For digoxin, simple fix
  to stubborn problem

July 2005
Cover Story

Laboratories have long relied on a dubitable practice when measuring digoxin levels. In this, they appear to have borrowed a page from the infamous Richard J. Daley, the Chicago mayor who repeatedly returned himself to office using a "vote early and often" scheme to steer the residents of his city; labs, taking the same approach, are consistently drawing and testing samples early, before equilibrium is reached.

Does it work?

Daley ruled his city with a czarist fist. Skyscrapers shot up, blight was kept at bay, and many (mostly white) residents found that their city hummed along quite nicely. On the other hand, "shoot to kill," the Chicago Seven, and corruption will forever be linked with his 21-year reign. One thing no one argues with—Daley could not be ignored.

That’s hardly the case with digoxin, though it’s arguably more dangerous to ignore the drug than the mayor. Toxicity is a serious complication, and therapeutic and toxic levels overlap. There’s a reason it was part of the arsenal of an East Coast nurse when he poisoned dozens of patients with intentional drug overdoses. But a disturbing pattern of laxity has settled over the way this drug is monitored.

How bad is it? A recent Q-Probes found that three out of five specimens with toxic digoxin levels were drawn at inappropriate times. "This means that most of the levels that come back elevated are noise; theyre not signal," says Frederick Meier, MD, one of four co-authors of "Patient Safety with Digoxin Measurements." "So what happens at best is the clinician ignores it." That’s hardly a great "best"—the lab runs a test, then hopes the results will be disregarded.

At worst, Dr. Meier says, a diagnosis of digoxin toxicity is delayed even when the high level is valid. "They assume an elevated dig level is an artifact. They assume it’s noise," says Dr. Meier, senior staff pathologist, Division of Anatomic Pathology, Henry Ford Hospital, and division head, system laboratories, Henry Ford Health System, Detroit. That played out in a horrific worst-case scenario for a handful of hospitals in New Jersey and Pennsylvania, where nurse Charles Cullen admitted to killing more than 40 patients, often using digoxin, starting in the late 1980s.

Cullen clearly was unhinged. He drifted from one institution to another—10 over a roughly 16-year period—and fell through every last crack in the medical, criminal justice, and mental health systems before being arrested in late 2003.

High digoxin levels weren’t an immediate signal that something was amiss at the institutions where Cullen worked. Nor are they the red flag they should be at many hospitals. Instead, a banner of indifference seems to hang over digoxin, and has for years.

The current Q-Probes adds numerical heft to the issue, looking at 59 institutions and data from 1,571 outpatients. More than 20 percent of the time (22.2 percent), the median institution collected digoxin specimens less than six hours after dosage. When a more stringent time was used—less than eight hours after digoxin ingestion—the rate of incorrect collection rose to 34.3 percent for the median institution.

The immediate question is, Why does the report use two different numbers to define the appropriate time for specimen collection? The answer: They reflect two sides of a debate. Some studies say six hours is fine; others say eight. Most of these studies—and there aren’t that many—date from the 1970s. Given the scant and dated information available, it’s difficult to make a specific recommendation. Says co-author Paul Valenstein, MD, pathologist at St. Joseph Mercy Hospital, Ann Arbor, Mich., "We didn’t want the study to lose its impact because somebody believes six hours is the right cutoff while we used eight in our study, or vice versa. So we analyzed the data using both cutoffs. Either way, there’s a lot of room for improvement."

What strikes all four authors is the lack of improvement since a previous Q-Probes (Howanitz PJ, et al. Arch Pathol Lab Med. 1993;117:684-690). That study, done in 1991, looked at inpatients as well as outpatients. But it’s not an apples/oranges comparison by any means. That first report noted that outpatients were more problematic than inpatients, notes Peter J. Howanitz, MD, an author on both reports, which was the reason for the more sharply focused second study.

One of the surprises is that even though the problem was clearly identified years ago, few institutions have placed solving it on their to-do lists, says Dr. Howanitz, director of clinical laboratories, State University Hospital, and vice chairman and professor of pathology, State University of New York Downstate Medical Center, Brooklyn. "As you look through the data, you’ll see that with almost all those specimens that were drawn at the wrong time, laboratories knew they were drawing them at the wrong time."

