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