Laboratory Tests Using Blood
Susan L. Reed
Diagnosis, treatment, and management of patients require a multimodal, multidisciplinary approach. Along with an in-depth history and physical, the clinician frequently depends on test results to complete the assessment picture. One of the most frequently used testing modalities is laboratory testing of blood specimens. Laboratory analysis comprises approximately 43% of the data used by health care workers to make clinical decisions.1 A host of variables can affect interpretation of blood specimen results. Accurate interpretation starts with proper specimen collection. The nurse has a key role in maximizing the conditions under which specimens are collected, thereby controlling for as many variables as possible.
BLOOD SPECIMEN COLLECTIONCollection of blood specimens is a process that involves three phases: patient preparation, collection of the blood sample, and interpretation of results. The nurse plays an important role during these phases. Tests should not have to be repeated due to errors in any of these three phases.2
Patient Preparation
Adequate preparation of patients and their families involves education. Frequently, proper specimen collection and interpretation requires compliance with instructions about food or fluid restrictions, taking or withholding medications, and meeting criteria for proper timing of the blood sample. When the blood sample is taken, patients should receive an explanation about what tests are being drawn, why they have been ordered, and when results will be available. If the sample is being obtained by venipuncture, arterial puncture, or vascular port access, preparation of the patient includes a reminder about pain during the procedure and the importance of complying with instructions to maintain a certain position.2
Universal Precautions
All blood is considered a source of potential infection. Universal precautions, as well as organizational policies and procedures, should be followed when collecting and transporting specimens. Universal precautions include proper handwashing, the use of gloves during phlebotomy (or at any time there is risk of exposure to blood or body fluids), complete avoidance of recapping needles, and proper disposal of sharps. When there is the potential that blood or body fluids will splash, protective clothing and eyewear should be worn. Spills should be cleaned with an Environmental Protection Agency (EPA)-approved germicide or a 1:100 solution of household bleach, and soiled linen should be bagged at the location where it was used.3
Blood Sample Collection
General guidelines for blood sample collection have been developed that help to ensure patient and clinician safety and maximize interpretation of results. The clinician should consider the policies and procedures of his or her organization with regard to blood specimen collection, as well as the standards for professional, national, and international organizations. Control of variability can be enhanced by use of proper technique during collection and processing of the specimen.
During specimen collection through venipuncture, the use of a tourniquet produces changes within the vein. Once a tourniquet is placed on the arm, veins dilate because of their inability to drain. Cellular injury and hemolysis can be caused by the prolonged use of a tourniquet, described as 3 minutes or longer. Under these conditions, return of fluid and electrolytes to the vein is decreased or prohibited, resulting in a hemoconcentrated specimen. In addition, despite decreased circulation of fresh blood to the tissues, cells continue their metabolic processes, leading to an increased concentration in metabolic waste products, such as lactate. In this more acidic environment, potassium leaks out of cells. In general, the tourniquet should not be left on more than 1 minute.2 Longer use may be unavoidable during a difficult venipuncture. In such cases, information about a difficult venipuncture should be noted on the laboratory slip to assist with interpretation of results.
Blood specimens can be contaminated in several ways. During collection, contamination may occur from intravenous (IV) fluids. Blood draws should not be done on the same arm as an infusion. If the infusion arm cannot be avoided, a tourniquet may be placed between the IV site and the phlebotomy site. Slowing the IV to a keep-open rate (if not contraindicated) for 3 to 5 minutes before the draw may help to reduce contamination of the blood sample. In any event, it should be noted on the laboratory slip that the sample was obtained under these conditions.
Contamination may also be introduced by improper use of blood tubes. Most specimen collection tubes contain some form of anticoagulant. If blood has been mistakenly collected in one tube containing anticoagulant, it should never be poured into a different tube. Also, blood entering one tube should never be allowed to contaminate remaining blood that will be introduced into another tube.
Another source of contamination is introduced when routine samples are drawn from arterial lines, vascular catheters, or
ports. The use of an indwelling intravascular catheter allows access to the patient’s blood supply without further invasive procedure. Comfort for the patient, ease, and speed of periodic specimen collection are some of the benefits of using an intravascular line for blood sampling. Intravascular catheters may be kept patent by continuous or intermittent infusion, or by instilling saline or heparin solutions. Sometimes, solutions delivered through the catheter may contain medications. The infusate or any additives may dilute blood constituents. This dilution would have the effect of lowering the concentration of the desired sample.
ports. The use of an indwelling intravascular catheter allows access to the patient’s blood supply without further invasive procedure. Comfort for the patient, ease, and speed of periodic specimen collection are some of the benefits of using an intravascular line for blood sampling. Intravascular catheters may be kept patent by continuous or intermittent infusion, or by instilling saline or heparin solutions. Sometimes, solutions delivered through the catheter may contain medications. The infusate or any additives may dilute blood constituents. This dilution would have the effect of lowering the concentration of the desired sample.
The diameter and length of the catheter are important determinants when collecting blood specimens. The institution’s policy and procedure manual should be consulted for recommended withdrawal and discard from vascular devices. Additional sources, such as professional nursing society standards, may assist in making decisions about recommended discard volumes.