"It’s a major problem," he adds. "We would have hoped in 14 years that some progress would have been made."

Indeed, says Dr. Meier, the problem appears to have worsened. In the first study, nearly 25 percent of toxic specimens were obtained in less than eight hours, versus the aforementioned 34.3 percent in the recent survey.

Equally disturbing are the rates at which levels stray out of therapeutic range. In aggregate, four percent of digoxin measurements were above therapeutic range and considered toxic. Of these, more than 60 percent were collected at inappropriate times.

On the other end, 33 percent were below therapeutic range, and at least 19 percent of such levels occurred less than six or less than eight hours from the digoxin dose. Says Dr. Meier, "I do wonder whether that underdosing is because physicians inappropriately fear that they have overdosed patients." Dr. Valenstein adds, "Some people are going to be denied the benefit of digoxin. And unlike many therapies in medicine, digoxin is of proven benefit."

How did things get so bad?

The Q-Probes traces the problem, in part, to the longstanding practice of giving hospitalized patients digoxin in the morning, after physicians made their rounds. As the report notes, true values of digoxin blood levels exist once the drug is distributed between the vascular and tissue compartment, which takes at least six to eight hours. So a patient who adheres to the traditional morning dosage runs the risk of having his or her blood drawn too early.

While that may explain the root of the problem, it doesn’t explain why it’s so intractable. The Q-Probes study does not address that either, given that it didn’t explore the psychology behind current practice. "We didn’t probe what people were thinking, just what they were doing," says Dr. Valenstein, who also chairs the CAP Quality Practice Committee. But there’s no shortage of opinions about why the problem persists.

Responsibility for accurate digoxin tests gets bobbled like a grenade.

"It’s a place where laboratorians have decided not to tread," says Dr. Howanitz. He recalls that after the 1991 digoxin study, he and his lab colleagues at the hospital where he was then working looked into their own practices. "We found the kinds of problems you would expect. There were a lot of errors. And then we called physicians about this and started notifying them, and a good number of them became very hostile. They told us we were telling them how to practice medicine." Early resistance to therapeutic drug monitoring may still be sending out ripples.

"Clinicians often insist that the samples be tested, even though the specimen was not properly collected," says Ana Stankovic, MD, PhD, MSPH, another co-author. "They sometimes think that any type of number is better than no number at all." But clinicians may never have been taught the finer points of digoxin testing, she says, and laboratories have yet to turn clinicians’ heads when it comes to preanalytic variables. Clinicians may be superficially aware of the six- or eight-hour rule but may assume it’s just another "quirk" on the lab’s part, "like requesting specimen transport on ice or in a particular tube," she says. "They don’t realize how important it is," says Dr. Stankovic, worldwide medical director, BD Diagnostics, Preanalytical Systems.

If laboratories are reluctant to challenge clinicians, they’re just as hesitant to disoblige patients by having them return at the appropriate time. "We serve at the convenience of the patient," Dr. Howanitz says. "If you refuse to draw the specimen, what does that do between the physician and their patient?" On the other hand, he muses, the median age of patients taking digoxin is 78, according to the Q-Probes, and it’s possible that senior patients may be less upset by testing delays than patients with busier schedules. "They may be very comfortable having laboratories taking a much more active role in delaying drawing the blood and asking these patients to come back than we ever thought," he says, "because the majority are retired. They don’t have very much else to do."

"I think times have changed," says Dr. Howanitz. "We must get involved and do this."

The solutions are there. Dr. Meier points to the tremendous range among the best- and worst-performing institutions. On the low end, four out of five specimens were collected in less than eight hours. In the best 10 percent, that number falls to one in 100. That suggests there are behaviors that work.

Yet they’re rarely carried out, if the Q-Probes numbers are any guide. Of the 1,556 levels analyzed, a third are subtherapeutic, one in 20 are "toxic," and less than two-thirds are therapeutic, says Dr. Meier. "We’ve got a problem. This is a measure of poor quality of therapy."

