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  • Metabolic Acidosis

    This type of acidosis has at least three main causes.

    Acid-gaining acidosis. Hydrogen ions not included in the CO2 system are added to the blood. The common situations are:

    1. Direct administration, such as treatment with ammonium chloride, or the late effects of salicylate poisoning. Ammonium chloride (NH4Cl) releases H+ ions and Cl– ions as the liver utilizes this compound for NH3 to synthesize urea. Aspirin is acetylsalicylic acid, which in large quantities will eventually add enough H+ ions to cause acidosis, even though in the early stages there is respiratory alkalosis (to be discussed later).

    2. Excess metabolic acid formation is found in diabetic ketoacidosis, starvation, or severe dehydration. These conditions cause utilization of body protein and fat for energy instead of carbohydrate, with production of ketone bodies and various metabolic acids.

    The results of acid-gaining acidosis are a decrease in free HCO–3, which is used up trying to buffer the excess H+. Thus, the numerator of the Henderson-Hasselbalch equation is decreased, the normal 20:1 ratio is decreased, and the pH is, therefore, decreased. The CO2 content (CO2 combining power) is also decreased because the bicarbonate which it measures has been decreased as a primary response to the addition of excess acid.

    Base-losing acidosis. Base-losing acidosis is caused by severe intestinal diarrhea, especially if prolonged or in children. Diseases such as cholera or possibly ulcerative colitis or severe dysentery might cause this. The mechanism is direct loss of HCO–3 from the lumen of the small intestine. Normally, HCO–3 is secreted into the small intestine, so that the contents of the small intestine are alkaline in contrast to the acidity of the stomach. Most of the HCO–3 is reabsorbed; however, prolonged diarrhea or similar conditions could mechanically prevent intestinal reabsorption enough to cause significant HCO–3 loss in the feces. In addition, the H+ ions that were released from H2CO3 in the formation of HCO–3 by carbonic anhydrase are still present in the bloodstream and help decrease pH. However, the primary cause is the direct loss of HCO–3; the numerator of the Henderson-Hasselbalch equation is decreased, the 20:1 ratio is decreased, and the pH is decreased. Naturally, the CO2 content is also decreased.

    Renal acidosis. Renal acidosis occurs in kidney failure that produces the clinical syndrome of uremia. As mentioned previously, the kidney has the major responsibility for excreting large excesses of H+. In uremia, H+ from metabolic acids that normally would be excreted this way is retained in the bloodstream due to loss of renal tubular function. As in acid-gaining acidosis, the excess H+ must be buffered; therefore, part of the available body fluid HCO–3 is used up. This decreases the numerator of the Henderson-Hasselbalch equation, decreases the normal 20:1 ratio, and therefore decreases pH. Again, the CO2 content is decreased.

  • Clinical Disturbances of pH

    With this background, one may proceed to the various clinical disturbances of pH. These have been clinically termed “acidosis,” when the pH is decreased toward the acid side of normal and alkalosis, when the pH is elevated toward the alkaline side of normal. Acidosis, in turn, is usually subdivided into metabolic and respiratory etiology, and the same for alkalosis.

  • Acid-Base Test Specimens

    In the early days, acid-base studies were performed on venous blood. Venous specimens are nearly as accurate as arterial blood for pH and HCO3 (or PCO2) measurements if blood is obtained anaerobically from a motionless hand or arm before the tourniquet is released. Nevertheless, arterial specimens have mostly replaced venous ones because venous blood provides less accurate data in some conditions such as decreased tissue perfusion due to shock. Even more important, one can also obtain blood oxygen measurements (PO2) with arterial samples. Arterial blood is most often drawn from the radial artery in the wrist. Arterial puncture is little more difficult than venipuncture, and there is a small but definite risk of extravasation and hematoma formation that could compress the artery. Although glass syringes have some technical advantages over plastic syringes or tubes (such as a slightly smaller chance of specimen contamination with room air than when using plastic syringes), most hospitals use only plastic. It is officially recommended that the specimen tube or syringe should be placed in ice immediately for transport to the laboratory, both to prevent artifact from blood cell metabolism and to diminish gas exchange between the syringe and room air. The blood must be rewarmed before analysis. Actually, it is not absolutely necessary to ice the specimen in most cases if the analysis takes place less than 15 minutes after the specimen is obtained. Icing the specimen in plastic tubes can elevate PO2 values a little if they are already over 80 mm Hg (10.7 kPa). One investigator found that at 100 mm Hg (13.3 kPa), the false elevation averages 8 mm Hg (1.06 kPa). Also, icing in plastic tubes increases plasma viscosity over time and interferes with resuspension of the RBC, which affects hemoglobin assay in those instruments that calculate O2 content from PO2 and total hemoglobin. If mixing before assay is not thorough, hemoglobin values will be falsely decreased somewhat. In addition, if electrolytes are assayed on the arterial specimen, potassium may be falsely increased somewhat.

