ClinLabNavigator Blog

Routine Health Screening may be Harmful to your Health

noreply@blogger.com (Fred Plapp) — Sat, 13 Sep 2008 18:12:00 +0000

Routine laboratory tests are often ordered regardless of findings elicited from the medical history or physical examination. Ordering tests indiscriminately is costly, counterproductive and may increase patient risk. Reference ranges for laboratory tests are usually chosen to include 95% of healthy individuals. Therefore, 5% of test results from patients without disease will fall outside the reference range. For example, if hemoglobin levels were measured on100 healthy individuals, 5 would be expected to have abnormal results. Ordering several tests further increases the chances of a healthy person having at least one abnormal result. If two tests are ordered on a healthy individual, the chances of both being normal are 0.95 X 0.95 = 0.90. That means there is a 10% probability that at least one of the results will be abnormal. The chance of at least one test being abnormal increases with the number of tests ordered. When ten tests are ordered, there is a 40% probability of at least one result being abnormal.

Patients can be harmed directly from follow-up of false positive or borderline positive results. Often times, additional confirmatory tests are ordered and patients may be referred to a specialist, who may perform an invasive procedure. Patients can be harmed indirectly when false positive tests divert a physician’s attention from more important patient care issues or unnecessarily result in postponement of a therapeutic procedure. Clearly, it is better medical practice to perform only those tests that provide more benefit for the patient than risk. Today’s health care environment mandates that pathologists and laboratory managers play an active role in promoting cost-effective utilization of laboratory services.

Plasma Transfusion is Ineffective for Correcting Minimally Elevated INR

noreply@blogger.com (Fred Plapp) — Thu, 19 Jun 2008 00:03:00 +0000

Today, much plasma is ordered prophylactically to correct an elevated protime (PT) prior to an invasive procedure. Physicians performing invasive procedures want to avoid hemorrhagic complications and often regard a mild elevation of a coagulation test result as an indication to order plasma. The decision to prophylactically transfuse plasma is based on three unproven assumptions. (1) Mild prolongation of PT/INR (defined as an INR <1.7) predicts bleeding from an invasive procedure. (2)Pre-procedure transfusion of plasma will correct a prolonged PT/INR. (3) Prophylactic plasma transfusions result in fewer bleeding events.

The evidence clearly contradicts the first assumption. PT and APTT begin to rise above the upper limit of the normal range when coagulation factor levels fall below approximately 70% of normal. When the INR increases to 1.3 - 1.5, vitamin K dependent coagulation factors are still 50% of normal. Even at an INR between 1.8 and 2.0, they remain at 30% of normal, which is still at or above the minimal hemostatic level of 20 -30%. These results explain why a mildly elevated PT/INR is not usually associated with spontaneous hemorrhage and does not increase the risk of bleeding during routine invasive procedures. Studies during the last 20 years in patients undergoing liver biopsies, bronchoscopic biopsies, renal biopsies, central line vein cannulation, thoracentesis and angiography have repeatedly demonstrated that PT and activated plasma thromboplastin time (APTT) are not predictive of hemorrhage. However, it must be remembered that the risk of bleeding is greater if the platelet count is decreased, platelet function is abnormal, or the patient has experienced massive trauma or is undergoing extensive surgery.

Additional evidence clearly disputes assumptions 2 and 3. Prophylactic transfusion of plasma to correct a mildly elevated INR prior to an invasive procedure is often not effective. When the INR is <1.7, transfusion of plasma corrects INR an average of only 0.1 per unit transfused, largely because the INR of plasma itself ranges between 1.0 and 1.3. The difference in coagulation activity between donor plasma and patient plasma is so small that plasma transfusions produce minimal demonstrable effect on the patient’s INR. While a patient with an INR of 1.7 or less may bleed during an invasive procedure, the medical literature clearly demonstrates that the incidence of hemorrhage is not different from that of patients with a normal INR.

In summary, plasma transfusion has minimal effect on normalizing the INR in patients with mildly prolonged INRs for the following reasons. (1) Plasma produced from healthy blood donors can have an INR as high as 1.3. (2) Plasma transfusion to a patient with an INR of less than 1.7 has minimal effect. (3) Plasma transfusion to patients with an INR of less than 1.7 does not decrease the INR more than usual medical care without plasma transfusion.

In view of this information, the common practice of prescribing plasma to correct a mildly elevated INR prior to an invasive procedure needs to be reevaluated. It is not necessary or efficacious to correct an INR below 1.7 to achieve adequate hemostasis.

Helicobacter pylori Treatment and Chronic ITP

noreply@blogger.com (Fred Plapp) — Sun, 11 May 2008 02:45:00 +0000

A recent study in Blood (2007;10:3833-3841) suggests that eradication of Helicobacter pylori may lead to a significant and persistently increased platelet count in patients with chronic immune thrombocytopenic purpura (ITP). In this study, 75 patients with ITP were screened for infection with H. pylori. Active H. pylori infection was found in 38 (51%) of these patients and effectively eradicated in 34 (89%) patients. The urease breath test was used to assess eradication 4 to 6 weeks following treatment. Platelet counts were then monitored at regular intervals; 2 weeks for the first 2 months, monthly for the next 4 months, and every 6 months thereafter. The average baseline platelet count in H. pylori infected ITP patients was 40.6 x 109/L [± 25.0 x 109/L]. The authors defined platelet responses as follows:
Complete response (CR): normal platelet count for at least 3 months after eradication.
Partial response (PR): platelet count not >149,000 or a doubling of the initial count above 40,000.
No response (NR): platelet count less than or equal to 40,000, even if the initial count doubled.
Five patients without H. pylori but with ITP were also given eradication treatment to act as control subjects.

After a median follow-up time of 60 months post treatment, 23 (68%) of the 34 patients with eradicated H. pylori infection showed a significant and persistent increase in their platelet count. Sixteen (46%) patients achieved CR, 7 (20%) achieved PR and 12 (34%) showed no response. Only 1 patient who was refractory to eradication treatment showed a response during follow-up. No H. pylori-negative patients experienced a platelet response. Overall, 55% of the H. pylori-positive patients with ITP who underwent eradication treatment were disease free at 60 months.