It feels like warning bells should be going off, alarms sounding. "Well, there are a lot of inside observers who feel the same way," says Dr. Meier.

It’s the kind of situation that could be considered ripe for plucking by the mainstream media. In fact, it happened, though tangentially, when The New York Times wrote a lengthy exposé tracing Charles Cullen’s deadly journey through the health care system.

At one institution, the Times reported, Cullen became a target of suspicion when blood tests on at least two patients revealed high levels of digoxin, though they had not been prescribed the drug according to the Times; one recovered but died three months later, and one died the following morning.

The hospital’s director of medicine at the time was, understandably, less than enamored of the coverage. The authors of the article, which ran Feb. 29, 2004, wrote that at this hospital "abnormal digoxin readings and indications that nurses took the incorrect medications were everyday occurrences," according to the administrator, who asked that his hospital not be identified in CAP TODAY. It also quoted him as saying, "The information we were receiving concurrently really didn’t stick out like a sore thumb and say, ’Charles Cullen is a problem.’"

He complains this account unfairly criticized the hospital’s lack of response to elevated digoxin levels, implying that such levels were "a once-in-a-lifetime occurrence," as he puts it. "What I was trying to explain to them was in any given month, we have hundreds of digoxin levels, some of which are subtherapeutic, some of which are slightly above normal—we don’t necessarily jump just because of that," he told CAP TODAY. Still, he says, the high levels of digoxin reported for several patients did trigger a critical value alarm.

The Cullen case can be seen as a dreadful exception, as can the level of scrutiny it received. It may, however, also serve as useful, if unintentional, guidance. By focusing on the exceptional aspects of the case, the Times overlooked an important question: Do false toxic digoxin levels suggest a more serious problem? Anyone who digs a little deeper—maybe by looking at the recent Q-Probes—would learn some unsettling answers, as well as some possible solutions.

Two success stories are worth a closer look, although the men who helped spark them are cautious about discussing their deeds, one because of the future, one because of the past.

The Q-Probes cites the University of Pennsylvania Medical Center, Philadelphia, which managed to eliminate ill-timed digoxin tests by making a simple switch—dosing patients in the evening.

"Simple" being a relative term, many pathologists would argue that this broad approach—one involving clinicians, pharmacists, nurses, and administrators—looks good only on paper.

Actually, it looks stunning on paper, in a study published in Clinical Chemistry (Bernard DW, et al. 1996;42:45-49). But it also works exceptionally well in practice. At the University of Pennsylvania, the change was triggered by the lab, which suspected it had an insupportable number of elevated digoxins. A resident reviewed the charts and discovered, among other things, that the drug was dosed at different standard times throughout the hospital. "We unwittingly were set up for this worse-case scenario," says Leslie Shaw, PhD, professor and director of the center’s clinical toxicology laboratory, Department of Pathology and Laboratory Medicine. Gathering more data confirmed initial impressions: Drawing specimens too early was causing too many wrong results.

The laboratory eventually presented its data to colleagues in pharmacy, nursing, and cardiology. The group "came up with a surprising—to me—solution," says Dr. Shaw, a co-author of the Clinical Chemistry paper. "And that is, the best time to dose digoxin in this hospital would be at nighttime."

Since then, inappropriately timed digoxin tests have been eliminated, both for inpatients and outpatients, Dr. Shaw says. And all of it was triggered by the laboratory’s suspicions about elevated digoxin levels. "Can you imagine?" he says, still sounding delighted. "From a lab exercise, changing a policy of dosing practice. It blew me away."

For all his success, Dr. Shaw is reluctant to talk about the digoxin transformation at Penn. In fact, his initial response to an interview request from CAP TODAY was to insist that the discussion move beyond digoxin and focus on broader therapeutic drug monitoring, or TDM, issues.

Dr. Shaw is uneasy directing the spotlight toward digoxin because, as he says, "In the year 2005, we’re way past digoxin for a lot of reasons." A conversation with him is a challenging but rewarding wrestling match that forces the mind to absorb the past and future simultaneously. It’s akin to viewing old paintings of biblical figures mingling with contemporary ones, like John the Baptist picnicking with 16th-century Flemish folk, or Mary and the infant Jesus surrounded by members of the Medici family and a pope or two.