    Capillary blood specimens from heelstick are often used in newborn or neonatal patients because of their small blood vessels. Warming the heel produces a semiarterial (“arterialized”) specimen. However, PO2 is not reliable and PCO2 sometimes differs from umbilical artery specimens. The majority of reports do not indicate substantial differences in pH; however, one investigator found a mean decrease in PCO2 of 1.3 mm Hg (0.17 kPa), a mean pH increase of 0.02 units, and a mean decrease of 24.2 mm Hg (3.2 kPa) in PO2 from heelstick blood compared to simultaneously drawn umbilical artery blood.

    Heparin is the preferred anticoagulant for blood gas specimens. The usual method is to wash the syringe with a heparin solution and then expel the heparin (which leaves about 0.2 ml of heparin in the dead space of the syringe and needle). If too much heparin remains or the blood sample size is too small (usually when the sample is <3 ml), there is a disproportionate amount of heparin for the amount of blood. This frequently causes a significant decrease in PCO2 (and bicarbonate) and hemoglobin values, with a much smaller (often negligible) decrease in pH. These artifactual decreases in PCO2 are especially apt to occur when the sample is obtained from indwelling catheters flushed with heparin.

  • Carbon Dioxide of pH and Carbon Dioxide

    This section describes the laboratory tests used in pH abnormalities, which, incidentally, are often called “acid-base problems” because of the importance of the bicarbonate and carbonic acid changes involved.

    Carbon dioxide combining power. Venous blood is drawn aerobically with an ordinary syringe and the serum is then equilibrated to normal alveolar levels of 40 mm Hg by the technician blowing his or her own alveolar air into the specimen through a tube arrangement. This maneuver adjusts the amount of dissolved CO2 to the normal amounts found in normal arterial blood. Bicarbonate of the serum is then converted to CO2 by acid hydrolysis in a vacuum, and the released gas is measured. The released CO2 thus consists of the dissolved CO2 of the specimen already present plus the converted HCO–3 (and thus the denominator plus the numerator of the Henderson-Hasselbalch equation). Subtraction of the known amount of dissolved CO2 and H2CO3 in normal blood from this measurement gives what is essentially a value for serum HCO–3 alone (called the “combining power,” since HCO–3 combines with H+). The inaccuracy that may be caused by these manipulations should be obvious.

    Carbon dioxide content. Total CO2 content is determined from heparinized arterial or venous blood drawn anaerobically. This may be done in a vacuum tube or a syringe that is quickly capped. (Mineral oil is not satisfactory for sealing.) The blood is centrifuged and the plasma removed. At this point, all the CO2 present is still at the same CO2 tension or partial pressure of dissolved gas that the patient possessed. Next, the plasma is analyzed for CO2 by a method that converts HCO–3 and H2CO3 to the gas form. Thus CO2 content measures the sum of HCO–3, H2CO3, and dissolved CO2. Since the amount of dissolved CO2 and H2CO3 in blood is very small, normal values for CO2 content are quite close to those of the CO2 combining power (which measures only HCO–3). Since the specimen has been drawn and processed with little or no contact with outside air, the result is obviously more accurate than that obtained from the CO2 combining power.

    Serum bicarbonate. An order for serum CO2, serum HCO–3, or venous CO2 will usually result in serum being obtained from venous blood drawn aerobically and assayed for HCO–3 without equilibration. This technique is used in most automated equipment that assays “CO2” (really, bicarbonate) in addition to performing other tests, and is also popular in many laboratories using manual methods since the patients usually have other test orders that require serum. It is somewhat less accurate than CO2 combining power. The serum is frequently exposed to air for relatively long periods of time. Only relatively large changes in CO2 or HCO–3 will be detected. Underfilling of specimen collection tubes to only one third of capacity significantly decreases bicarbonate values.