With an average follow-up time of 60 months, the results of this study demonstrated that H. pylori eradication treatment may lead to a sustained improvement in the platelet count and possibly long-term cure in patients with chronic ITP. Therefore, the authors suggest that because the eradication of H. pylori is a simple, safe, effective and inexpensive approach, all patients with ITP should be screened for H. pylori at diagnosis and treated with H. pylori eradication therapy prior to starting or in conjunction with other treatments for ITP.

Troponin I Cutoff on Beckman Coulter Analyzers

noreply@blogger.com (Fred Plapp) — Sat, 09 Feb 2008 19:20:00 +0000

Cardiac troponins have become the preferred laboratory tests for the diagnosis of myocardial injury. Clinical and laboratory associations have endorsed the implementation of the 99th percentile reference value for cardiac troponin I for the detection of myocardial ischemia. Elevation of cTnI above the 99th percentile has become the definition of non ST-elevation myocardial infarction. Several recent articles have published the 99th percentile values for second generation cTnI in plasma.

In 2004, Panteghini etal (Clin Chemistry 2004;50:327-32) determined that the 99th percentile for the Beckman Coulter Access Accu TnI on the Access 2 instrument was 0.04 ng/mL (ug/L). This finding was later confirmed by Apple and Murakami in 2007 on a large study of almost 5000 specimens from apparently healthy individuals (Clin Chemistry 2007;53:1558-9).

Our health system has a mixture of Beckman Coulter Access 2 and DxI analyzers, which have very similar performance characteristics. For this reason, our laboratory adopted 0.04 ng/dL as the 99th percentile for cTnI system wide. After almost one year of operation, some interventional cardiologists commented that they were seeing too many with slightly elevated cTnI in patients without discernable ischemic heart disease. A subsequent analysis of cTnI results of healthy individuals participating in an annual health fair revealed that the 99th percentile was actually 0.07 ng/mL. Accordingly, the cutoff point for cTnI was immediately changed from 0.04 to 0.07 ng/mL.

Our experience emphasizes that clinical laboratories definitely need to determine their own 99th percentile for cTnI. Values calculated by carefully controlled research studies may be lower than those obtained by a busy clinical laboratory that does not have as tight of control over specimen collection, transportation and processing.

Leukocytosis is a Risk Factor for Thrombosis

noreply@blogger.com (Fred Plapp) — Mon, 03 Dec 2007 00:35:00 +0000

White blood cell count has previously been linked to the incidence of thrombosis in the general population. Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative disorders which are considered hypercoagulable states, due to the high incidence of thrombotic complications, associated with high morbidity and mortality. Ten percent to 30% of patients with these disorders present with major thrombotic complications, and a similar proportion develop a thrombotic complication during their disease course. Arterial thromboses, especially affecting the cerebral or coronary arteries, are more common than venous thromboses. Recent studies on the pathogenesis of thrombosis in myelo-proliferative disorders have suggested a role for leukocyte activation, and leukocyte interaction with platelets and endothelial cells. Two recent studies investigated a possible association between leukocyte count and thrombosis in PV and ET.

In PV, major known risk factors for thrombosis include age over 65 years and previous thrombotic history. A recent study (Blood. 2007;109:2446-2452) analyzed the role of other potential risk factors, including white blood cell count and classic cardiovascular risk factors, in a large database of 1638 patients with PV. Patients with a white blood cell count >15,000/uL had a significant increase in the risk of thrombosis compared with those with a white blood cell count below 10,000/uL, mainly due to an increased risk of myocardial infarction (hazard ratio 2.84). Smoking was also associated with an increased risk of arterial thrombotic events.

In ET, age over 60 years and prior thrombotic events are known independent predictors of vascular complications. These two factors are widely used to stratify thrombotic risk in these patients for cytoreductive drug treatment decisions. A recent study (Blood. 2007;109:2310-2313) of 439 patient with ET investigated whether an increased white blood cell count was associated with thrombosis, and whether this effect could be modulated by cytoreductive therapy. The authors reported that a white blood cell count greater than the median value (8,700/uL) at diagnosis was associated with an increased risk of thrombosis during follow-up (hazard ratio 2.3), and that hydroxyurea-induced lowering of the white blood cell count was associated with a reduction of this thrombogenic risk. The presence of JAK2 mutation was not identified as a risk factor for thrombosis in this study, despite a significant association between the mutation and leukocytosis.

Interestingly, neither hematocrit nor platelet count elevations influenced thrombotic risk in either PV or ET. In summary, leukocytosis is a significant risk factor for thrombosis in PV and ET. The authors of these studies suggest that leukocyte count should be considered in defining vascular risk in patients with myeloproliferative disorders, and should be taken into account as an additional factor in cytoreductive treatment decisions. Validation of these findings in prospective studies is indicated.

Decreased Nitric Oxide in Banked Blood Associated with Adverse Outcomes

noreply@blogger.com (Fred Plapp) — Mon, 03 Dec 2007 00:32:00 +0000

Several studies have shown that blood transfusions increase the risk for myocardial infarction, heart failure, stroke and death. Although differences between banked blood and red blood cells in vivo have been recognized, the mechanisms resulting in these adverse outcomes have not been delineated.

In two studies published online in the Proceedings of the National Academy of Sciences, Duke University Medical Center researchers suggested that shortly after blood is collected, its nitric oxide content becomes depleted leading to impaired vasodilation and decreased tissue perfusion (PNAS.2007;104(43):17058-17068). They further proposed that as a result of banked blood’s inability to dilate small blood vessels, red blood cells may build up and further obstruct larger vessels, resulting in more ischemia. This scenario was suggested as a possible explanation for the adverse outcomes seen in ischemic patients following blood transfusion.