Digoxin was one starting point for expanding TDM efforts at Penn, Dr. Shaw acknowledges, and it would be an excellent starting point for other labs as well. But, he argues, labs must look beyond digoxin and adopt a panoptic view of TDM. In this he is relentless, a one-man press gang. Laboratorians have no choice but to become more comfortable with their interpretive duties and doing pharmacokinetic consultations, he says. "Is it a piece of cake? No. It’s not a piece of cake to start something new. Is it a piece of cake to think that physician acceptance will be automatic? No. Is it worth doing nonetheless? Yes," he says.

Dr. Shaw has other grounds for de-emphasizing digoxin. "The field of congestive heart failure has moved so far in terms of therapeutics—digoxin is no longer the medicine of choice," he says.

Angiotensin-converting enzyme inhibitors, along with diuretics, have become a mainstay of CHF treatment plans and may be the most beneficial, he says, although digoxin still has its role. Indeed, an article by Robert McKelvie, MD, in Clinical Evidence (2004;112:115-143) suggests that digoxin improves morbidity in patients already receiving ACE inhibitors and diuretics, according to Dr. Meier. And Dr. Howanitz agrees that digoxin has become less widely used, though he notes that its use has fluctuated over the years. "It may be that it will have a rebirth in the future," he says. But if the drift persists, digoxin may prove to be just a small part of TDM and CHF, the unruly oboe in a symphonic orchestra, given its intensive monitoring needs.

Digoxin’s part in atrial fibrillation is also drawing fresh scrutiny, says Dr. Shaw. The neurohormonal effects of the drug may be achieved by serum concentrations between 0.5 and 1.0 ng/mL, he says, citing The Digitalis Investigation Group (N Engl J Med. 1997;336:525-533), which showed an apparent increased risk of death as levels rose. Traditionally, the acceptable range has been considered to be between 0.8 and 2 ng/mL. "But today, the standard of practice is such that I’d be shocked if we saw lots of 1.5s and 1.8s and 2s," he says. (The recent Q-Probes does not distinguish the indications for digoxin among the institutions surveyed, and there’s no clear range recommendation, although the authors note that therapeutic ranges vary.)

Ultimately, Dr. Shaw wants to move beyond the digoxin debate—his primary goal is to have labs think liberally about their roles as clinical consultants. "I’m not trying to make a big deal out of it—but you can see there’s been a real change in practice, as far as what the target is for digoxin." Only by being serious clinical consultants will labs be aware of such shifts as they happen.

When wrestled back to digoxin, however, Dr. Shaw agrees that monitoring remains critical, and he applauds the Q-Probes. "I’m impressed with this study," he says. "They’re asking the types of questions you need to ask of any drug that’s monitored."

At the aforementioned hospital that employed nurse Cullen, personnel tiptoe around digoxin for other reasons. As the administrator there says: "We have made a lot of changes, and some of them we’re proud of and we can talk about it, and others, we’re being sued and we have to watch what we say."

When the laboratory and colleagues looked at the problem, says the medical director of the laboratory, they discovered not everyone knew of the minimum time requirement between dosage and timing of sample draw—instead, they assumed a linear relationship between dosage and timing. Nor was there a check in the computer system to track timing of the last dose. The hospital now requires a six-hour delay between dose and draw, both for inpatients and outpatients. The lab also has a program to review printouts of abnormal values, which may be less critical now that the six-hour rule is in place and Cullen is gone. "It may be closing the barn door after the horse is gone," says the lab’s medical director, "although I don’t know how much I can talk, because of the ongoing suits."

He praises the support of his administrators and colleagues as the hospital struggled to recover. "I am proud of what this hospital did, although it’s taken flak," he says.

Like the University of Pennsylvania, his hospital is looking at monitoring other drugs as well. But both began, in part, with digoxin. It could be an excellent kickoff for many hospitals, says Dr. Shaw, particularly since the Q-Probes report is so strong. It should give people the data they need to make much-needed changes, as was the case at Penn. "We had a resounding consensus," he says, because "from our data it was so obvious that there was a deficiency."