    Partial pressure of carbon dioxide (PCO2).

    PCO2 is the partial pressure of CO2 gas in plasma or serum (in mm of Hg or in Torr); this is proportional to the amount of dissolved CO2 (concentration of CO2). Since most of the denominator of the Henderson-Hasselbalch equation represents dissolved CO2, and since PCO2 is proportional to the amount (concentration) of dissolved CO2, PCO2 is therefore proportional to the denominator of the Henderson-Hasselbalch equation and may be used as a substitute for the denominator. In practice, a small amount of whole blood (plasma can be used) collected anaerobically is analyzed for PCO2 by direct measurement using a PCO2 electrode. The HCO–3 may then be calculated (from the Henderson-Hasselbalch equation), or the PCO2 value itself may be used in conjunction with pH to differentiate acid-base abnormalities. PCO2 determined by electrode is without question the method of choice for acid-base problems. The pH is usually measured at the same time on the same specimen.

    pH measurement. pH determination originally involved measuring the difference in electric charge between two electrodes placed in a solution (e.g., plasma or whole blood). Current equipment uses a single direct-reading pH electrode, which makes pH determination very simple and reliable and enables pH determination to be a routine part of blood gas measurement. On the technical side, it should be noted that at room temperature, plasma pH decreases at the rate of about 0.015 pH unit every 30 minutes. Unless measurement is done within 30 minutes of drawing, the blood should be refrigerated immediately; it can then be kept up to 4 hours.

    There is not a universally accepted single reference range for arterial or venous acid-base parameters.

  • Blood pH: The Bicarbonate-Carbonic Acid System

    The term pH comes from the French puissance hydrogen, meaning the strength or power of hydrogen. The hydrogen ion concentration of blood expressed in gram molecular weights of hydrogen per liter (moles/L) is so much less than 1 (e.g., 0.0000001) that it is easier to communicate this information in terms of logarithms; thus, 0.0000001 becomes 1 x 10–7. The symbol pH represents an even greater simplification, because pH is defined as the negative logarithm of the hydrogen ion concentration (in the preceding example, 1 x 10–7 becomes 10–7, which then becomes 7.0). In this way, a relatively simple scale is substituted for very cumbersome tiny numbers. In the pH scale, therefore, a change in 1.0 pH unit means a tenfold change in hydrogen ion concentration (a change of pH from 7.0 to 6.0 represents a change from 10–7 to 10–6 moles/L).

    The normal pH of arterial blood is 7.4, with a normal range between 7.35 and 7.45. Blood pH must be maintained within relatively narrow limits, because a pH outside the range 6.8-7.8 is incompatible with life. Therefore, the hydrogen ion content is regulated by a series of buffers. A buffer is a substance that can bind hydrogen ions to a certain extent without inducing a marked change in pH. Among substances that act as buffers are hemoglobin, plasma protein, phosphates, and the bicarbonate-carbonic acid system. Bicarbonate is by far the body’s most important buffer substance; it is present in large quantities and can be controlled by the lungs and kidneys.

    A brief review of the bicarbonate-carbonic acid system recalls that carbon dioxide (CO2) in aqueous solutions exists in potential equilibrium with carbonic acid (CO2 + H2O = H2CO3). The enzyme carbonic anhydrase catalyzes this reaction toward attainment of equilibrium; otherwise the rate of reaction would be minimal. CO2 is produced by cellular metabolism and is released into the bloodstream. There, most of it diffuses into the red blood cells (RBCs), where carbonic anhydrase catalyzes its hydration to H2CO3. Carbonic acid readily dissociates into hydrogen ions (H+) and bicarbonate ions (HCO–3). Eventually only a small amount of dissolved CO2 and a much smaller amount of undissociated H2CO3 remain in the plasma. Therefore, the great bulk of the original CO2 (amounting to 75%) is carried in the blood as bicarbonate, with only about 5% still in solution (as dissolved CO2 or undissociated H2CO3) and about 20% coupled with hemoglobin as a carbamino compound or, to a much lesser extent, coupled with other buffers, such as plasma proteins.