Whether sampling from a pulmonary artery catheter, central venous line, arterial catheter, or other intravascular catheter, attention should be paid to the feasibility of interruption of the system. The pulmonary artery catheter presents particular problems. Both the right atrium (RA) port and venous infusion port (VIP) are useful for the administration of drugs and fluids. Although the RA port allows access to the central circulation, use of this port for thermodilution cardiac output calculations makes it difficult to infuse drugs or fluids (a large amount of the infusate might be delivered during delivery of the cardiac output injectate). Consequently, the VIP is chosen for fluid and drug infusion. In this situation, the use of the RA port may be preferable for blood withdrawal. If vasoactive drugs are not infusing through the VIP, it may also be used for blood sampling. The proximal opening into the RA is upstream of any drugs or fluid infusing through the RA port; therefore, the possibility of contamination of the blood sample by infusates is minimized. Typically, the distal port of the pulmonary artery catheter is only used for blood sampling when measuring a mixed venous blood gas from the pulmonary artery where venous blood mixes after circulating through the superior and inferior vena cavae, coronary sinuses, and the chambers in the right side of the heart.
Many institutions have shifted to the use of saline in lieu of heparin in IV lines and pressure tubing however, questions persist about appropriate discard from vascular catheters (instilled with heparin) when drawing blood for coagulation studies. Inconsistent results may increase the cost to the patient through repeated testing, wasted blood, or erroneous treatment decisions. Again, the nurse may refer to policy and procedure manuals or professional organization standards for guidance. In any event, coordination in obtaining multiple blood specimens decreases the amount of blood that is eventually discarded and the number of times that the sterile system is invaded, thus reducing risk of introducing infection.
Sepsis has been associated with intravascular monitoring equipment including stopcocks and pressure transducers, which may be the most frequent reservoirs for endemic contamination. The incidence of local infection and bacteremia has been reduced by the use of disposable transducers and the percutaneous sheath systems used to introduce pulmonary artery catheters. The withdrawal of blood from an intravascular catheter should be considered a sterile procedure. Once removed, caps used to cover stopcock openings should always be replaced with a sterile cap. The person performing the procedure should be gloved. Syringes, used once, should be discarded.
Types of Specimens
When blood is withdrawn from the body, it eventually clots. The fluid that separates from the clot is called serum. Plasma, from unclotted blood, contains fibrinogen, which is eventually converted to fibrin. Most blood tests are done on serum, and therefore require use of a tube that allows blood to clot. Red-top tubes contain no additives; they are used for chemistries, drug monitoring, radioimmunoassays, serology, and blood typing. Lavender-top tubes, which contain ethylenediaminetetraacetic acid (EDTA), are usually used for hematology and certain other chemistries. Greentop tubes contain heparin as the anticoagulant and can be used for chemistries, arterial blood gases, hormone levels, and some immune function studies. Blue-top tubes, used for coagulation studies, contain citrate. Sodium fluoride, found in gray-top tubes, prevents glycolysis and may be used to test blood glucose in its in vivo state.2
When multiple blood samples are drawn at the same collection time, the preferred order is as follows: blood culture tubes, tubes with no preservative (red-top); tubes with mild anticoagulants (blue then green); tubes with EDTA (lavender-top); and oxalate/fluoride tubes (gray-top) should be collected last. Blood for coagulation studies should never be drawn first because tissue injury can initiate the clotting process and result in falsely low levels of coagulation factors. Specimens in tubes with additives should be rotated gently to mix the anticoagulant with the blood and should never be shaken.2
Hemolysis refers to the lysis of red blood cells (RBCs). When extracellular fluid (plasma) is used for analysis, inaccurate results are produced if the specimen is hemolyzed. Hemolysis may occur in vivo, as in hemolytic disease states such as transfusion reactions. Hemolysis may also occur in some infections and with the use of some drugs. A deficiency of the enzyme glucose-6-phosphate dehydrogenase, responsible for generating chemicals needed for maintenance of normal red cell fragility, contributes to hemolysis.
Hemolysis may also occur as a result of improper specimen collection technique or specimen transport. Hemolysis is the cause for specimen rejection in most nonemergent situations. Specimens may be hemolyzed if they are collected from a poorly flowing venipuncture. The selection of the appropriate size needle and catheter is essential when performing venipuncture. Failure to dry alcohol from the venipuncture site also results in hemolysis. Blood should never be forcibly withdrawn from the venipuncture, nor should it be forcibly entered into the collection tube by pushing on the syringe barrel to fill faster. Specimens should be handled carefully when placed in collection tubes and when transported to the laboratory; rough handling may lead to hemolysis.
Hemolysis increases the laboratory values of creatine kinase (CK), potassium, magnesium, calcium, and phosphorus.2 Hemolysis invalidates the results of most coagulation tests and can mask hemolyzing antibodies in the antibody screen and crossmatch.2 If unexpected elevated laboratory values are reported, the blood should be redrawn if hemolysis is suspected.