Nitric oxide levels begin to decline rapidly within three hours after collection and are reduced by 70% during the first day of storage. Levels are undetectable by day 21. Based on these findings, the researchers suggested that even “fresh” blood may lead to adverse clinical outcomes. The reduction in nitric oxide directly correlated with stored red blood cell’s inability to promote vasodilation. Nitric oxide depleted blood transfusions led to decreased coronary blood flow in canines. However, when stored red blood cells were replenished with nitric oxide prior to transfusion, coronary perfusion increased. These differences in blood flow were most noticeable during hypoxemic states.

Although adding nitric oxide to stored red blood cells prior to transfusion looks like a promising solution, the authors acknowledged that a large-scale randomized clinical trial in humans is needed to determine whether adding nitric oxide back to stored blood before transfusion or preventing nitric oxide depletion would actually improve patient outcomes. The Duke University studies once again demonstrated that blood transfusions have risks as well as benefits.

Lessons Learned from Community Based Thyroid Screening

noreply@blogger.com (Fred Plapp) — Mon, 05 Nov 2007 02:52:00 +0000

A retrospective analysis of the computerized database of a large health medical organization in Tel Aviv, Israel that included 2800 primary care physicians and 2.3 million insured persons, recently revealed some very interesting findings about routine thyroid screening (Arch Intern Med 2007;167(14):1533-38). A total of 422,242 persons aged 21 years and older with no known thyroid disease or previous treatment with thyroid medications, who had at least one TSH measurement during 2002 and were available for follow-up through 2006, were included in the study. The TSH reference range used for this study was 0.35-5.5 mIU/L.

Ninety five percent of the initial TSH concentrations were within normal limits, whereas 3.7% were elevated and 1.2% were decreased. Thirty seven percent of patients with abnormal initial TSH levels were treated with medication and excluded from further analysis. The remaining patients had an average of 3.7 additional TSH measurements during the 5 year follow-up.

Of the patients with initially normal TSH results, 98% remained normal at the end of 5 years.

Of the patients with initially elevated TSH results, 38% remained elevated and 62% returned to normal.

Of the patients with initially decreased TSH results, 47% remained decreased and 52% reverted to normal.

Two important conclusions can be drawn from this study. When TSH concentration is normal and there are no new clinical indications of a thyroid disorder, the likelihood of a subsequent abnormal TSH level within 5 years is only 2%. This finding supports recent evidence based recommendations against population based TSH screening. Secondly, more than 50% of patients with abnormal TSH results revert to normal without medical intervention, suggesting that at least two TSH measurements should be obtained before considering treatment.

Clostridium difficile becoming more aggressive

noreply@blogger.com (Fred Plapp) — Wed, 03 Oct 2007 23:53:00 +0000

Clostridium difficile is a Gram-positive, spore-forming, anaerobic bacillus that can cause pseudomembranous colitis. C. difficile-associated disease (CDAD) ranges in severity from mild diarrhea to fulminant colitis. Risk factors for CDAD include antibiotic use within three months prior to symptom onset, and exposure to a health-care setting. Colonization with C. difficile is common in hospitalized patients (20-40%), while only 3% of healthy adults are colonized. Exposure to antibiotics is believed to alter the normal gut flora, resulting in overgrowth of C. difficile. Production of exotoxins A & B by the organism subsequently results in CDAD, and detection of toxin is the basis for diagnostic laboratory tests.

CDC data indicates that the incidence and severity of CDAD has increased since the year 2000. Two recent publications (NEJM 2005; 353:2433-2449) describe an apparently new, more virulent strain of C. difficile that has been responsible for hospital outbreaks in the U.S. and Quebec, Canada. This epidemic strain differs from common strains in that it produces 16 times more toxin A and 23 times more toxin B, which may result from a deletion in the negative regulator gene, tdC. The epidemic strain was also resistant to fluoroquinolones, and prior use of fluoroquinolones was identified in 52% of cases. More severe CDAD is associated with the epidemic strain, including more frequent toxic megacolon, leukemoid reaction, shock, and death, particularly in the elderly.

Equally alarming, community-acquired cases of severe CDAD in individuals with minimal risk factors have been reported recently (MMWR 2005;54:1201-1205). Analysis of the organism responsible for two of these infections showed they were not caused by the epidemic strain. Another report suggests that use of proton pump inhibitors increases the risk of community-acquired CDAD by 2-3 times (JAMA 2005; 294:2989-2995).

Hand hygiene is of particular importance in reducing the incidence of CDAD. Of note is that hand-washing with soap and water is necessary for C. difficile eradication, as its spores are resistant to alcohol-gel based preparations. In light of the apparent changing epidemiology of CDAD, the CDC has stressed the importance of judicious antibiotic use, and the need for a high index of suspicion for community-acquired CDAD in patient with severe diarrhea.

The newest diagnostic tests for CDAD are enzyme immunoassays (EIA), which detect 100 to 1000 pg of cytotoxin A & B. The sensitivity and specificity of the test are 95% and 97% respectively. A positive test indicates the presence of Clostridium difficile. Normal stools are negative for toxins.

Case Study of Progressive Weakness & Sensory Loss

noreply@blogger.com (Fred Plapp) — Mon, 03 Sep 2007 00:26:00 +0000

An 80 year old man has a 6 month history of progressive weakness and seonsory loss in both legs. Serum total protein is 6.5 g/dL. Serum protein electrophoresis detected an IgM kappa monoclonal antibody at a concentration of 0.5 g/dL. Bone marrow aspirate did not detect a lymphoproliferative disorder, but flow cytometry detected a mino clonal population of B cells with monotypic kappa light chains. What is the patient's most likely diagnosis and how does it explain his neurological symptoms? What additional testing would you order to confirm your diagnosis?

