exceptions. For example, they have beenwilling to provide some incentives to hospitals that adopt cer-tain technologies. More of that would be helpful. But I thinkhospitals are largely going to have to sort through the equationfor themselves, and think about whether or not each of thesethings will pay off for them and over what timeframe.* TheCenters for Medicare and Medicaid Services (CMS) is increas-ingly less willing to pay hospitals for adverse events, and thatcould also change the way that hospitals think about this.

Dr.Wachter: The issue of measurement is incredibly important.David has been the world’s leader in trying to define the numberof medication errors and their patterns.As he notes, it is awfullyhard to measure them.

The difference between quality and safety is often subtle, butI think this is one area where the difference is profound. Bylooking at administrative data or reviewing charts, I can easilydetermine whether a patient with a heart attack was givenaspirin or a beta blocker, or what their door-to-balloon timewas for an angioplasty. But from that kind of review I reallyhave no good way to figure out whether there was a medicationerror, a handoff error, or virtually any kind of error.

Strategies such as transparency and putting perfor-mance information on the Web work surprisingly well inquality, because the data can be collected in a fairly stan-dardized way and posted for everybody to see. That seemsto generate change.

Those strategies don’t work very well in safety, because wedon’t have the same ease of measurement. For example, if atone hospital the number of incident reports in the last year hasgone up by 20%, what do they say? “Terrific. This shows we’vegenerated this culture of safety, the reporting system is work-ing, so we’re getting safer.”At another hospital incident reportshave gone down 20%. What do they say? “We’re getting safer;there are fewer incidents being reported.”We don’t know whichis true. This measurement problem, which might seem a littlebit arcane and wonkish, turns out to be extraordinarily impor-tant as you search for policy interventions to make safetyimprovement work.

In terms of the dominant tensions in the field, I think we’rein an incredibly interesting phase. After the initial IOM report,the mantra was mostly “No blame.” We now know that mosterrors are committed by good, competent people trying to dothe right thing. The right strategy is not to blame them, becausethat pushes the errors underground and we don’t learn fromthem. But the mantra now is “accountability,”meaning that it’ssomebody’s fault if we don’t fix this. How do you reconcile “noblame” with “accountability”?

I think the answer is that “no blame” remains the appropri-ate strategy for frontline providers who slip and make mistakes

little by little, but it’s harder than I think people thought it wouldbe. We’re seeing some missteps, overreaches, and unanticipatedconsequences. But there’s no question in my mind that the safetyand quality movements are for real, and that the pressure to get itright is only going to accelerate. To me that’s a good thing.

Dr. Vanderveen: The IOM report recommended severalthreshold improvements, including a 50% reduction inmedical errors in five years. Almost ten years later, what isyour report card on meeting the IOM goals?

Dr. Bates: With respect to the 50% reduction, the truth is thatwe don’t really know, because we don’t have good metrics forsorting out how common medical errors are in most institu-tions. We do know vastly more about the epidemiology of safe-ty than we did, and hospitals are starting to take the steps that itwill take to substantially improve safety.

Safety is a lot higher on the priority list of hospital leadersand of boards than it was eight or ten years ago. A nationalstudy done around that time showed that safety was somethinglike 57th on the priority list of a large group of hospital CEOs.Now when our CEO talks with the key supporters of our hos-pital and our board, safety is right at the top of the list. We’remaking progress; we just haven’t really figured out exactly howto measure that progress.

Dr. Vanderveen: Your study from 1995 showed that pre-scribing was associated with 39% of medication errors;transcribing, 12%; dispensing, 11%; and administration,38%. Typically only 2% of errors in the administrationphase would be detected. Do you think these statistics havechanged?

Dr. Bates: In hospitals that have implemented computerizedprescriber order entry (CPOE), I would suspect that the propor-tion of errors related to prescribing would be smaller and cer-tainly the percentage related to transcribing would be minimal.The same is true for technologies that improve the safety of dis-pensing and administration. But we don’t have many recent,comparable studies in hospitals that have these technologies inplace. Doing some studies like that would be very interesting.