Nursing research continues to evaluate different techniques and equipment in determining the best method to withdraw blood, obtain accurate results, and reduce hemolysis. Controversy
still exists as to whether aspirating blood from an IV catheter or saline lock provides less hemolysis than venipuncture with a needle. Dugan et al.4 found drawing blood from a size 22-gauge IV catheter caused the most hemolysis in their emergency department. Lowe et al.5 and Grant6 found that venipuncture had less hemolysis than IV catheters, Kennedy et al.7 found larger size IV catheters caused less hemolysis than smaller sized catheters, and Cox et al.8 found using a 5-ml vacuum collection tube demonstrated better results than 10-ml vacuum tubes. However, Corbo et al.9 and Sliwa10 determined aspirating the sample from a saline lock after discarding blood did not result in more hemolysis than venipuncture. Arrants et al.11 found similar results using 18-gauge saline locks for use with coagulation studies. These studies demonstrate how important technique is to specimen collection.
still exists as to whether aspirating blood from an IV catheter or saline lock provides less hemolysis than venipuncture with a needle. Dugan et al.4 found drawing blood from a size 22-gauge IV catheter caused the most hemolysis in their emergency department. Lowe et al.5 and Grant6 found that venipuncture had less hemolysis than IV catheters, Kennedy et al.7 found larger size IV catheters caused less hemolysis than smaller sized catheters, and Cox et al.8 found using a 5-ml vacuum collection tube demonstrated better results than 10-ml vacuum tubes. However, Corbo et al.9 and Sliwa10 determined aspirating the sample from a saline lock after discarding blood did not result in more hemolysis than venipuncture. Arrants et al.11 found similar results using 18-gauge saline locks for use with coagulation studies. These studies demonstrate how important technique is to specimen collection.
Proper specimen collection includes accurate identification of the patient and accurate labeling of the specimen at the site of collection. It also includes rapid transport to the laboratory, because cells remain viable after collection and continue their metabolic processes. Specimens that are left to stand unprocessed often yield inaccurate results.
Interpretation of Results
Inherent physiologic variability exists based on patient age, sex, ethnicity, and health status (such as, pregnancy or post-myocardial infarction [MI]). These physiologic differences affect interpretation of results. Physiologic changes associated with the aging process bring concomitant changes in some expected laboratory results. Because men usually have more muscle mass than women, gender differences are seen in substances related to muscle function or metabolism, such as creatinine. There may be significant differences among European, African, and Asian populations in testing for cholesterol, enzymes, and hormones. Various physiologic states, such as pregnancy, stress, obesity, and endurance exercise, also introduce situational changes in expected results.12
Cyclic variability produces daily, monthly, or yearly patterns in physiologic states. These cycles are often taken into consideration in the collection or interpretation of laboratory results.12 As a result, most routine specimens, at least in the hospital setting, are drawn in the early morning to control for any circadian variability.
Blood tests are sometimes affected by the ingestion of food or fluids. Not only are results affected by the absorption of dietary components into the blood after a meal, but hormonal and metabolic changes occur as well. Partial control for the variability introduced by food or fluid ingestion can be achieved either by drawing early morning, pre-meal specimens, or by having the patient fast for 8 to 12 hours. The latter is especially important in lipid testing.13
Sometimes, differences based on position are negligible. In other cases, they are significant. Patient position during (and before) sampling can affect results. In the upright position, there may be a shift in extracellular fluid volume into the tissues. With the resulting increased concentration of proteins and protein-bound substances in the vascular space, samples for proteins, enzymes, hematocrit (Hct), hemoglobin (Hb), calcium, iron, hormones, and several drugs may show an average 5% to 8% increase. Redistribution of extracellular fluid volume and electrolytes within the vascular space does not stabilize until a patient has assumed the sitting position for at least 15 minutes (from a standing position), and in some cases 20 to 30 minutes. In some settings, such as the hospital, it is not difficult to stabilize the patient’s position and thus reduce variability. In other settings, such as ambulatory care, significant variability is introduced if the patient is not made to sit for at least 15 minutes before the blood draw. Because control over sitting time is not usually feasible or practical, care should be taken in the interpretation of results. Exercising immediately before blood sample collection frequently produces significantly erroneous results, especially with enzyme evaluation. Forearm exercises before blood withdrawal may lead to hemolysis.
The timing of blood sampling should include consideration of the effect of medications on the interpretation of results. Medications affect results of many specimens drawn for chemistry, hematology, coagulation, hormonal, and enzyme studies. Knowledge of the effect of the drug assists in proper timing or subsequent interpretation of the results. Consideration should also be given to the effects of other influences, including over-the-counter medications, caffeine, nicotine, ethanol, home remedies, and herbal therapies.
In therapeutic drug monitoring, blood drug levels are monitored to evaluate the effects of drug therapy, make decisions regarding dosage, prevent toxicity, and monitor patient adherence. Timing of the blood sample usually depends on the half-life of the drug; samples drawn at projected peak level assist in monitoring for toxicity, whereas levels drawn at trough help to verify the minimum satisfactory therapeutic level for that patient. Regardless of the purpose of the blood sample, drugs that may affect interpretation of results should be noted on the laboratory slip. For therapeutic drug monitoring, it is important to note the date and time of the last dose as well.
Different laboratories use different equipment and methods by which to test specimens. Specific reference ranges are usually reported alongside the patient’s results on the laboratory report. In an effort to establish a standard for communicating laboratory results, the World Health Organization has recommended that the medical and scientific community throughout the world adopt the use of the International System of Units (ISU). An international unit is defined as the number of moles of substrate converted per second under defined conditions. Thus, many laboratories may report results in different ways, depending on their accepted standard of practice. Most laboratories also report critical (or panic) values. These values should be reported promptly to the provider so that results may be evaluated (and decisions made) in light of the patient condition.
Most reference ranges have been established for venous blood samples. Because arterial blood has higher concentrations of glucose and oxygen and lower concentrations of waste products (i.e., ammonia, potassium, and lactate), an arterial source (instead of venous) should be noted on the laboratory slip. Capillary samples yield results that are closer to arterial blood than venous.