PSA Threshold for Prostate Biopsy

noreply@blogger.com (Fred Plapp) — Mon, 03 Sep 2007 00:08:00 +0000

One of the most difficult dilemmas that has arisen after widespread PSA testing is deciding the optimal PSA threshold at which prostate biopsy should be performed in asymptomatic patients. Using a PSA value that is too low results in unnecessary biopsies and detects indolent cancers, while using a threshold that is too high misses aggressive tumors. Traditionally, a PSA of 4.0 ng/mL has been recognized as the lower limit for biopsy consideration. Approximately 35% of men with a PSA level between 4 and 10 ng/mL have cancer. However, more recent studies have suggested that a cutoff of 4.0 is too high of a threshold for biopsy because 25% of men with PSA levels in the range of 2.5 to 4.0 have clinically significant cancer. Lowering the threshold to 2.6 would nearly double the rate of detecting cancer in men younger than 60 years old with little loss of specificity.

A recent study published in BJU International (2007;99:1427-31) examined the performance of the five most commonly used methods to measure PSA concentration. The study was comprised of 596 untreated Caucasian males referred to a urology clinic. Of this total, 314 men had histologically confirmed prostate cancer while 282 did not have detectable cancer in 8 to 12 biopsy cores. The median age of men with cancer was 66 years and the median age of the men without cancer was 63 years. The median PSA concentration in men with cancer was 6.2 ng/mL (range 5.8-6.6) compared to a median value of 3.8 ng/mL (range 3.1-4.5) in men without cancer.
The performance of the Beckman Coulter PSA assay in detecting prostate cancer at a threshold of 4.0 and 2.5 is shown below.

True Positive rate at 4.0 ng/mL was 78%
True Positive rate at 2.5 ng/mL was 92%
True Negative rate at 4.0 ng/mL was 51%
True Negative ratge 2.5 ng/mL was 34%

Another way to look at this data is to realize that 68 out of 314 men with prostate cancer (22%) had PSA values less than 4.0 ng/mL and would not have been referred for biopsy using this threshold. In contrast, only 26 men with prostate cancer (8%) were missed, when the PSA threshold was lowered to 2.5 ng/mL. Clearly, lowering the PSA threshold detects significantly more cancer cases.

However, the trade off for increased sensitivity is decreased specificity. When a PSA threshold of 4.0 ng/mL was used, 139 of 282 men without cancer (49%) had elevated PSA values, but the number of false positives increased to 187 (66%) when the threshold was lowered to 2.5 ng/mL. Thus, lowering the PSA threshold to 2.5 ng/mL, meant that almost two thirds of men referred for biopsy did not have detectable cancer.

The National Comprehensive Cancer Network guidelines recommend biopsy for men with a PSA higher than 2.5 ng/mL.

Phosphorus as a Risk Factor for Cardiovascular Disease

noreply@blogger.com (Fred Plapp) — Sat, 28 Jul 2007 19:02:00 +0000

Data from the Offspring Cohort of the Framingham Study recently revealed an association between higher levels of serum phosphorus and increased cardiovascular disease (CVD) risk (Arch Intern Med 2007;167:879-885). With a sample size of 3,368 and a mean follow-up time of 16 years, investigators used statistical methods to relate serum phosphorus levels to the occurrence of a first CVD event. The data was adjusted for traditional CVD risk factors as well as standard risk factors that influence phosphorus levels including GFR, hemoglobin, albumin, proteinuria and CRP. Patients were divided into quartiles according to their phosphorus levels.

First Quartile: 1.6-2.8 mg/dL
Second Quartile: 2.9-3.1 mg/dL
Third Quartile: 3.2-3.4 mg/dL
Fourth Quartile: 3.5 mg/dL or more

Analysis of the data showed that as phosphorus levels increased, there was a continuous increase in CVD risk. People falling in the 4th quartile had a 55% higher CVD risk compared to the 1st quartile. In this study, the normal range for serum phosphorus was 2.8–4.5 mg/dL, so patients in the top quartile were within the normal range. If this association is confirmed, it may be necessary to reevaluate the normal range for phosphorus.

While this study suggests an association between phosphorus levels and CVD risk, more research will be required to determine whether it truly causes CVD. Three pathogenic mechanisms have been proposed.
1. High serum phosphorus is a marker of elevated PTH, which is proinflammatory
2. High serum phosphorus directly injures endothelium and promotes calcification
3. High serum phosphorus may be a biomarker for subclinical chronic kidney disease.
The last possibility appears less likely because CVD risk was adjusted for GFR.

Molecular Diagnostics Trends

noreply@blogger.com (Fred Plapp) — Sat, 30 Jun 2007 17:45:00 +0000

Although molecular testing has been available for many years, automation is just now being introduced. The Cepheid GeneXpert is the first fully automated FDA cleared instrument platform that does DNA preparation and real time PCR analysis. Roche's Cobas Ampliprep/Cobas TaqMan system for HIV testing is also a fully automated FDA-cleared system for HIV viral load testing. The introduction of these fully automated platforms will make it possible for more labs to implement molecular testing because dedicated molecular laboratory space will no longer be required.

The GeneXpert Group B Streptococcus assay is FDA cleared as moderate complexity, which is the first time a molecular test has been classified as such. This automated instrument may even be placed in an automated or rapid response laboratory instead of in a molecular laboratory to facilitate 24/7 testing. A perfect example of this application is stat enterovirus testing for patients admitted to the emergency department with suspected meningitis. Patients who test positive can be discharged, while patients who test negative can be admitted and treated with antibiotics for possible bacterial meningitis.

Medical practice for diagnosing Group A Streptococcus is changing. Some experts recommend replacing rapid Strep tests in physician offices with a molecular assay, because of its higher sensitivity. Alternatively, Group A Strep PCR testing can replace culture as a more rapid confirmatory test for patients with negative rapid strep tests.

Traditional virology laboratory procedures will gradually be replaced by molecular testing. Molecular testing is now considered to be the gold standard for two of the most commons viruses, herpes simplex virus (HSV) and cytomegalovirus (CMV). In the near future, molecular testing will be performed for the rapid diagnosis of respiratory illnesses.
Molecular tests are being implemented to screen for and monitor hospital-acquired infections such as methicillin resistant Staphylococcus aureus (MRSA) and vancomycin resistant enterococcus (VRE). More hospitals will initiate these screening programs to decrease the risk of nosocomial infections.