Dr.Vanderveen: Is it possible to change the system as it relatesto the medication use process? If so, who will pay for it?

Dr. Bates: I definitely think it’s possible to change the system.When we started our studies, technologies such as CPOE, bar-coding, smart pumps and monitoring for adverse drug eventseither did not exist or were used in only a few places. All thosetechnologies can dramatically change the game in this area.Another frontier is medication reconciliation, bringing in datafrom outside the hospital to the point of care so that it is avail-able to providers.

July/August 2009 ■ Patient Safety & Qual i ty Healthcare

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because they’re human. But it’s very clear that the public hasabsolutely no appetite for “no blame”being the dominant phi-losophy when they look at a hospital and figure out that thereare too many medication errors, people aren’t washing theirhands, or you name the safety hazard. The dominant modelthat we’re going to be operating under is one of intenseaccountability, with more public reporting, more transparen-cy, and more accreditation pressure.

Who’s going to pay to do all of this? I believe David is com-pletely right. It was a pipe dream that somebody would swoopin with a big pot of cash and say,“We understand your plightand here’s extra money for you to computerize, do safety train-ing, or buy simulators.” That’s not going to happen.*

The hospitals will pay for this when it becomes in theirinterest to do so.All the hesitations about computerization seento melt away when it becomes more expensive not to be com-puterized than to be computerized. How does that happen? Payfor performance might get us part of the way there. But whenyou’re under intense regulatory pressure and are reporting allyour errors to the state, if you have a major medication error,the state will come in. To fix it, a hospital may have to hire 50full-time-equivalents (FTEs) of people to scrutinize every doc-tor’s order to be sure that nobody used an unapproved abbre-viation. At some point it becomes cheaper to have CPOE.

That’s the environment that we find ourselves in. If you lookat all of the pressures on hospitals, many are designed to shiftthe business case, to make it in their financial interest to focuson safety in new ways, whether that’s training, staffing, or com-puterization.

Dr. Vanderveen: Dr. Wachter, recently you wrote that yourpriorities on implementing patient safety technologies hadchanged. Can you share some of the thinking that led toyour commentary?

Dr. Wachter: I’ve been thinking a lot about this over the pastcouple of years. I consider myself an amateur in this, and Davidis a pro. But here is what I’ve seen.

Until the last year or two, the recommendation I heard wasthat if you were going to stage your implementation of com-puterized technologies, CPOE should come first. It delivers thebiggest bang for the buck, it’s the master technology, and oth-ers should follow. That made a lot of sense. But I think part ofthe reason CPOE was positioned first was that most researchersin safety generally, and in medication safety in particular, havebeen physicians. To them prescribing errors seem the most pal-pable.A doctor’s handwriting is sort of iconic as a cause of safe-ty problems. So it was natural to focus on the prescribingprocess as the key part of the problem. Obviously, it is extraor-dinarily complex and error prone. Not only are there issues inprescribing itself, but it becomes the scaffolding for computer-ized decision support—which may ultimately provide thebiggest bang for the buck of all.

Second, I began to realize that much of David’s work wasdone in the Brigham and Women’s Hospital, which has beenworking on computerization for almost a generation. Thequestion was, would their results translate to the rest of us whoare going to buy vendor systems, put them in, and turn themon? To my mind, that remains an open question, although Ithink David will help educate all of us.

Third, I think that developments other than CPOE mayhave made the prescribing process better and safer. Manyphysicians can easily look up drug interactions, doses, etc. ontheir PDA or smartphone. Also, to the extent that people arefollowing the National Patient Safety Goals such as eliminatingcertain high-risk abbreviations, prescribing has gotten safer,independent of computerization.

