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POC in motion—the changing face of mobile testing June 2003 The future of point-of-care testing could yield a wide array of options
Widespread POC testing “would be the final triumph of consumerism,” says Larry Kricka, DPhil, professor of pathology and laboratory medicine and director of general chemistry, University of Pennsylvania Medical Center, Philadelphia. “This vision would perhaps see the demise of the central lab.” Thanks to microchip technology, he says, we might all carry a “personal laboratory” in our pockets that can monitor clinical indicators. Dr. Kricka and other experts participated in a March and April audioconference series presented by the American Association for Clinical Chemistry, which covered subjects ranging from the future of POC testing to using brain natriuretic peptide and troponin at the point of care. Widespread POC testing would require social, technological, and regulatory changes, Dr. Kricka says. POC testing is already expanding beyond the hospital, into physicians’ offices and the home. As micro technologies shrink the instruments needed for tests, consumers will do more of the tests themselves, and the results will be transmitted to physicians. Further into the future are implantable microlab devices. Personal laboratories, however, will not become commonplace unless they are convenient to store and to use. In particular, “people won’t want to stick themselves to provide specimens,” Dr. Kricka says, so less-invasive technology will be needed. In addition, consumers want “all-in-one tests,” for which they simply add a substance to produce a result. Micro technology “takes a complicated system from the lab and condenses it into something effective, easy, cheap, and small,” he says. Such technology already exists, as with the GlucoWatch, which is worn on the wrist and uses an electrode-based biosensor to sense glucose through the skin and produce a reading. Another example is the Persona contraceptive system, used by a woman to identify her fertile period. The GlucoWatch and Persona represent “micro miniaturization of extremely complicated tests,” Dr. Kricka says. Handheld instruments used by labs, such as the i-Stat portable analyzer, which contains a silicon chip with reagents for a series of tests, could conceivably be used by consumers someday, he adds. Other industries are also using chip-based assays. One example is a combination gas chromatograph, acoustic wave sensor, and preconcentrator that tests air for biowarfare agents. “The fruits of this technology will be available for medical use,” Dr. Kricka predicts. Consumers might want a personal lab menu to include common chemistry, immunoassay, genetic, and proteomic tests. The latter two are difficult to run and remain the “exclusive domain of central labs,” but that could change, Dr. Kricka says. Convenient genomic testing, he adds, will be needed for pharmacogenomics—tailoring drug therapy to individual genetics. In this case, the personal lab could be used in a physician’s office to perform a genetic test to determine which drug should be prescribed. “This is one of the most compelling reasons to do POC tests,” Dr. Kricka says. “It’s a win-win-win. The doctor prescribes the correct drug, the patient gets a drug that works, and the pharmaceutical company finds its drugs used effectively.” Dr. Kricka described how a POC genetic test could work using existing technology. “All the components are there already,” he says. The blood sample could be drawn via a laser or microneedle and then applied to a chip that isolates the white blood cells and performs PCR. The resulting products could be run through a microchip with channels to separate out the DNA and look for a particular fragment or fragments. Personal labs will not only run tests but also provide a portable medical record. “The personal lab could have a wireless download to a virtual doctor,” says Dr. Kricka, “where someone would look at the results and suggest courses of action.” Before this brave new world arrives, however, the medical community must address ethical issues. For example, the personal labs will have to contain lockout mechanisms because “you don’t want someone else looking at your data or analyzing your tissue.” There’s even the possibility of “genomic blackmail” if someone obtains your personal genetic information, suggests Dr. Kricka. But there are compelling reasons for personal labs: consumers’ demand for more control over their health, ease of use, and improvement in health care delivery if routine wellness tests were to become commonplace. For this to become reality, Dr. Kricka sums up, “the benefits would have to be shown in terms of overall health.” Presenting