Pharmacogenomic testing will become reality in the very near future. Warfarin is being relabeled to include a recommendation for genetic testing. The advent of this high volume testing may open up other opportunities as physicians embrace the concept of pretreatment pharmacogenomic testing.

Molecular tests are being used more frequently to classify leukemia and lymphoma and to assess remission status. Studies are ongoing that may further indicate a prognostic role for many of these tests.

The laboratory is experiencing a rapid increase in the number of esoteric tests, including molecular diagnostics. Physicians are having difficulty staying abreast of this information explosion. Pathologists and laboratories will need to provide more meaningful interpretive reports to assist physicians in understanding the clinical significance of these tests. Comprehensive web sites, such as www.clinlabnavigator.com and www.arupconsult.com , will play an increasingly important role in physician education.

Laboratory information systems (LIS) and electronic medical records (EMR) have not kept pace with the rapid expansion of molecular diagnostics. Only Cerner Corporation and SCC Soft Computer have developed LIS modules specifically for molecular diagnostic laboratories. The major obstacles to effectively communicating molecular testing results to the EMR is the lack of standard nomenclature for molecular methods and genes and their mutations and the inability to easily translate complex molecular data in to a meaningful interpretive clinical report. Because much of the more esoteric molecular testing will be performed in reference laboratories, common standards will need to be developed to permit transmission of this data to hospital LIS and EMR. Future EMR will need to be able to graphically display this data.

Glucose Meter Accuracy

noreply@blogger.com (Fred Plapp) — Sun, 17 Jun 2007 19:55:00 +0000

The introduction of tight glycemic control protocols in hospitals has increased the need for more accurate bedside glucose meters. In 1987, the American Diabetes Association (ADA) recommended that glucose meters should have a total error (analytic plus user) of <10% at glucose concentrations between 30 to 400 mg/dL. More recently, ADA urged manufacturers to further decrease total error to 5%. Currently available meters do not meet these performance goals. Recent proficiency testing results from the College of American Pathologists demonstrate that glucose meters have much more instrument to instrument variability than chemistry analyzers in central laboratories. For example, the interlaboratory precision at a glucose value of 400 mg/dL ranged from 4.1% to 13.7% for glucose meters compared to 1.6% to 2.8% for chemistry analyzers.

The laboratory often receives questions concerning the disparity between a glucose result obtained with a glucose meter and a subsequent result performed on a chemistry analyzer in the laboratory. In most instances, the glucose meter result has been incorrect. The most common causes of erroneous results obtained with glucose meters include under or overfilling of the glucose strip, contamination or dilution of the sample (especially if drawn from a line), and clotting of the sample due to delayed testing.

Workplace Drug Testing

noreply@blogger.com (Fred Plapp) — Wed, 02 May 2007 23:58:00 +0000

Drug testing of job applicants and employees is mandated for many federal government agencies and has also been adopted by many other large and small businesses. Each year, Quest Diagnostics publishes the Drug Testing Index, which provides the positive test rates for the most common drugs of abuse. The most recently published index reflects the results of more than 7.3 million workplace drug tests performed in 2005. Because this index is comprised of such a large data set, it most likely reflects trends in the U.S. workforce.

The 2005 data indicates that workforce drug use was at the lowest level since the index was first published in 1988. The combined workforce positive rate was 4.1% in 2005 compared to a positive rate of 13.6% in 1988. The positive rate for government workers is about half the rate of the general workforce. The major reason for this encouraging downward trend has been a significant decrease in marijuana positives in the combined workforce.

The complete report is available in the Test tab under the title of "Drugs of Abuse Workplace Testing.

Umbilical Cord Blood Stem Cells

noreply@blogger.com (Fred Plapp) — Wed, 02 May 2007 23:41:00 +0000

Stem cells from umbilical cord blood have increasingly become a viable alternative source of progenitor cells for hematopoietic cell transplantation (HCT). To date, cord blood stem cells have been used in over 6000 unrelated-donor transplantations throughout the world.

When autologous stem cells are not an option, the ideal source of progenitor cells is from the bone marrow or peripheral blood of an HLA-matched sibling. An HLA match decreases the risk of severe graft-versus-host disease (GVHD) and increases the chances of a successful engraftment. However, a full HLA-match occurs in only 25% of sibling donors. While HLA-matched allogeneic donors may be used, the process of finding a suitable donor can be lengthy and a fully HLA-matched donor may never be found for some patients. A full match from an unrelated donor is even less likely for potential recipients with a non-Northern European heritage due to fewer non-white donors and genetic heterogeneity. For these reasons, umbilical cord blood from unrelated, partially HLA-mismatched donors has become a reasonable alternative source of stem cells for bone marrow reconstitution.

Transplantation across HLA barriers, rapid availability and decreased risk of transmission of infectious diseases are advantages of the use of cord blood over peripheral blood or bone marrow HCT. In addition, studies have shown that the incidence and severity of GVHD decreases with partially HLA-mismatched cord blood HCT when compared to partially mismatched unrelated bone marrow or peripheral blood HCT.

The New York Blood Center (NYBC) recently collaborated with the Center for International Blood and Marrow Transplant Research (CIBMTR) in the analysis of HCT treatment of children (under 16 years old) with leukemia or myelodysplasia. They found similar three-year survival rates for those receiving unrelated cord blood transplants and those receiving equally well-matched unrelated bone marrow transplants.

Adults have also been found to be good candidates for cord blood HCT. According to a study published in the November 25, 2004 issue of the New England Journal of Medicine (NEJM), "HLA-mismatched cord blood should be considered an acceptable source of hematopoietic stem-cell grafts for adults in the absence of an HLA-matched adult donor." This study involved 600 adults and resulted in participants who received cord blood with a 5/6 or 4/6 HLA match doing as well as those who received bone marrow with a 5/6 HLA match.