Finally, if you think about the medication management pro-cess, there are many opportunities for an upstream error suchas in writing a prescription to be caught downstream, perhapsby a pharmacist or by a nurse at the point of care. It seems thata disproportionate number of the most critical errors areadministration errors, e.g., giving a patient the wrong pill or anincorrect intravenous (IV) dose through a pump. I think it’spartly because there’s no one to catch those errors right at theend of the medication use process. I also began to think aboutthe extraordinary expense and complexity of implementingCPOE. Solutions such as smart pumps, barcodes, etc., are prob-ably easier to bite off than transforming the entire prescribingprocess.

Thinking about all of that—this is completely non-evidencebased, just one person’s musing—I might start with one of thepoint-of-care solutions, either barcoding or smart pumps, andwork out from there. I don’t know whether that’s right.

At the end of the day, of course, the whole medicationmanagement process has to be computerized and all thepieces linked together in a seamless way. Ultimately we allhave to have CPOE and barcodes and smart pumps, theyall have to weave together seamlessly, and there has to beterrific, embedded decision support. It’s not a question ofwhether you should implement one and stop. It really is aquestion of how do you get started?

Dr.Vanderveen: Dr. Bates, as someone who has been at theforefront of basically all the medication safety technologyand adoption, what are your thoughts on setting priorities?

Dr. Bates: I disagree with Bob a bit, although there is much weagree about, too. The older epidemiological studies of harm arethe principle reason that I disagree. Those show that most of theharm that comes to patients comes from prescribing errors ofvarious types.

I really don’t think that prescribing has gotten that muchsafer. We did a study in six community hospitals in the Bostonarea and found that the frequency of adverse drug events waseven higher than in the older studies and that many more of the

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adverse drug events were preventable. Especially importantissues were using drugs in patients with renal insufficiency andnot considering laboratory tests when prescribing to patients.The best evidence is for CPOE, especially compared to barcod-ing and smart pumps, where the evidence is much less strong.

I do agree that we still don’t have good evidence about theimpact of CPOE using vendor applications in settings such ascommunity hospitals. From an academic hospital, a number ofstudies that show that CPOE does a very good job at reducingmedication error rates. The evidence about preventable adversedrug events is still equivocal, because large enough studies havenot been done.

That being said, if I had a finite amount of money, the orderthat I would do things in would be CPOE, then barcoding orsmart pumps. But as Bob noted, in terms of ease of implemen-tation the order is quite different. Smart pumps are by far theeasiest of these technologies to implement. A number of insti-tutions were able to install them across the whole institutionover a 12- to 24-hour period. It took us a year to two to put inbarcoding, but the biggest challenge was to generate the capitalto do it. CPOE is by far the hardest to implement.

At the individual hospital level, I think that the choice ofwhich technology to do first depends a lot on your informationsystems, the assets you have available, and the cohesiveness ofyour medical staff. At the end of the day, you want to do all ofthese. That’s really the important message.

It is going to be hard for hospitals to gather the necessaryresources. The price tag for each of these things is not inconse-quential, and they really should be linked. That has not beendone at many places today.

Dr. Vanderveen: What are your thoughts on the relativevalue, either proven or perceived, of safety measures suchas CPOE, pharmacy review, and drug/drug interaction soft-ware that are implemented further from administrationversus the “sharp end” safety measures such as positivepatient identification, barcode medication administration,and smart pumps?

How important is the need for evidence in adopting newtechnologies that often seem intuitive? For example, scan-ning a patient’s barcode wrist band and matching thepatient to the medication, or providing an alert that theinfusion pump is programmed to give a tenfold overdoseand preventing that.

Dr. Bates: For CPOE the evidence is now reasonably robust,although there are certainly many additional questions thatneed to be answered. How big is the benefit? What happensusing various vendor systems? What are the most importanttypes of decision support to include? To get the benefit that youwant with CPOE, you have to have a good bit of decision sup-port. I’ve worked with Leapfrog and First Consulting Group tohelp develop an evaluation for CPOE applications that will helphospitals assess their decision support (Metzger et al., 2008July/August). Many hospitals don’t have a good sense of how

much they have in place when they implement CPOE. It’s tricky,because if you put in too much at the beginning, that can affectadoption. The expert advice is to start with relatively little deci-sion support and then ramp it up. Pharmacy review has beenaround for awhile, and the existing evidence is reasonably com-pelling. It makes sense to just continue doing that.