Critical evaluation of laboratory results should take into account how the reference or “normal” values were determined. Patients who have been seen for a long time by the same provider, or those who have been seen within the same health care organization, sometimes establish their own reference range. Reference ranges for a specific disease are sometimes established through large-scale clinical trials.
In most circumstances, each laboratory establishes its own reference values by testing a group that is easy to recruit. It is possible, however, that this technique may not reflect the usual values or range of values of the group that the organization serves. When samples are taken from volunteers, such as those who agree to give a blood sample for reference testing in exchange for a free cholesterol screening, bias may be introduced because those who are likely to volunteer may be those who have or suspect they have illness already. When reference samples are taken from patients who are undergoing routine physical examinations or elective surgery, results may reflect a mix of the surrounding population. Again, these reference values need to be considered in light of who was included or excluded from testing. Usually, those who drink alcohol, smoke, or take certain medications are excluded from reference range testing. However, this exclusion is likely to establish a narrow range of “normal” values, thereby increasing the number of people in the served population who fall outside the established range. Additional care should be taken in interpreting results if the laboratory reports only one set of reference values.
Clinicians who are aware of how reference ranges are obtained are in a better position to interpret laboratory results accurately for their patients. In all situations, interpretation of results should be done in light of all factors that introduce variability, and in light of the clinical condition, remembering that “normal” values do not necessarily indicate absence of disease; just as “abnormal” values do not necessarily establish a pathologic state.
Sensitivity and Specificity of Laboratory Tests
Clinicians should use measures of test performance to judge the quality of a diagnostic test for a particular disease. The ability of a laboratory test to identify a particular disease is quantified by two measurements: sensitivity and specificity.14
Sensitivity is the frequency of a positive (abnormal) test result among all patients with a particular disease or the likelihood that a diseased patient has a positive test. If all patients with a given disease have a positive test, the test sensitivity is 100%. Sensitivity is calculated by testing a population of patients who have been found to have a particular disease by some “gold standard” method (a procedure that defines the true disease state of the patient).14
Specificity is the frequency of a negative (normal) test among all persons who do not have the disease or the likelihood that a healthy patient has a negative test. If all patients who do not have a particular disease have a negative test, the test specificity is 100%. A test with a high specificity is helpful to confirm a diagnosis, because a highly specific test will have few results that are falsely positive. Specificity is calculated by testing a population of patients who have been found to have a particular disease by some gold standard method.14
Under the best of circumstances, no blood test is perfect and results may be misleading. Sensitivity and specificity may be altered by the coexistence of other diseases or complications from the primary disease. The most sensitive tests are used to rule out a suspected disease so that the number of false-negative tests is minimal; thus, a negative test tends to exclude the disease. The most specific tests are used to confirm or exclude a suspected disease and minimize the number of false-positive results.15
Point-of-Care Testing
Point-of-care testing (POCT) also known as Bedside Testing or Alternative Site Testing, is the laboratory testing of blood that is performed outside of a central laboratory. The goal of POCT is to reduce the time it takes to diagnose and treat the patient (decision cycle time). Since laboratory analysis of blood comprises approximately 43% of the data used by health care workers to make clinical decisions,1 POCT provides a decrease in the number of steps required to obtain a blood sample, process the sample, and receive the data, and therefore reduces decision cycle time. POCT is ideal in intensive care units, emergency departments, cardiac catheterization laboratories, and surgical suites where the need for rapid turnaround time of laboratory data is desired. Benefits of POCT include decreased turnaround time, improved patient management, increased patient satisfaction, improved job satisfaction of nurses and physicians, decreased operating room time, decreased mortality and morbidity, and less blood sample volume.
Glucose monitoring has been available for years as POCT to guide dosage of insulin administration. Hospitals have also used portable activated clotting time (ACT) monitors to guide anticoagulation and heparin administration during interventional cardiology procedures and during cardiovascular surgery. In addition to glucose and ACT, POCT assays that are available for care of cardiac patients include Hct, Hb, arterial blood gases (ABGs), electrolytes, blood urea nitrogen (BUN), creatinine, ethanol, drugs of abuse, troponin-I, troponin-T, myoglobin, CK-MB, and Type-B natriuretic peptide (BNP). Use of POCT cardiac biochemical marker testing has increased from 4% in 2001 to 12% in 2004 and is expected to rapidly expand.16
To ensure accuracy of data, a POCT system requires that there be up front training of non-laboratory personnel on how to use new equipment, continued proficiency testing of staff, and assurance that electronic quality control requirements are met. It is important that POCT systems are linked to hospital or laboratory systems by radiofrequency and infrared to ensure that information handling, storage, and billing are done properly.
Possible limitations of using a POCT system include its use by personnel with limited training in laboratory technology and the lack of understanding of quality control. POCT is considered to be more expensive than traditional laboratory analysis because the cost of cartridges is more expensive. Cost analysis needs to include the decreased labor by nursing and laboratory personnel plus the ability to make rapid decisions about acutely ill patients that may alter their course of illness.1
Administration of a POCT system includes designating someone to be responsible for the POCT service, which would include: knowing who is performing POCT and which test they are performing, maintaining quality control documentation, selecting appropriate equipment, troubleshooting all aspects of POCT, coordinating training, and serving as a liaison between nursing and other services.