    This situation can best be visualized by means of the Henderson-Hasselbalch equation. This equation states that    pH = pK + log(base/acid)  where pK is the dissociation constant (ability to release hydrogen ions) of the particular acid chosen, such as H2CO3. The derivation of this equation will be disregarded to concentrate on the clinically useful parts, the relationship of pH, base, and acid. If the bicarbonate-acid system is to be interpreted by means of the Henderson-Hasselbalch equation, then base/acid = HCO3- / H2CO3 since bicarbonate is the base and carbonic acid is the acid. Actually, most of the carbonic acid represented in the equation is dissolved CO2 which is present in plasma in an amount greater than 100 times the quantity of undissociated H2CO3. Therefore the formula should really be … but it is customary to let H2CO3 stand for the entire denominator. The next step is to note from the Henderson-Hasselbalch equation that pH is proportional to base/acid. This means that in the bicarbonate-carbonic acid system, pH is proportional to …  The kidney is the main regulator of HCO–3 production (the numerator of the equation) and the lungs primarily control CO2 excretion (the denominator).

    The kidney has several means of excreting hydrogen ions. One is the conversion of monohydrogen phosphate to dihydrogen phosphate (HPO42– to H2PO4–). Another is the formation of ammonia (NH3) in renal tubule cells by deamination of certain amino acids, such as glutamine. Ammonia then diffuses into the urine, where it combines with H+ to form ammonium ion (NH4+). A third mechanism is the one of most concern now, the production of HCO–3 in the renal tubule cells. These cells contain carbonic anhydrase, which catalyzes the formation of H2CO3 from CO2. The H2CO3 dissociates, leaving HCO–3 and H+. The H+ is excreted in the urine by the phosphate or ammonium pathways or combined with some other anion. The HCO–3 goes into the bloodstream where it forms part of the pH buffer system. Not only does HCO–3 assist in buffering H+ within body fluids, but HCO–3 filtered at the glomerulus into the urine can itself combine with urinary H+ (produced by the renal tubule cells from the H2CO3 cycle and excreted into the urine).

    The lungs, on the other hand, convert H2CO3, into CO2 and water with the aid of carbonic anhydrase and blow off the CO2. In this process, a mechanism for excreting H+ exists, because the HCO–3 in the plasma can combine with free H+ to form H2CO3, which can then be eliminated from the lungs in the form of CO2, as was just described. This process can probably handle excretion of most normal and mildly abnormal H+ quantities. However, when large excesses of free H+ are present in body fluids, the kidney plays a major role, because not only is H+ excreted directly in the urine, but HCO–3 is formed, which helps buffer additional amounts of H+ in the plasma.

    Going back to the Henderson-Hasselbalch equation, which is now modified to indicate that pH is proportional to HCO–3/H2CO3, it is easy to see that variations in either the numerator or denominator will change pH. If HCO–3 is increased without a corresponding increase in H2CO3, the ratio will be increased and the pH will rise. Conversely, if something happens to increase H2CO3 or dissolved CO2, the denominator will be increased, the ratio will be decreased, the pH will fall, and so on. Clinically, an increase in normal plasma pH is called “alkalosis” and a decrease is called “acidosis.” The normal ratio of HCO–3 to H2CO3 is 20:1.

  • Acid-Base and pH Measurements

    Fluid and electrolyte problems are common in hospitalized patients. Most of these problems are secondary to other diseases or are undesirable side effects of therapy. There are a few diseases regularly associated with certain pH or electrolyte alterations that can help suggest the diagnosis and can be used to monitor therapy.

    Fluid and electrolytes in one form or another make up nearly all of the human body. It is useful to think of these constituents as though they were contained in three separate compartments between which are variable degrees of communication: individual cells, containing intracellular fluid; vascular channels, containing blood or lymph; and the extracellular nonvascular tissue containing the interstitial fluid. Shifts of fluid and electrolytes between and within these compartments take place continually as the various activities concerned with homeostasis, cell metabolism, and organ function go on. To some degree, these changes can be monitored clinically by their effects on certain measurable parameters, including the pH and concentration of certain ions (electrolytes) in a fairly accessible substance, the blood. This chapter covers blood pH and its disturbances; the next chapter discusses certain electrolyte and fluid disorders.

  • Radionuclide Bone Scanning

    Certain disorders affecting bone are discussed elsewhere (hyperparathyroidism, metastatic tumor in bone). The commonest diagnostic problems involve fractures, osteomyelitis, and metastatic tumor. The nonradiologic procedures most frequently used in bone disease are serum alkaline phosphatase and bone scanning.