a shorter-term vision, Kent Lewandrowski, MD, associate Not only have POC technologies themselves improved, particularly with bedside glucose testing, but “we’re getting better at managing POC,” Dr. Lewandrowski says. POC testing accounts for eight percent of laboratory tests at Massachusetts General and continues to increase in share. Massachusetts General uses POC testing for glucose, urinalysis, fecal occult blood, gastric occult blood, blood gases, provider microscopy, and pregnancy. The hospital recently added rapid cardiac markers, rapid strep, and rapid influenza. Dr. Lewandrowski expects POC tests to come on board soon for continuous blood gas analysis, drugs of abuse, transcutaneous bilicheck, and thromboelastography. “The menu is expanding, and the technologies are getting more sophisticated,” he says. Dr. Lewandrowski advises labs not to focus solely on unit cost when considering where to add POC testing. “If we focus on high-acuity patients, the unit cost per laboratory test is not the issue, but unit effectiveness.” For example, producing rapid cardiac markers for patients with chest pain can be important in influencing treatment and deciding whether to admit. Lab testing represents roughly four percent of the hospital budget but influences almost all clinical decisions, Dr. Lewandrowski points out. “When you look at the costs of these new technologies,” he says, “consider the impact on utilization, patient care, efficiency, and outcome.” When Massachusetts General had a problem with overly lengthy stays in the emergency department, “the lab was challenged to help reduce those lengths of stay,” Dr. Lewandrowski recounts. “We didn’t know if changing lab turnaround time would affect turnover of patients, but it was worth trying.” Dr. Lewandrowski and his colleagues set up a POC testing lab to do urinalysis, pregnancy, glucose, cardiac markers, and rapid strep and influenza. “We cut turnaround time by 87 percent,” he says. Emergency department physicians’ overall satisfaction with lab turnaround time doubled, while satisfaction with test accuracy was similar to what it had been with the central lab. Emergency department lengths of stay declined an average of 41 minutes per patient after POC testing was implemented in 2000. The number of diversions—times when the emergency department was overcrowded and had to send patients to other hospitals—also declined (Lee-Lewandrowski E, et al. Arch Pathol Lab Med. 2003;127:456–460). Cardiac markers can streamline care in the emergency department. EDs typically use necrosis markers, such as troponin and CK-MB, but only 13 percent of patients can be ruled out at presentation using these, Dr. Lewandrowski says. “The vast majority of patients fall into a gray zone.” A potentially better measure of risk for acute myocardial infarction, he adds, is a new test, ischemia-modified albumin. In a study of low-risk chest pain patients, IMA presumably had a nearly 100 percent negative predictive value, he says, “although more studies will be needed to confirm these optimistic numbers.” (See “Better cardiac calls.") Use troponin, IMA, and an electrocardiogram, suggests Dr. Lewandrowski. “IMA doesn’t replace previous technologies but augments them and allows the patient to be evaluated more effectively.” In another study, adding IMA to the mix allowed a hospital ED in London to rule out 35 percent of patients. “More hospitals need to evaluate this marker,” he says. Not all POC tests perform as well as those done in the central lab, notes Dr. Lewandrowski. For instance, studies have shown significant differences in performance in hypoglycemic monitoring of neonates using bedside glucose devices versus central lab testing. Glucose meters may deviate from the true value by as much as 35 percent. “Bedside glucose does not perform well in this setting [intensive-care neonates],” he says. “Some technologies designed for one setting won’t work in an alternative setting for which they weren’t intended.” On the other hand, the transcutaneous monitor for bilirubin in neonates, which is placed on the forehead and produces a readout, “performs very well compared to the central lab,” Dr. Lewandrowski says. “It’s simple, noninvasive, and provides rapid results.” Another example
of a useful new POC technology, he says, is a system for continuous
noninvasive monitoring of blood gases and electrolytes during surgery.