Ng et al.17 and Singer et al.18 studied use of POCT of cardiac biomarkers in the triaging of patients with chest pain. Cardiac marker POCT reduced length of stay in the emergency department18 and allowed for accurate triaging of chest pain patients within 90 minutes of presentation to the emergency department.17
BIOCHEMICAL MARKERS OF MYOCARDIAL INJURYThe internal environment of the healthy person is in a state of balance with respect to water, electrolytes, energy storage and use, and metabolic end products. Stability is maintained through homeostatic mechanisms that regulate the activities of cells and organs. During periods of critical illness, a disruption in cell membrane stability may cause chemical substances that are responsible for intracellular homeostatic mechanisms to appear in the blood. Frequent evaluation of blood results is a means by which the status of the internal environment and the extent and nature of tissue damage can be monitored. These blood tests can be run expeditiously and require small sample volumes, and provide important information concerning the diagnosis and management of patients.19
Certain intracellular enzymes and proteins are rarely found in measurable amounts in the blood of healthy people. However, after an event leading to cellular injury or death, these substances may leak into the blood. A continued question with ongoing research is the extent to which reversible cell damage can cause protein leakage.20 Because of the importance of the timing of the appearance (and disappearance) of enzymes and proteins in the blood, it is crucial that ordered tests are drawn on time. It is equally important that the date and time of the blood draw are noted on the laboratory slip so that the temporal sequence of the rise and fall can be established by those interpreting the results.
Over the years as more specific biochemical markers of myocardial injury have become available, detecting MI has become more accurate. The original marker, glutamine-oxaloacetic transaminase was replaced by lactate dehydrogenase (LDH) and later by CK and CK-MB. Troponin has now become the preferred laboratory test for diagnosing MI and the other markers are becoming obsolete.21 Initial diagnosis of MI, reinfarction, or other types of myocardial damage is made through evaluation of clinical signs and symptoms, 12-lead ECG, biochemical markers including myocardial proteins (troponins) and if troponin not available, cardiac enzymes (see Chapter 22).22 A comparison of the sensitivity and specificity of various tests to detect myocardial injury is in Table 11-1.
Table 11-1 ▪ COMPARISON OF SENSITIVITY AND SPECIFICITY OF VARIOUS TESTS FOR MYOCARDIAL INFARCTION | ||||||||||||||||||||||||||||||
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Myocardial Proteins
Troponins
Troponins are protein complexes that regulate the calcium-dependent interaction of myosin with actin in the muscle contractile apparatus of striated muscle. They are found in both cardiac and skeletal muscle. Three isotypes have been identified: troponin-I (cTnI), troponin-T (cTnT), and troponin-C (cTnC). Troponins T and I are both found in the myocardium. Troponin-T binds the troponin complex to tropomyosin, and troponin-I inhibits the muscle contraction in the absence of calcium and troponin-C.2 Troponin-C lacks cardiac specificity; therefore, it is the least studied of the troponins and has no assay available in the clinical setting.
Because of the high specificity and sensitivity for detecting myocardial injury, troponin has become the most important addition to clinical laboratory testing for assessment of myocardial injury.12 In patients with acute coronary syndrome, troponin is an enormously useful biochemical marker in the early diagnosis of MI because it is either low or undetectable in healthy people, but in the event of an MI, is detectable as early as 2 to 3 hours after injury.19 Testing for troponin is typically done at the time of the initial workup for suspected acute coronary syndrome or myocardial damage and then 6 to 9 hours later. An additional sample may be measured between 12 and 24 hours if biochemical markers have not shown elevation and MI is still suspected.22,23 Because most troponin is so tightly bound to muscle, it is released slowly and may remain detectable for 1 to 2 weeks post-MI.22 This late-phase presence of troponin represents death of the contractile apparatus. Because troponin remains elevated longer than CK-MB and is more specific than LDH, troponin is now the preferred test for patients who seek medical attention more than 24 to 48 hours after myocardial injury. The appearance of troponin in the blood indicates necrosis or injury to the myocardium and follows a predictable rise and fall over a specified time. See Table 11-2 and Figure 11-1 for the typical appearance, peak, and disappearance of various biochemical markers and enzymes.
In patients with ST-segment elevation MI, percutaneous coronary intervention (PCI) or fibrinolytic therapy should not be delayed waiting for biochemical marker evaluation.21 For other patients with suspected cardiac symptoms, troponin is used along with clinical signs and symptoms and 12-lead ECG to make
treatment decisions concerning emergency angiogram versus fibrinolytic therapy.
treatment decisions concerning emergency angiogram versus fibrinolytic therapy.