Overall, I think the importance of drug/drug interactions isquite a bit overrated, in that hospitals will want to only show theones that are most important. If they show too many, that canreally create problems. It creates a lot of extra work for the phar-macy. If you do it with CPOE, it can even cause failed adoptions.There have been a number of those around the country, becauseit is possible to show too many alerts. That has a couple ofdownsides. People find it annoying. But second, it may makethem even more likely to overlook the truly important alerts.

The sharp end measures are also extremely important, inpart for the reasons that we talked about earlier. If you make anerror at the sharp end, it is going to make it through to thepatient. Smart pumps are especially important, because manyof the agents that are given by smart pump are especially likelyto cause problems. If you give somebody a tenfold overdose ofmany of the drugs used intravenously, it can be very bad. Ithink that many of those errors just were not detected in thepast and were written off to some other problem that thepatient was having.

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I do think it’s important to have evidence, even aroundadopting new technologies that seem intuitive. Hospitals havevery scarce resources and are desperately trying to prioritizethese various technologies—and not just the ones that we’vetalked about. Hospitals are also thinking about buying a newMRI scanner, a new PET scanner, etc. Having evidence to jus-tify the benefits of medication safety technologies is going to bevery helpful in getting hospitals to actually adopt them.

Dr. Vanderveen: Dr. Wachter, you recently wrote about the“hype cycle” of emerging technologies. Using CPOE as anexample, can you take us through the various stages, start-ing from the “Technology Trigger” and ending up at whatis called the “Plateau of Productivity”?

Dr.Wachter: The “Technology Hype Cycle”(Figure 1) was pop-ularized by the consulting company, Gartner, a few years ago.CPOE is a pretty interesting example, in that it is followingalong that curve. The technology was developed in the late ’60sor early ’70s and began to get hyped fairly quickly, in partbecause it’s a compelling story. It makes a lot of sense to peopleand it should work. The early research on it by David and otherswas extraordinarily positive and led people to feel that this tech-nology is absolutely essential and works quite well. The endorse-ment of CPOE in 2002 by the Leapfrog Group as one of threesafety standards may have been the height of that cycle, when itwas being promoted by a national organization as a “musthave.”

New technologies tend to follow a predictable path.Tremendous initial excitement surrounds the launch, but fewtechnologies live up to this hype, meaning that the peak isinevitably followed by a trough. But if the technology is anygood, some hearty individuals and organizations will say,“Thisis probably not as good as it looked in phase two (the peak ofthe hype), but it’s not as bad as it looks in phase three (thetrough of disappointment). Let’s keep working on it, let’s refineit, let’s improve the technology, let’s do research to demonstrateits value.” Technologies that make it through the cycle end upin a realistic, useful place where they get adopted, because theyactually are making the world a better place. This process hasalready been seen with CPOE, and a similar progression will beseen with barcoding, smart pumps and other new technologies.Knowing the cycle can enable you to anticipate the next phase.

Over the last four or five years as we look at the literature,CPOE is going through a bit of the trough. The much-cri-tiqued study out of Pittsburgh Children’s Hospital that showedan increase in mortality rate after the adoption of CPOE waspart of that. Literature in the last several years about unintend-ed consequences, workarounds and the experiences of organi-zations that have had difficult or failed implementations haveall led to some disillusionment with the technology. And thetechnology itself needed to improve.

Frequently as part of this cycle, the initial technology onlygets better after people work on it and get feedback from users.I think we’re now entering these last two phases where people

are more realistic about how challenging it is to implementCPOE. The systems are getting better, hospitals are having suc-cessful implementations, beginning to talk about that, and theresearch is getting better. So I think we’re on our way towardthe Plateau of Productivity. As you look at the implementationnumbers, you see they’re beginning to go up more and morewith the quality of the systems.You’re starting to see some con-solidation in the industry, and the winners are developing bet-ter systems, far more user-friendly than ones introduced evenas recently as five years ago.