This replaces repetitive testing by the central lab, which can provide
only intermittent results. Natriuretic peptides are hormones and their metabolites that can help track the remodeling of myocardial tissue that occurs when the homeostatic fluid balance is disrupted, as it is in congestive heart failure. About half of CHF patients are asymptomatic, Dr. Christenson says. “We don’t have much evidence that there is a difference in performance” between BNP and NTproBNP in diagnosing heart failure, he adds. NTproBNP is cleared by the kidneys and has a longer half-life in the body—one to two hours compared with 20 minutes for BNP. “There may well be utilization differences in renal insufficiency patients and in therapeutic monitoring,” he says, “but we don’t know for sure yet.” “If you want to test for natriuretic peptides at the point of care, say in the emergency department,” says Dr. Christenson, “then the standard BNP test is the only option.” NTproBNP must be done on the Roche Elecsys in the central lab. Biosite offers a point-of-care BNP test. “There is no evidence that one is better than the other for most presently approved applications, so at our hospital we’re doing it as POC,” he adds. Hospitals that are just starting to use the marker may want to begin with BNP, because it doesn’t require as much training and the initial cost probably will be lower. “BNP is much simpler to implement and you don’t have to bring in a big instrument to run a single test,” he says. “Of course, if you already have an Elecsys, then performing NTproBNP is a viable option.” BNP tests can be performed in emergency departments, critical care units, and physicians’ offices. “Many [CHF] patients weigh themselves to try to keep track of fluid balance,” says Dr. Christenson. “There could be a role for a home BNP testing in the future, provided the testing system is robust, accurate, precise, and easy to use.” For BNP testing, the Biosite assay requires whole blood or plasma that is stable for up to about four hours after collection. The test can be run in about 15 to 20 minutes. NTproBNP uses serum or plasma, which can be refrigerated for up to three days, and, after sample preparation, takes about 18 minutes on the Elecsys, he says. BNP is a strong indicator of CHF, according to recent studies cited by Dr. Christenson. The values are significantly higher for CHF patients, and higher values correlate with greater severity of illness and poorer prognosis. For patients who come into emergency rooms with shortness of breath, there’s a 90 percent chance that elevated BNP levels—above 100 pg/mL—will equate to a diagnosis of CHF. With BNP values below 20 pg/mL, there’s only a 12 percent probability of CHF. Using BNP to screen asymptomatic patients, however, is not recommended at present, Dr. Christenson says. “In a well-run study published in JAMA [Vasan RS, et al. 2002;288: 1252–1259], the performance was suboptimal for screening. However, it must be noted that there were questions about the criteria used to categorize LV dysfunction, and diastolic dysfunction was not addressed,” he says. This is a particular problem in women and the elderly. “BNP added nothing to the ability of clinical indicators to assess left ventricular function,” Dr. Christenson adds. With NTproBNP, there seems to be an age and gender difference in the values. People younger than 45 show substantially lower values than patients 75 years or older. And NTproBNP values tend to run substantially higher in women, especially older women, than in men. “So we may need age- and gender-adjusted reference intervals for these tests,” Dr. Christenson says. As with BNP, elevated levels of NTproBNP show a strong association with a diagnosis of heart failure. Someone with elevated NTproBNP is at a 22-fold higher risk for heart failure mortality than someone without an elevated rate, according to studies cited by Dr. Christenson. In summary,
Dr. Christenson says, current evidence suggests that BNP Clinicians want results of this marker to assist in detecting AMI within 60 minutes, preferably within 30 minutes. If the central laboratory can perform continuous troponin testing with turnaround times of less than an hour, that’s satisfactory, he says. “If that can’t be accomplished, implementation of POCT should be considered.” An increase in troponin levels by itself does not necessarily equate to a heart attack. “It must be accompanied by symptoms of ischemia,” Dr. Apple says. For a patient with chest pain, a normal troponin level results in a diagnosis of unstable angina. If troponin is elevated, “it’s classified as a heart attack.” Dr. Apple says troponin assays at the 99th percentile reference cutoff should have a total analytical imprecision of 10 percent or less; if not, there’s a potential for false-positives. No assays meet that goal, however, so he suggests choosing the lowest concentration that provides the 10 percent imprecision (or coefficient of variation) as the medical decision cutoff (Apple FS, et al. Am Heart J. 2002;144:981–986). “As the manufacturers improve the quality of their assays, that lowest [10 percent CV] concentration will eventually equate to the 99th percentile,” he says. Whether troponin
is performed at the point of care or in a central lab, Troponin testing does result in higher quality care. Dr. Apple cited studies showing a two- to fivefold improvement in outcomes based on therapies guided by troponin results obtained at presentation. Three manufacturers—Biosite, Roche, and Dade-Behring—have approved quantitative POC troponin assays. And i-Stat and Response Biomedical are developing POC troponin assays, he says. When Hennepin County Medical Center put a POC system into its cardiac short stay unit, the mean turnaround time on a troponin assay declined from 83 minutes to less than 15 minutes, Dr. Apple says. (These data represent the time from blood draw to result delivery.) And nurses and physicians have reported positive patient health benefits from being able to see real-time numbers rather than waiting for results. In the future, he says, as assays at the low end improve, “we hope to be able to triage patients earlier, both as inpatients and outpatients.” IMA, he adds, has recently been approved by the FDA to help rule out acute coronary syndrome in low-risk patients. But implementing IMA, says Dr. Apple, “still requires an evidence base and cost justification.” Karen Southwick is a writer in San Francisco. |
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