Table 11-2 ▪ TIMING OF APPEARANCE AND DISAPPEARANCE OF COMMONLY USED CARDIAC BIOMARKERS AND ENZYMES IN RELATION TO ONSET OF CARDIAC SYMPTOMS | ||||||||||||||||||||||||||||||||
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 ▪ Figure 11-1 Patterns and timing of elevation for aspartate aminotransferase (AST), creatine kinase (CK), lactate dehydrogenase (LDH), and troponin. (From Pagana, K. D., & Pagana, T. J. [2007]. Mosby’s diagnostic and laboratory test reference [8th ed.]. St. Louis: Mosby Elsevier.) |
In the setting of acute coronary syndrome and MI, rapid reperfusion through coronary intervention, a rapid peak or “washout” of troponin-I may be seen indicating reperfusion of the ischemic muscle tissue. This elevation is considered a favorable prognostic indicator.2,24 Troponin has also been shown to correlate well with estimating myocardial infarct size. Nuclear scintigraphy and/or magnetic resonance imaging have both correlated well with troponin peak levels and infarct size.25, 26, 27, 28
Between 15% and 48% of patients with unstable angina have an elevated troponin level with normal CK-MB. On coronary angiography, these patients frequently have active, unstable plaques, whereas patients without elevated troponin levels have stable plaques.29 These patients are considered to have minor myocardial damage. Patients with detectable levels of troponin have a higher in hospital chance of suffering an adverse cardiac event. The risk is correlated with level of troponin: the higher the troponin, the worse the outcome.24,30
In patients who have had a recent MI and reinfarction is suspected, troponin is not as helpful since it may still be elevated from the first event.23 Recurrent MI may be diagnosed if there is a greater than 20% increase in the value in the second sample.22
A troponin level (I or T) greater than the 99th percentile of normal reference population (upper reference limit [URL]) is indicative of myocardial necrosis.22 Troponin rarely exceeds 0.1 ng/mL in healthy individuals.20 Elevation of troponin reflects myocardial necrosis; however, it does not indicate the mechanism of the injury and may not be from ischemia caused by coronary artery disease.22 If other clinical evidence of myocardial ischemia is absent, a search for other causes of cardiac damage should be examined.
Elevation of troponin can be detected in a variety of conditions other than coronary ischemia. Other conditions that may release troponin (possibly from myocyte membrane permeability) include tachycardia, pericarditis, heart failure, and strenuous exercise. In addition, a mismatch between myocardial oxygen supply and demand may result in troponin release. Sepsis, hypotension, extracellular fluid volume deficit, atrial fibrillation, and tachycardia may increase the oxygen demand of the heart and cause troponin to leak into the bloodstream in patients with no evidence of coronary artery disease. Patients with critical illness and troponin elevations have been found to have a worse prognosis.21,31 See Display 11-1 for elevations of troponin in the absence of overt ischemic heart disease.
Troponin elevation may be seen in patients with pulmonary diseases. This elevation is usually associated with right heart strain. Of patients diagnosed with moderate-to-large pulmonary embolism (PE), 30-50% have elevated troponin levels. This elevation may be from the acute right heart overload and has been associated with significant increase in mortality.21,31
Assessing for myocardial damage after blunt cardiac trauma may be difficult given the high rate of false-positive and false-negative results when using CK-MB. Troponin-I along with ECG has emerged as an accurate test for confirming presence of myocardial damage after cardiac contusion.24,32
As with any test, there are documented incidences of falsepositive troponin elevation. These elevations may be caused by heterophilic antibodies, rheumatoid factor, fibrin clots, microparticles, or analyzer malfunction.21,31 The clinician must always
evaluate the clinical signs and symptoms and other diagnostic tests to ensure accurate diagnosis and treatment.
evaluate the clinical signs and symptoms and other diagnostic tests to ensure accurate diagnosis and treatment.
DISPLAY 11-1 Elevations of Troponin in the Absence of Overt Ischemic Heart DiseaseTrauma (including contusion, ablation, pacing, implantable cardioverter-defibrillator firings including atrial defibrillators, cardioversion, endomyocardial biopsy, cardiac surgery, after interventional closure of atrial septal defects)
Congestive heart failure, acute and chronic
Aortic valve disease and hypertrophic obstructive cardiomyopathy with significant left ventricular hypertrophy
Hypertension
Hypotension, often with arrhythmias
Postoperative noncardiac surgery patients who seem to do well
Renal failure
Critically ill patients, especially with diabetes, respiratory failure
Drug toxicity, e.g., adriamycin, 5-fluorouracil, herceptin, snake venoms
Hypothyroidism
Apical ballooning syndrome
Coronary vasospasm
Inflammatory disease, e.g., myocarditis, Parvovirus B10, Kawasaki disease, sarcoid, smallpox vaccination, or myocardial extension of bacterial endocarditis
Post-percutaneous coronary intervention patients who seem to have no complications
Pulmonary embolism, severe pulmonary hypertension
Sepsis
Burns, especially if total body surface area is >30%
Infiltrative disease including amyloidosis, hemachromatosis, sarcoidosis, and scleroderma
Acute neurological disease, including cerebrovascular accident, subarachnoid bleeds
Rhabdomyolysis with cardiac injury
Transplant vasculopathy
Vital exhaustion
Jaffe, A. S., Babuin, L., & Apple, F. S. [2006]. Biomarkers in acute cardiac disease— The present and the future. Journal of the American College of Cardiology, 48(1), 1-11.
Cardiac Enzymes
Enzymes are protein substances that catalyze chemical reactions in cells but do not themselves enter into the reaction. Substrates in the cells bind to the enzymes and form products. After the reaction, the enzyme molecule is free to undergo the same reaction with other substrate molecules. Specific enzymes are responsible for nearly every chemical reaction in the body. Some enzymes are present in almost all cells; others are specific to cells of certain organs.