    Strontium 85 was the first agent to be widely used in bone scanning. Its relatively high patient radiation dose and problems with excretion by the colon led to replacement by fluorine 18, which, in turn, has been superseded by the technetium-labeled phosphates. Bone scan abnormality is due to increased osteoblastic activity, whether neoplastic, reactive, reparative, or metabolic. Local hyperemia is also a factor.

    Bone scan provides important information in the evaluation of trauma and unexplained pain in areas where an occult fracture is a possibility. Whereas some fractures are immediately evident on x-ray film, in many cases the fracture line cannot be seen, especially in the spine, ribs, face, and smaller bones of the extremities. The radiologist is then forced to look for secondary changes produced by healing, which will not become evident before 10-14 days and in some cases may never be detectable. On bone scan, many fracture sites become abnormal by 3 days after trauma, and the great majority in 5 days. Once evident, the abnormality persists for a variable length of time, the average being approximately 2 years. A fracture site revealed on x-ray film but not on scan at least 7 days after trauma usually represents an old healed injury. Severe osteoporosis or severe malnutrition retards osseous reaction and may result in an equivocal or false negative scan. As noted previously, various types of joint disease can be visualized on the bone scan and may on occasion present problems in differentiation of the disease from possible fracture in the neighborhood of the joint.

    Osteomyelitis is another disease in which bone scan may be invaluable. X-ray changes do not usually appear before 10-14 days after onset and may be delayed further or be difficult to interpret. Bone scan shows abnormalities days or weeks before x-ray films. Although the exact time after onset necessary for most patients to display abnormality is not as clearly defined in osteomyelitis as in fracture, the literature seems to suggest 5-7 days. If the bone scan is normal and osteomyelitis is strongly suspected, a gallium scan may be helpful, or the bone scan may be repeated after several days. Certain conditions resemble osteomyelitis clinically and to some degree on scan. These include cellulitis, arthritis, and focal bone necrosis or infarct. Patients already receiving steroid or antibiotic therapy before onset of osteomyelitis may display changes in normal bone response. These changes can affect the bone scan latent period or the image characteristics.

    Metastatic tumor detection is the reason for most bone scan requests. All malignancies capable of metastasis may reach bone. Some of these, including prostate, breast, lung, kidney, urinary bladder, thyroid follicular carcinoma and possibly malignant lymphoma, are more likely to do so than other tumors. Formerly, bone scanning was widely used to establish operability of these neoplasms by excluding bone metastases after a primary tumor was discovered. Most reports on breast carcinoma patients in early (potentially operable) stage disclosed a very small incidence of abnormal bone scans (usually <10%) unless there was some other evidence of bone metastases such as bone pain or elevated alkaline phosphatase levels. For example, in stage I and II breast carcinoma, there is an average reported incidence of 6% bone scan abnormality (literature range, 1%-40%). False positive abnormality due to conditions other than metastasis is also a problem (3%-57% of cases, average about 10%). Therefore, bone (and also liver or brain) scans are not being recommended in most institutions as routine preoperative tests in breast carcinoma. Fewer data are available for lung carcinoma, but there may be a better case for preoperative bone scans in potentially resectable patients based on higher rates of detectable occult metastases and the greater magnitude of the operation, which becomes unnecessary if metastases are found.

    Tumor-related bone scanning is indicated in several situations: (1) to investigate bone pain when x-ray films do not show a lesion, (2) to document extent of tumor in nonresectable malignancies known to have a high rate of bone metastasis to follow results of therapy, and (3) in some cases, to help investigate unexplained symptoms that may be due to occult tumor. Until bone scanning became available, skeletal x-ray survey was the mainstay of diagnosis. Numerous comparisons have shown that bone scanning detects 15%-40% more bone metastases (literature range, 7%-57%) than x-ray. This difference is related to osteoblastic reaction induced by the tumor, which may occur even when the lesion is osteolytic on x-ray film. On the other hand, about 5% of metastases are seen on x-ray film but not on scan (literature range, 3%-8%); these are usually pure osteolytic lesions. The implication of these figures is that bone scan is sufficient for routine detection of metastases in the major bone-seeking tumors and that x-ray should be reserved for specific anatomical areas in which the scan is equivocal or the etiology of scan abnormality is in doubt. X-ray is also useful when there is strong suspicion of bone malignancy yet the scan is normal, when the scan is normal in areas of bone pain, and to help differentiate metastasis from focal severe osteoarthritis.