What is interesting to me about the cycle is that you can playit out with almost any technology. I think we’ll see similarthings with barcoding, smart pumps, and other new technolo-gies that are coming down the pike. It’s worth knowing thecycle because you can anticipate the next phase.

Dr. Vanderveen: What are some of the lessons learnedabout the successful implementation of technologies suchas smart pumps, which add new capabilities to replacepumps that have been in use for over 40 years, and of oth-ers such as BCMA and CPOE that are completely new?

Dr. Wachter: The lessons often relate to the challenges of theinterface between human behavior, human frailty, and technol-ogy. Some of the key lessons are that everything is harder than itappears to be when a technology is being used by the pioneers.Early studies are done at selected places with people that are verypassionate about the technologies and everybody is onboard.Those results often outstrip what you see when a technologygets rolled out nation-wide.

We’ve learned that initial budgeting for implementing tech-nologies such as CPOE was inadequate. People didn’t reallyunderstand the importance of having backup systems anddecision support and of educating everybody. The budget hasto include not just the people on staff today but all the newnurses, travelers, and possibly residents every year. I think peo-ple have gotten much more realistic about budgeting for thecosts of these sorts of things and for decision support.

People have also become much more realistic about antici-pating “unanticipated consequences” that are completely pre-

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MEDICATION SAFETY TECHNOLOGIES

Figure 1. The Technology Hype Cycle (Gartner, Inc.)

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dictable. There is recognition now that there is an engineeringaspect to technology implementation and a socio-culturalaspect. A new technology or a new process can look really goodwhen you’re sitting in a conference room or in your laboratorydeveloping it. But it is absolutely critical to go to the workplaceto see what happens when users try to implement it. Moretimes than not, you see workarounds and unintended conse-quences.You have to be open to what you can learn from mon-itoring user behavior in adopting the technology.

Dr. Bates: I would largely agree. I hope with respect to CPOEthat we are through the Trough and heading up towards thePlateau. I think the key thing that came out of the Han studyfrom Pittsburgh (2005) was that if you implement badly, it canhave serious consequences. There are lots of questions aboutthat study, but the mortality rate amongst kids who were trans-ferred in actually went up after implementation of CPOE (Han,2005). Subsequently, another site used exactly the same com-mercial application, did the implementation better, and themortality rate went down (Del Beccaro, 2006). The decrease wasnot statistically significant but was certainly clinically significant.

Some of the messages that I take away from the unintendedconsequences literature are that it is absolutely essential to mea-sure the new problems that you create and have a systematicapproach to going through and fixing those in an ongoing way.For example, at one time or another we had virtually all of theissues with CPOE at the Brigham that Ross Koppel noted at theUniversity of Pennsylvania (2005), but we’d gone through andwe fixed them.

Looking back, I have to say that we didn’t devote enoughresources at the beginning to do that sort of thing. Our thoughtwas that we would be able to take the technology, put it in, andthen be done and move on to other things. With CPOE, any-way, that’s not the way that it works. With some of these othertechnologies, you don’t have to do quite as much on an ongo-ing basis, but you have to maintain all of them. ❙PSQH

This discussion continues at www.psqh.com, where Drs. Bates,

Wachter, and Vanderveen discuss smart-pump data and CQI, drug

libraries, unintended consequences, diagnostic errors, never events, the

role of public reporting, transparency, and other aspects of medication

safety technologies.

David Bates is chief of the Division of General Medicine at Brighamand Women’s Hospital, Boston, and one of the most prolificresearchers in medication safety. He has been a leader in helpinghospitals understand the nature and frequency of medication errorsand the impact of various technologies that help to address errordetection and prevention. Bates and his colleagues have publishedextensively on virtually every medication safety technology, includingCPOE, smart pumps and barcode medication administration.