Creatine Kinase
Creatine kinase is an enzyme specific to cells of the brain, myocardium, and skeletal muscle, but also is found in minimal amounts in other tissues, such as smooth muscle. In these organ systems, the function of CK is primarily that of energy production, where it serves as a catalyst in the phosphorylation of adenosine diphosphate (ADP) to creatine and adenosine triphosphate (ATP). In this manner, CK is responsible for the transfer of an energy-rich bond to ADP. This reaction provides a rapid means of forming ATP for contractile activity in muscle as well as for energy requirements in nonmuscle tissue. The reaction is reversible, and ATP can phosphorylate creatine to form creatine phosphate and ADP during periods of rest.
In an acute MI, inadequate oxygen delivery to the myocardium causes cell injury. An acidic environment promotes the activity of lysosomal enzymes, which are responsible for cell membrane damage or destruction. CK is among the cellular enzymes that diffuse from the damaged cell into the blood. CK is released after irreversible injury. The appearance of CK in the blood indicates cardiac, cerebral, or skeletal muscle necrosis or injury and follows a predictable rise and fall over a specified time (see Fig. 11-1).
Age, sex, race, physical activity, lean body mass, medications, and other unidentified factors are known to affect total CK. A patient’s baseline CK level is related to his or her overall muscle mass. Adults have lower values than children. Serum CK declines with age and older adults have very low values. CK values measured in women are lower than those of men; European Americans have lower values than African Americans. Chronic exercise raises serum CK levels; however, there is a training effect, and well-trained athletes have smaller increases in CK after physical exertion. Medications that may increase CK include anticoagulants, aspirin, furosemide, captopril, lidocaine, propranolol, and morphine. In addition, high-intensity lipid-lowering therapy with lipophilic statins (i.e., simvastatin or lovastatin) have been found to increase CK.33 Early and abnormally high increases in CK are sometimes seen after reperfusion by PCI (Chapter 23) or thrombolytic agents.2,3
The importance of monitoring the concentration of serum CK is related to its specificity in the organ in which it functions. Slightly different molecular forms (isoenzymes or isozymes) of CK have different tissues of origin. The three CK isoenzymes are combinations of the protein subunits, named for their primary sites of isolation—the muscle (M) and brain (B). CK-MM is the predominant muscle isoenzyme, found in cardiac and skeletal muscle. It also can be detected in normal serum. The myocardium is primarily responsible for the CK-MB form. CK-BB is present in the brain, lung, stomach, prostate, and smooth muscle of the gastrointestinal tract and bladder. Diagnostic precision depends on laboratory analysis of CK isoenzymes and may well be imperative in critically ill patients with multiple organ system involvement.
Because of the wide range in baseline values among “healthy” people, and various enzyme assay techniques, there are no uniform reference values for CK and CK isoenzymes. Consequently, the practice of reporting the isoenzyme as a percentage of the total CK, as well as in U/L has been encouraged.
Creatine Kinase-BB.
The brain fraction CK-BB (CK-1) is seen infrequently in serum. Its rare appearance has been associated with brain trauma, cerebral contusions, and cerebrovascular accidents. The presence of CK-BB in association with cancer has been reported. Other causes of serum CK-BB activity include malignant hyperthermia, renal failure, and after central nervous system surgery.3 With the significant improvement in diagnostic imaging techniques, CK-BB is now rarely evaluated.
Creatine Kinase-MM.
CK-MM constitutes almost the entire CK total in healthy people. Skeletal muscle injury or severe muscle exertion is the most frequent source of high serum CK-MM (CK-3) levels. Specific examples include myopathy, vigorous exercise, multiple intramuscular (IM) injections, electroconvulsive therapy, cardioversion, surgery, muscular dystrophy, convulsions, and delirium tremens. Elevations in CK-MM fractions have also been noted in conditions producing less obvious effects on muscle, such as hypokalemia and hypothyroidism.3
Creatine Kinase-MB.
Prior to the discovery of troponin, CK-MB (CK-2) isoenzyme analysis had been an accepted means for diagnosis of an acute MI. Although troponin has superseded CK-MB in the diagnosis of MI, most institutions continue to evaluate CK, CK-MB, and troponin if MI is suspected.
When CK-MB is released from myocardial tissue, it has a biologic half-life in blood of hours-to-days. Total CK and CK-MB rise within 2 to 8 hours after an acute MI. Peak levels are seen within 18 to 36 hours and are more than six times their normal value. If no additional myocyte necrosis occurs, levels return to normal within 3 to 4 days. See Table 11-2 and Figure 11-1 for the typical appearance, peak, and disappearance of various biomarkers and enzymes.
Elevated CK-MB levels have also been reported after myocardial damage from unstable angina, cardiac surgery, coronary angioplasty, after defibrillation, in vigorous exercise, and after IM injections, trauma, and surgery. Early and abnormally high increases in CK are sometimes seen after reperfusion by PCI or thrombolytic agents. By 6 to 8 hours postangioplasty, 20% of patients have a mild increase in CK-MB. Elevations are occasionally seen in pericarditis, myocarditis, viral myositis, and sustained tachyarrhythmias. An increase in CK-MB may occur after cardioversion, but that time course for increase is different for that of MI, with the mild increase of CK-MB peaking within 4 hours of cardioversion.
Specimens for CK and CK-MB are collected on admission and 8 to 12 hours later. CK and CK isoenzyme results should be evaluated along with troponin, myoglobin, ECG results, and clinical signs and symptoms for the detection of MI. Laboratory slips should be marked with the date and time of any IM injections given to the patient in the prior 24 to 48 hours.