    Bone scanning does have disadvantages, chief of which is nonspecificity. The variety of conditions that may produce abnormal bone scans include fractures (even those of long duration), osteomyelitis, active osteoarthritis, joint synovial inflammation, areas of bone necrosis or infarct, myositis ossificans, renal osteodystrophy, Paget’s disease of bone, certain benign bone tumors such as fibrous dysplasia and osteoid osteoma, and various artifacts such as ossification centers in the sternum or costochondral junction calcification. On the other hand, when tumor produces widespread bone marrow invasion, the spine or other bones may sometimes have a homogeneous appearance on scan that may be misinterpreted as normal unless certain other findings are taken into account. As a general rule, the greater the number of focal asymmetric lesions on bone scan, the more metastatic tumor should be suspected. Healing fractures (which actually may have occurred at different times) and Paget’s disease create the most interpretative difficulty. Some institutions routinely scan only the spine, pelvis, and ribs instead of the total body. A question may arise about the probability of metastases elsewhere. One large study encompassing a wide variety of tumors indicates that the incidence of solitary uptake (other skeletal areas negative) in the skull is about 4%; in the extremities as a unit, about 9%; in the humerus, about 1%; in the femur, 5%; in the tibia or fibula, 2%; and elsewhere in the extremities, quite rare.

  • Radionuclide Joint Scanning

    Besides synovial fluid examination, radionuclide joint scanning is a procedure that may offer useful information. For screening purposes, the scan could be performed with one of the isotope-labeled phosphate compounds used for bone scanning. These scans reveal abnormality in most joints that have a significant degree of inflammation, even when subclinical. Joint scanning permits a reasonably accurate assessment of the number, location, and degree of activity of involved joints and offers an objective (although only semiquantitative) method for evaluating results of therapy. Although fairly sensitive, the phosphate agents are not ideal for joint scanning, since increased concentration denotes increased activity of bone osteoblasts in response to adjacent synovial abnormality rather than a primary synovial reaction. Other etiologies for osteoblastic stimulation, such as osteochondritis dissecans, traumatic joint disease, active osteoarthritis, healing fractures, and the later stages of aseptic necrosis, may all produce abnormal bone scan images, which sometimes are hard to differentiate from arthritis. In such cases other compounds may be employed, including technetium pertechnetate or labeled albumin. These tend to remain in blood vessels, thereby indicating regions of increased vascularity or hyperemia such as the synovial membrane when involved by active arthritis. These compounds are a little less sensitive than the phosphates but are more specific for synovial disease.

  • Synovial Fluid Analysis

    When synovial fluid is aspirated, 1 ml or more should be placed into a sterile tube for possible culture and a similar quantity into a heparinized tube for cell count. The remainder can be used for other procedures. A cell count is performed on anticoagulated fluid using 0.9% saline as the WBC pipette diluent (the usual diluent, Turk’s solution, contains acetic acid, which coagulates synovial fluid mucin and produces clots that interfere with accuracy of the WBC count).

    Synovial fluid tests

    Mucin clot. The Ropes test for mucin clot is performed by adding a few drops of aspirate to 10-20 ml of 5% acetic acid in a small beaker. After 1 minute, the beaker is shaken. A well-formed clot remains compact; a poor clot is friable and shreds apart easily. In general, noninflammatory arthritides form a good clot. In noninfectious inflammation, the clot may be good to poor, whereas the clot of acute bacterial infection is poor.

    Viscosity (string sign). Aspirate is allowed to drip slowly from the end of a needle. The length of the strand formed by each drop before it separates is the end point. In normal fluid and in noninflammatory arthritides the strands string out more than 3 cm. In acute inflammatory conditions fluids drip with little, if any, stringing.

    Synovial fluid glucose. Synovial fluid glucose value is usually within 10 mg/100 ml (0.5 mmol/L) of the serum glucose value and is always within 20 mg/100 ml. A blood specimen for glucose should be obtained as close as possible to the time of joint aspiration. The patient should have fasted at least 6-8 hours to achieve baseline values and to compensate for delay in glucose level equilibration between blood and synovial fluid. In degenerative arthritis, synovial fluid glucose levels are usually normal. In acute inflammatory noninfectious arthritis (SLE, RA, gout, etc.) there may be a mild or even a moderate decrease (up to 40 mg/100 ml below serum levels). In acute bacterial (septic) arthritis there typically is a marked decrease of more than 40 mg/100 ml (2.22 mmol/L) below serum glucose levels, but a decrease of this extent is said to occur in only about 50% of cases.