Cord blood transplantation can be limited by the number of cells present in a given unit, particularly for adults or larger pediatric patients. If a single unit is inadequate for engraftment, multiple cord blood units are sometimes attempted. A double umbilical cord blood transplantation has been shown to have success (in terms of GVHD, rates of engraftment, survival and transplant-related mortality) similar to single umbilical cord blood transplantation and unrelated bone marrow transplantation. Other studies involving ex vivo expansion of cord blood stem cells to increase their numbers per unit are also under investigation.

New Anticoagulant Drugs

noreply@blogger.com (Fred Plapp) — Sun, 25 Feb 2007 21:30:00 +0000

The traditional anticoagulant drugs warfarin, unfractionated heparin (UFH) and low molecular weight heparin (LMWH) have a number of limitations, including issues regarding laboratory monitoring, food and drug interactions (warfarin), and a narrow therapeutic window. Ideal characteristics of new anticoagulant drugs include the following features: good bioavailability, no food or drug interaction, rapid onset of action, a wide therapeutic window, a predictable anticoagulant response making laboratory monitoring unnecessary, availability of an antidote, and effectiveness and safety at least equivalent to the currently available drugs. Whereas the older anticoagulant drugs have an effect on multiple factors in the coagulation pathway, the new drugs selectively inhibit a single coagulation factor, most notably thrombin (factor IIa) and factor Xa.

These new drugs may be classified according to their target coagulation factor, and whether they are orally or parenterally administered (see below). Here follows a brief overview of these agents, and a more detailed discussion of the parenteral factor Xa inhibitor fondaparinux.

Classification of new anticoagulant drugs
(asterisk indicates FDA-approval)

Thrombin inhibitors
· Parenteral -
o Hirudin (Lepirudin)*
o Argatroban*
o Bivalirudin*
· Oral -
o Ximelagatran (withdrawn from market)
o Dabigatran

Factor Xa inhibitors
· Parenteral
o Fondaparinux*
o Idraparinux
· Oral
o Rivaroxaban
o Apixaban
o Others

The parenteral direct thrombin inhibitors lepirudin and argatroban are approved for the treatment of heparin-induced thrombocytopenia (HIT). They are both administered intravenously and monitored by the APTT (target range 1.5-2 x baseline for lepirudin, 1.5-3 x baseline for argatroban). Lepirudin is excreted by the kidneys, while argatroban is metabolized by the liver. Bivalirudin is approved for percutaneous coronary interventions. All of these drugs have short half-lives (25-60 min).

The promising oral direct thrombin inhibitor ximelagatran, which required no laboratory monitoring, was recently withdrawn from the market due to hepatotoxicity. Dabigatran is another agent in this class, currently undergoing evaluation.

Parenteral factor Xa inhibitors act as indirect inhibitors since their effect is mediated through antithrombin (formerly known as antithrombin III). Fondaparinux is a pentasaccharide obtained by chemical synthesis. It binds to antithrombin resulting in a conformational change in the antithrombin molecule, thereby greatly potentiating its inhibition of factor Xa. It is administered once daily by subcutaneous injection in a fixed dose, and no laboratory monitoring is required. This drug shows no cross-reactivity with HIT antibodies, and has not been associated with any instance of HIT. The drug is excreted by the kidneys, and has a half-life of 17 hours. No antidote is available.

Fondaparinux has been shown to be effective in the prevention of venous thromboembolism (VTE) following orthopedic surgery. A meta-analysis of four large trials (Arch Int Med. 2002;162:1833-40) showed that fondaparinux was significantly more effective than LMWH in reducing the incidence of VTE after hip replacement, hip fracture surgery and major knee surgery, with an overall 55% decrease in risk reduction compared with LMWH. Fondaparinux was shown in other trials to be at least as effective and safe as LMWH/UFH in the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), in the prevention of VTE after abdominal surgery, and in the treatment of acute coronary syndrome. Fondaparinux is the first selective factor Xa inhibitor to be FDA approved as an anticoagulant. It is currently approved for prevention of VTE following hip fracture surgery, total hip and total knee replacement, and major abdominal surgery. It is also approved for the initial treatment of DVT and PE. The drug in both prophylactic and therapeutic doses prolongs the PT by approximately 1 second, and the APTT by approximately 4-5 seconds, however laboratory monitoring is not indicated.

Oral factor Xa inhibitors (rivaroxaban, apixaban and others) act as direct inhibitors; their effect is not mediated by antithrombin. These drugs also require no laboratory monitoring. They are currently undergoing extensive phase II and phase III studies on prevention and treatment of VTE, and initial reports look promising.

In conclusion, selective inhibitors of specific coagulation factors (thrombin and factor Xa) represent a new class of anticoagulants. They have the potential to be at least as effective and safe as conventional anticoagulants without the need for laboratory monitoring.

Red Blood Cell Transfusion Trigger

noreply@blogger.com (Fred Plapp) — Sun, 25 Feb 2007 21:24:00 +0000

The Transfusion Requirements in Critical Care Trial (TRICC) was a multi-center prospective randomized controlled clinical trial conducted in Canada in 1999, which compared the clinical outcomes in intensive care patients randomized to a restrictive versus a liberal transfusion strategy (NEJM 1999; 340: 409-17). Patients in the restrictive cohort were transfused when their hemoglobin concentration fell below 7 g/dL and their hemoglobin was maintained between 7–9 g/dL, while patients in the liberal transfusion group were transfused when their hemoglobin concentration fell below 10 g/dL and their hemoglobin was maintained between 10–12 g/dL.

Patients in the restrictive group were transfused with one half the number of red blood cell units as patients in the liberal group. The 60 day survival rate for patients in the restrictive group was 77% compared to 74% in the liberal group. The TRICC trial demonstrated that a more restrictive transfusion strategy was safe in the ICU patient population and that the liberal use of transfusions increased the risk of death. Multiple other studies have subsequently demonstrated that allogeneic transfusions cause immunomodulation leading to increased ICU and hospital length of stay as well as nosocomial infections and mortality.