Caution should be exercised in interpretation of CKs drawn in the emergency department. Only 25% to 40% of patients who are having an MI have an abnormal CK at that point. An initial
normal CK level should never be used to make a decision about discharge from the emergency department, or to withhold thrombolytic therapy.
normal CK level should never be used to make a decision about discharge from the emergency department, or to withhold thrombolytic therapy.
Myoglobin
Myoglobin is a low-molecular-weight, oxygen-binding protein found in the myocardium and skeletal muscle. Myoglobin is released into the circulation after damage to the heart or skeletal muscle.2 Because of its release from other muscle tissues, troponin rather than myoglobin is the biomarker of choice for diagnosing MI. After MI, myoglobin levels increase in 2 to 3 hours, peak in 6 to 9 hours, and return to normal (undetectable) as early as 12 hours but more typically after 24 to 36 hours (see Table 11-2).3
Elevated myoglobin levels are seen after MI, reinfarction, cocaine use, skeletal muscle injury, trauma, exercise, IM injections, severe burns, electrical shock, polymyositis, alcoholic myopathy, delirium tremens, metabolic disorders (e.g., myxedema), malignant hyperthermia, systemic lupus erythematosus, muscular dystrophy, rhabdomyolysis, and seizures.2,3 Myoglobin may not be excreted in renal failure, so caution should be used when interpreting results.2 Further, very high levels of myoglobin are toxic to the kidneys and thus, careful monitoring of renal function is warranted.
Biochemical Marker Activity after PCI
After elective PCI for stable angina, biomarker elevation is fairly common. CK and CK-MB elevation occurs in 5% to 30% of patients. These elevations have been associated with increased risk of death, MI, and need for repeat revascularization.34 Prasad et al.35 found that troponin elevation is frequent after elective PCI. Of the patients in their study, 19% had an elevated troponin level. These patients had more complex angiographic characteristics and had undergone multivessel PCI. They found that an elevated troponin level was associated with increased morbidity and mortality. Miller et al.29 measured troponin before (baseline) and after PCI and found that prognosis was most often related to the baseline troponin level and not the biomarker response after the procedure. Nallamothu et al.36 analyzed 1,157 patients who underwent elective PCI and found that troponin-I elevation was common after the procedure (29%), and that large troponin elevations, up to eight times normal, were associated with decreased long-term survival. Taken together, these studies demonstrate that continued use and evaluation of biochemical markers is essential after coronary intervention.
Biochemical Marker Activity after Cardiac Surgery
All types of cardiac surgery involve considerable injury to the myocardium. However, differentiating between ischemic alterations associated with surgery and peri-operative MI may be difficult. The evaluation of troponin and cardiac enzymes is common after cardiovascular surgery. Researchers have focused on the prognostic implication of elevated troponin and cardiac enzymes measurements after surgery. Klatte et al.37 and Costa et al.38 found that elevated levels of CK-MB in serial measurements after coronary artery bypass graft (CABG) surgery were associated with increased mortality, and that the higher the level of CK-MB, the higher risk of mortality in the immediate to long-term postoperative period. With troponin evaluation becoming more common, Januzzi et al.39 determined troponin-T levels offered a superior predictor of complications from cardiac surgery than CK-MB. Kathiresan et al.40 and Croal et al.41 found similar results, the higher the troponin, I or T, the increased risk of mortality after CABG surgery. These studies demonstrate that biomarker evaluation postoperatively also is important and should not be considered inconsequential.
BLOOD LIPIDSAn accumulation of lipids within the arterial wall is considered a part of the process of atherogenesis. Alteration of blood lipid levels has been identified as a coronary heart disease (CHD) risk factor. Certain lipoproteinemias have been identified as contributing to total plasma cholesterol levels. Plasma normally contains insoluble lipid elements: free fatty acids; exogenous triglycerides; endogenous triglycerides, which are manufactured in the liver; cholesterol; and phospholipids. To be transported, each is attached to a protein. Distinguishing lipoprotein abnormalities is useful because therapy is based on an understanding of the origin of the problem.
Blood Lipid Laboratory Measurement
Elevated lipid levels are considered a risk factor for cardiovascular disease. Cholesterol and the protein components of high-density lipid (HDL), low-density lipid (LDL), and triglycerides are evaluated by electrophoresis when hyperlipoproteinemia is suspected.42 See Table 11-3 for recommended levels of cholesterol and its components. In most people, the cholesterol values remain constant over 24 hours; a nonfasting blood sample for measurement of total blood cholesterol is acceptable. However, a nonfasting sample for HDL, LDL, and triglyceride levels is of less value. National Cholesterol Education Program 2001 guidelines on cholesterol screening recommend everyone over age 20 have a fasting lipoprotein profile (total cholesterol, LDL, HDL, and triglycerides) every 5 years.13 Lipoprotein electrophoresis is necessary to evaluate serum for hyperlipoproteinemia. LDL is more difficult to isolate and measure. Therefore, if LDL is not measured in a screening lipoprotein test, it may be calculated using the Friedewald formula. The Friedewald formula is inaccurate if the triglycerides are greater than 400 mg/dL (see Display 11-2).43
It is recommended that lipid profile tests should be performed after a 12-to-14 hour fast and having a stable diet for 2 to 3 weeks prior to testing. It is also recommended that testing occur in the absence of acute illnesses including stroke, trauma, surgery, acute infection, weight loss, and pregnancy. These conditions often result in values that are not representative of the person’s usual level.13
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