    Microbiologic studies of synovial fluid. Gram stain is reported to demonstrate organisms in 40%-75% of patients with septic arthritis (literature range, 30%-95%), more often with gram-positive than with gram-negative bacterial infection. However, Gram stain is not always easy to interpret, especially when only a small number of organisms are present, due to debris from the joint that may take up some of the stain. Culture of synovial fluid is the mainstay of diagnosis in septic arthritis. Since gonococci are a major cause of joint infection, provision should be made for the special conditions necessary to culture these organisms. It has been reported that blood cultures may be positive and synovial fluid cultures negative in 15% of patients with septic arthritis. Previous antibiotic therapy considerably decreases the chance of diagnosis by culture.

    Synovial fluid white blood cell count. There is considerable overlap between WBC counts of noninflammatory conditions and noninfectious inflammatory diseases in the area of 500-2,000 WBCs/ mm3 (0.5-2.0 x 109/L) and between infectious disease and noninfectious inflammatory conditions in the area of 10,000-100,000 WBCs/mm3 (10-100 x 109/L). Thus, only very high or very low WBC counts are of great help without other information. A very high percentage of neutrophils (>75%, usually >90%) is said to occur in most cases of untreated acute bacterial infectious arthritis. A neutrophil percentage of more than 90% may therefore be a more reliable indicator of bacterial infection than cell count, synovial glucose level, or Gram stain (unless the cell count is >100,000, the synovial glucose level is >40 mg/ 100 ml below the fasting, simultaneously drawn serum glucose level, or the Gram stain discloses unequivocal organisms).

    Other examinations. Other examinations include a serologic test for RA. The RA tests on synovial fluid occasionally show positive results before serum tests. In SLE, LE cells sometimes form in synovial fluid and can be demonstrated on the same Wright’s-stained smear used for differential cell count. Synovial fluid total complement (CH50, Chapter 22), is said to be decreased in SLE and active RA (more often if the patient with RA has a positive latex tube agglutination test result). Total complement is reported to be increased in Reiter’s syndrome. Most other noninflammatory and inflammatory arthritic diseases are associated with normal synovial fluid complement levels. However, there are sufficient exceptions to these general observations that synovial fluid complement assay has not become popular. For example, in one study, 15% of SLE patients had normal synovial fluid total complement values and only about 40% of patients with Reiter’s syndrome had elevated levels.

    Synovial fluid specimen collection

    An anticoagulated tube is necessary for cell count, WBC differential, and examination for crystals. Heparin is preferred, but liquid ethylenediamine tetraacetic acid can be used. Without anticoagulation, spontaneous small or large clots may form that trap WBCs and alter the cell count. A sterile tube should be used for fluid that is to be cultured; heparin anticoagulant is preferred. This must be sent to the laboratory immediately. A tube without anticoagulant is needed for the mucin test, complement assay, and glucose assay. Some prefer a tube with fluoride anticoagulant for glucose to help preserve the specimen. Fluid for complement assay should be frozen immediately if the assay is not performed within 1-2 hours.

  • Other Conditions Associated with Arthritis

    Arthritis and arthralgia may be present in 4%-23% of patients with primary biliary cirrhosis. One report indicates that many more have radiologic abnormalities of erosive arthritis but have no symptoms. About 50% of patients with hemochromatosis and about 25% of patients with chronic active hepatitis develop arthritis or arthralgias; up to 40% of patients with hepatitis virus hepatitis have arthralgia (usually not true arthritis); and arthritis may occasionally be found in patients with viral infections of various etiology (e.g., rubella). Patients with cancer may develop joint symptoms due to direct extension from or a reaction to a nearby primary site or from joint area metastasis. Joint metastasis usually involves one of the knees and is most often due to carcinoma of the lung or breast. Metastasis to the hand is most often due to lung carcinoma. Childhood acute leukemia rather frequently appears to produce joint pain for a variety of reasons. Neoplasia have been associated with gout, vasculitis, and occasionally, syndromes resembling some of the collagen diseases. Occasionally, there may be arthritic symptoms without neoplastic joint involvement. Sarcoidosis may occasionally produce arthritis.