That’s precisely how the Q-Probes study should be used, says Dr. Howanitz. "Digoxin has always been the model for therapeutic drug monitoring, and pharmacokinetics is taught using digoxin as the model." Obtaining specimens at the right time for TDM is a problem for clinicians as well as laboratories, he notes. "And it’s one of the major problems that laboratorians must improve."

The calculations of safety and security are often simple and sober. Use a seatbelt and check the tire pressure regularly. Pay yourself first. Exercise. Use energy-efficient light bulbs.

In medicine as in life, however, the eye often drifts to more exciting activities. Just witness the Times coverage of the digoxin errors. "The errors capture the public’s attention, but not their cause," says Dr. Valenstein. Problems in medicine are traced back only as far as the error—and no further. "We don’t ask ourselves why we allowed a culture to develop that accepts errors as a normal part of doing business," he says. "Here we have a practice—allowing digoxin levels to be drawn at completely inappropriate times—that is guaranteed to create errors." But the adverse consequences occur far down the road. "And the solution—don’t draw patients too early—is embarrassingly simple and comes without any technological wizardry. So there’s no glamour in it, and patients suffer as a result," Dr. Valenstein says.

It’s time for labs to focus on the bland.

Dr. Valenstein argues that the more protection built into the system, the better. "Everyone would like their physicians to be all-knowing and people in the lab to be all-knowing, but the fact is, they aren’t. So we need protective systems that make up for our defective memories." Reminder steps might include having the pharmacy insert instructions telling patients when they should be tested for the drug; having the test requisition state X number of hours are required between testing and dose; and having phlebotomists ask patients the time of their last dose. "You want to give the patient a chance to do it right upfront. But having failed that, another check in the system at the time of phlebotomy "would be nice," he says.

Giving instructions to patients may or may not help—it’s difficult to tell from the Q-Probes. Providing instructions, written or oral, did not correlate with better performance. On the other hand, suggests Dr. Howanitz, providing instructions 100 percent of the time would probably improve matters somewhat; in the Q-Probes, 29.4 percent provided verbal and 43.4 percent provided written instructions, though there’s no way of knowing the quality of the counsel.

The Q-Probes notes that labs that routinely monitor digoxin did better than others, the only unambiguous cause-and-effect variable. "Attention to the problem improves performance," says Dr. Valenstein. He himself likes reminders at the time of phlebotomy, or systems that prevent phlebotomists from drawing blood if the last dose was too recent. The other factor that popped up as one associated with better performance was a tad weird—private not-for-profit institutions outperformed others, a link that hints at some other variable that still needs to be unearthed. "No patient looks up the corporate structure of their laboratory and says, ’Oooh, it’s a not-for-profit, I think I’ll wait a full eight hours before getting my digoxin level,’" Dr. Valenstein says. "Something else must be going on that we don’t know about."

Dr. Stankovic suggests shoring up the weak kinship between clinicians and pathologists. At smaller institutions—which were the majority of those surveyed in the Q-Probes—forging bonds may be difficult because smaller pathology staffs are so thinly stretched. Her solution: think big. A single community hospital may not be able to support a clinical pathologist, but groups of local laboratories could create a consulting service for the area. "We need to be a little bit more creative," she says. She also urges clinical chemists to take a cue from microbiologists, who work closely with infection control specialists at hospitals. "Clinical chemists need to partner with pharmacists to do therapeutic drug monitoring."

Even easier, she says, is simply making sure patients take digoxin in the evening. "There’s a really, really easy remedy to this situation," she says.

Dr. Meier also seeks simplicity. "If you just refuse to draw patients early, then you don’t have this problem."

Dr. Valenstein, who says he is "disturbed" by the poor Q-Probes showing, sounds like he has run out of patience. "Anytime you’re getting 60, 70, even 80 percent compliance with recommendations, that’s not very good," he says. He admires the labs that participated in the study— "and were willing to face this problem," he says. But he doesn’t admire performance levels in the lab industry. "This is medical care; we’re supposed to do better."

Karen Titus is CAP TODAY contributing editor and co-managing editor.