Transfusion medicine has evolved over the last few years. Because allogeneic transfusions are a potential risk for patients, physicians should attempt to limit transfusions by aggressively preventing anemia in hospitalized patients. The decision to transfuse RBCs should be based on the entire clinical picture and not solely on the hemoglobin level. Current transfusion guidelines are available at www.clinlabnavigator.com.

Harmful Effects of Herbs

noreply@blogger.com (clinlabnavigator) — Sun, 16 Jul 2006 14:57:00 +0000

Recent surveys indicate that more than 50% of the population use some form of complementary and alternative medicine. In the United States, the sale of herbal medicines now exceeds $4 billion per year. Marketing campaigns often imply that any natural product is safe. However, herbal medicines are classified as dietary supplements and do not have to be proven safe before being released into the marketplace. Many herbs have been associated with adverse effects due to assay interference, herb-therapeutic drug interaction, or organ toxicity. The following list was compiled to provide a quick reference.

View/Download the entire article here:
http://www.clinlabnavigator.com/Flash/harmfuleffectsherbs.pdf

Herbal Supplement Effects on Lab Tests

noreply@blogger.com (Fred Plapp) — Mon, 08 May 2006 01:02:00 +0000

Herbal medicines are classified as dietary supplements and do not have to be proven safe before being released into the marketplace. Many herbs have been associated with one or more abnormal laboratory test results. Abnormal results may occur by any of the following mechanisms:
¨ Assay interference
¨ Herb-therapeutic drug interaction
¨ Organ toxicity
The most common abnormalities are summarized below.

Some herbs have structural similarity with digoxin and interfere with the digoxin immunoassay. Digoxin levels may be falsely elevated or decreased depending on the type of assay used in the laboratory. The herbal products that most often interfere with digoxin measurements are Chan Su, Dan Shen, Uzara root, Asian Ginseng and Siberian Ginseng. Fortunately, the Bayer Centaur assay used in the Saint Luke’s Health System is not adversely affected by these herbs.

Several herbal medicines lower the seizure threshold maintained by several anticonvulsants including phenobarbital and phenytoin. The most common offenders are Evening Primrose, Borage Oil and Shankhapushpi. Therapeutic drug levels may decrease up to 40% after ingestion of these products.

Many herbal medicines interact with warfarin and potentiate its anticoagulant effect, increasing the risk of bleeding. Some herbs can produce as much as a two-fold rise in INR. Examples include angelica root, arnica flower, ansine, bogbean, borage seed oil, Boldo-genugreek, capsicum, Dan Shen, Dong Quai, feverfew, garlic, ginger, Ginkgo biloba, licorice root and willow bark.

Other herbal medicines interfere with warfarin’s anticoagulant properties, leading to subtherapeutic INR values. In some cases, these herbs have been reported to decrease INR as much as 50%. The main culprits are ginseng, Saint John’s Wort and soy milk.

Some herbs can increase the risk of bleeding by inhibiting platelet aggregation. The best known examples are Dan Shen, garlic and Ginkgo biloba.

Besides interfering with warfarin, Saint John’s Wort has been reported to decrease the therapeutic concentration of several other medications. St. John’s wort induces the CPY3A4 mixed function oxidase, which is responsible for metabolism of 45% of CYP450 mediated drug metabolism. It also induces the P-glycoprotein drug transporter, reducing the efficacy of drugs in which hepatic metabolism is not the major pathway of clearance. Self medication with St. John’s wort can cause treatment failures due to an increase in the clearance of many prescribed medications. Examples include oral contraceptives, immuno-suppressants, HIV protease inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, cardiac drugs and anti-neoplastic drugs such as irinotecan and imatinib mesylate. Specific examples include:
· Lower concentrations in oral contraceptives may cause failed birth control.
· A rapid and significant reduction in cyclosporine and tacrolimus concentrations in transplant patients may cause rejection.
· A reduction in the AUC of indinavir by a mean of 57% and the trough level by 81%. Atazanavir lopinavir and ritonavir are similarly affected.
· A decrease in the therapeutic level of theophylline requiring an increase in dosage from 300 mg bid to 800 mg bid.
· Significantly decreased methadone levels, resulting in reappearance of withdrawal symptoms.
· Significantly reduced levels of simvastatin, resulting in decreased cholesterol lowering effect. However, Pravastatin is not affected.
· Decreased digoxin trough levels by 33% and peak levels by 26%.
· Verapamil clearance is significantly increased.

Different brands of St. John’s wort may vary widely in the magnitude of these effects, because herbal supplements are not subject to rigorous pharmaceutical standards.

Some herbal medicines are hepatotoxic. Kava is the most notorious hepatotoxin and can produce a 70 fold increase in ALT and AST. Mistletoe berries have also been reported to elevate ALT and AST. Chaparral and germander have been associated with cholestatic hepatitis. Comfrey may cause hepatic veno-occlusive disease.

Kelp is promoted as a thyroid tonic and anti-inflammatory medicine. Kelp tablets contain substantial amounts of iodine, which can cause hyperthyroidism. T4 and T3 are increased, while TSH is suppressed.

Some herbal medicines affect glucose levels. Chromium is a trace metal that helps to regulate glucose metabolism. Athletes and bodybuilders take chromium supplements to enhance performance. Large doses can induce hyperglycemia. In contrast, ginseng has been associated with hypoglycemic episodes.

Licorice is used as an anti-inflammatory herb and as a remedy for peptic ulcers. Carbenoxolone, one of the components of licorice, can elevate blood pressure and cause hypokalemia. In extreme cases, licorice ingestion has been associated with hypokalemic myopathy. In these cases the mean plasma potassium level is 1.98 mEq/L and the mean CK level is 5300 IU/L.

Unexpected lead poisoning may occur from the use of herbal medicines contaminated with lead. Some Chinese herbs have been found to have lead content as high as 20,000 ppm. Ingestion of these products can lead to blood lead levels exceeding 100 ug/dL. Some patients may present with intoxication porphyria secondary to lead poisoning.