Robert Wachter is chief of the Division of Hospital Medicine andMedical Service at UCSF Medical Center, San Francisco. Wachter iscredited with founding the Hospitalist specialty, the fastest growingspecialty in medical history. He has published two books on patientsafety, Internal Bleeding: The Truth Behind America’s Terrifying

Epidemic of Medical Mistakes and Understanding Patient Safety,and writes Wachter’s World (http://www.wachterworld.org/) one ofhealthcare’s most widely read blogs.

Tim Vanderveen is vice president of the Center for Safety andClinical Excellence. He is responsible for ensuring Cardinal Health’scommitment to education and innovation to reduce variation inclinical practice, and to supporting hospitals’ patient safety initiatives.Prior to this position, Vanderveen was the director of clinical affairs,medication management systems, for ALARIS Medical Systems. Hehas been instrumental in the development of many of the innovationsand safety and performance enhancements in drug infusion.

Vanderveen served a hospital pharmacy residency at BronsonMethodist Hospital in Kalamazoo, Michigan. From 1972 to1983 hewas on the faculty of the College of Pharmacy at Medical University ofSouth Carolina and was Director of the Division of Clinical Pharmacy.He also had a faculty appointment in the College of Medicine and wason staff at the Charleston VA Hospital. Vanderveen received his BS andMS degrees from Purdue University School of Pharmacy and hisPharmD degree from the Medical University of South Carolina. Hemay be contacted at tim.vanderveen@cardinal.com.

Bates, D. W., Leape, L. L., Cullen, D. J., Laird, N., Petersen, L. A.,Teich, J. M., Burdick, E., et al. (1998, October 21). Effect ofcomputerized physician order entry and a team intervention onprevention of serious medication errors. JAMA, 280(15), 1311-1316.

Del Beccaro, M. A., Jeffries, H. E., Eisenberg, M. A., & Harry, E. D.(2006, July). Computerized provider order entryimplementation: no association with increased mortality ratesin an intensive care unit. Pediatrics, 118(1), 290-295.

Gartner, Inc. Stamford, CT. http://www.gartner.com/ (accessedMarch 5, 2009).

Han, Y. Y., Carcillo, J. A., Venkataraman, S. T., Clark, R. S., Watson,R. S., Nguyen, T. C., Bayir, H., Orr, R. A. (2005, December).Unexpected increased mortality after implementation of acommercially sold computerized physician order entry system.Pediatrics, 116(6), 1506-1512.

Institute of Medicine. Committee on Quality of Health Care inAmerica. (2000). To err is human: Building a safer healthsystem. L.T. Kohn, J. M. Corrigan, & M. S. Donaldson (Eds.).Washington, DC: National Academy Press.

Koppel, R., Metlay, J. P., Cohen, A., Abaluck ,B., Localio, A. R.,Kimmel, & S. E., Strom, B. L. (2005, March 9). Role ofcomputerized physician order entry systems in facilitatingmedication errors. JAMA, 293(10), 1197–1203.

Metzger, J. B., Welebob, E., Turisco, F., & Classen, D. (2008,July/August). The Leapfrog Group’s CPOE standard andevaluation tool. Patient Safety & Quality Healthcare, 5(4),22–25.

Metzger, J. B., Welebob, E., Turisco, F., & Classen, D. (2008,September/October). Effective use of medication-relateddecision support in CPOE. Patient Safety & Quality Healthcare,5(5), 16–24.

Poon, E. G., Cina, J. L., Churchill, W., Patel, N., Featherstone, E.,Rothschild, J. M., Keohane, C. A., et al. (2006, September).Medication dispensing errors and potential adverse drugevents before and after implementing bar code technology inthe pharmacy. Annals of Internal Medicine, 145(6), 426-434.

Rothschild, J. M., Keohane, C. A., Cook, E. F., Orav, E. J., Burdick, E.,Thompson, S., Hayes, J., & Bates, D. W. (2005, March). Acontrolled trial of smart infusion pumps to improve medicationsafety in critically ill patients. Critical Care Medicine, 33(3),533-540.

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