Because of these complications, the American Society of Anesthesiologists has suggested that in general patients should discontinue their herbal medicines at least 2 weeks before surgery. Other investigators have recommended that those herbal medicines that interfere with platelet function or coagulation should be discontinued at least 7 days prior to surgery.

In summary, herbal medicines should be considered whenever an otherwise healthy individual has an abnormal laboratory result. They should also be considered whenever a patient has an unexpected response to a prescribed medication or presents with unexplained organ toxicity.

Community Acquired MRSA

noreply@blogger.com (Fred Plapp) — Wed, 12 Apr 2006 20:18:00 +0000

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as a distinctly different infectious agent than MRSA that causes health-care associated infections (HA-MRSA). CA-MRSA is predominantly associated with skin and soft tissue infections in otherwise healthy children and young adults. Outbreaks have been documented among sports teams and correctional facility inmates. Fatal pulmonary infections in children have also been reported. CA-MRSA is typically resistant only to B-lactam antibiotics and erythromycin, while HA-MRSA is usually resistant to multiple antibiotics.

The molecular characteristics of CA-MRSA have recently been published. Hundreds of CA-MRSA organisms have now been analyzed by pulsed-field gel electrophoresis (PFGE). PFGE is a strain typing method that is used to determine how closely related 2 or more bacterial isolates are to each other. This technique has revealed that most CA-MRSA strains within the U.S. belong to just two clones, designated USA 300 and USA 400. The latter is associated with severe pneumonia in children and skin infections in Native American populations. USA 300 accounts for the majority of the remaining CA-MRSA skin and soft tissue infections, and has now been identified in several outbreaks ranging geographically from Washington State to Florida.

Staphylococcus aureus is known to produce multiple toxins which contribute to its virulence. A toxin known as Panton-Valentine leucocidin (PVL) has been identified in the majority of CA-MRSA isolates, but not in HA-MRSA. PVL genes encode membrane toxins which target leukocytes, and are epidemiologically linked to severe skin infections and necrotizing pneumonia. Another molecular characteristic of CA-MRSA is its resistance gene, designated SCCmec type IV, that is distinct from the mec A resistance gene harbored by HA-MRSA.

In summary, CA-MRSA organisms are distinct clones, and not hospital-associated organisms that have moved into the general public. The prevalence of CA-MRSA is rapidly increasing. Clinicians should have a high index of suspicion for CA-MRSA, particularly when a wound resembling a “spider-bite” is present. Culture and susceptibility testing should be requested.

Hand Sanitizer Quality

noreply@blogger.com (Fred Plapp) — Tue, 14 Mar 2006 18:57:00 +0000

Alcohol based hand sanitizer products have been recommended to reduce communicable diseases. Many different products are commercially available. A recent study published in Emerging Infectious Diseases (March 2006;12:527-29, www.cdc.gov/eid) demonstrated convincingly that some of the hand sanitizers available to the public are not effective in reducing bacteria on hands. The critical factor appears to be the alcohol content of the product. Products containing only 40% alcohol are no more effective in reducing bacterial counts than tap water. Products containing at least 60% alcohol reduced bacterial counts by 90%. The FDA recommends that alcohol based hand sanitizers should contain between 60% and 95% ethanol or isopropanol. Unfortunately, some retail stores, especially discount stores, sell substandard products containing only 40% alocohol. Also, some of the products listed on the internet do not contain the alcohol content. Consumers need to check the alocohol content before purchasing hand sanitizer products.

PolyHeme Safety

noreply@blogger.com (Fred Plapp) — Mon, 13 Mar 2006 20:26:00 +0000

A recent series of articles in the Wall Street Journal have revealed that PolyHeme, the blood substitute made by Northfield Laboratories, was associated with heart attacks in 10 of 81 patients, compared to 0 of 71 patients treated with convential therapy, in patients undergoing surgery for aneurysm repair. This complication may be due to the depletion of nitric oxide according to a recent article in JAMA (April 6, 2005;293:1653-62). According to this review article, high concentrations of plasma hemoglobin deplete haptoglobin and subsequently nitric oxide. Depletion of nitric oxide leads to vasoconstriction, endothelial activation and platelet activation and aggregation. These pathophysiological changes may be associated with thrombosis and could possibly explain the complications seen with PolyHeme infusion.

Bayer DCA 2000 Hemoglobin A1c

noreply@blogger.com (Fred Plapp) — Mon, 13 Mar 2006 20:17:00 +0000

Bayer DCA 2000 is a point of care instrument for measuring hemoglobin A1c. A method evaluation study, comparing the DCA 2000 with the Biorad Variant II, demonstrated outstanding results. Correlation coefficient was 0.98. This instrument is easy to perform, accurate and precise.

Greiner plastic blood collection tubes

noreply@blogger.com (Fred Plapp) — Tue, 14 Feb 2006 01:18:00 +0000

The laboratory has received many complaints from phlebotomists since switching from BD glass blood collection tubes to Greiner plastic tubes. Plastic tubes fill much more slowly than glass tubes and also are more likely to lose their vacuum during storage and shipping. Plastic tubes also tend to pushback from the needle and needle holders during blood collection. Together, these less desireable characteristics have increased the number of tubes that are incompletely filled. The biggest problem has occurred with blue top tubes used for coagulation. Industry needs to address these issues to improve patient care and customer satisfaction

Newborn screening

noreply@blogger.com (Fred Plapp) — Sun, 12 Feb 2006 22:51:00 +0000

Many of the health departments that are performing newborn screening use the Perkin Elmer AutoDelfia Neonatal 17 alpha hydroxy progesterone kit to screen for congenital adrenal hyperplasia. A recently released lot of this kit has higher crossreactivity with 17 alpha hydroxypregnenolone and 11 deoxycortisol. Both of these metabolites are present in high concentrations in premature infants. This crossreactivity has resulted in a significant increase in the number of borderline and positive results. As many as 0.8% of newborns may be falsely classified as abnormal. If Perkin Elmer does not correct this problem immediately, laboratories need to readjust their cutoff values. This problem is causing great hardships for patients and hospitals.