Obtaining a Urine Specimen

Several methods are available for obtaining a urine specimen. They can be found in Table 67-1 and are listed in order of increasingly precise collection techniques, which comes at the cost of increasing difficulty, patient discomfort, or both.

General Considerations regarding Urine Collection

The advantages and disadvantages of each of the techniques listed in Table 67-1 can be determined only by the purpose of the urine test and the clinical context. The clinical context influences interpretation of the results. For the great majority of clinical scenarios, the basic dichotomy is between specimens obtained for infectious versus noninfectious reasons. With the exception of testing for red blood cells (RBCs) and white blood cells (WBCs), most of the noninfectious tests (e.g., ketones, glucose, bilirubin, protein) are not affected by the collection method. Urine specimens collected to diagnose infection can be contaminated in a number of ways, and the choice and interpretation of tests are intricately influenced by the clinical scenario.

Urinary tract infections (UTIs) are either symptomatic or asymptomatic, and the symptoms determine which collection method is required (Fig. 67-1). With symptomatic UTI, extremely low levels of bacteriuria (10² colony-forming units [CFUs]/mL) and pyuria are of clinical significance.^1,2 This may be obscured in some clinicians’ minds by an alternative, more widely promulgated fact: in asymptomatic patients the threshold for “significant bacteriuria” is 1000-fold higher at greater than 10⁵ CFUs/mL.^3,4 Symptomatic patients constitute a clinically distinct group who require a urine test that is much more sensitive and thus will render a false-positive result with much lower levels of contaminants. Although many studies do not show a statistically significant increase in contamination rates with less stringent urine collection techniques, most show increased accuracy with more meticulous or invasive collection methods.^5–8 Because it takes only marginally longer, it makes sense to always strive for the highest-quality urine specimen available, especially in view of the delays, repeated testing, and additional cost entailed by false-positive results. A frequent misconception is that contaminated specimens are characterized by the isolation of multiple pathogens, but in fact, up to 50% of symptomatic women may have polymicrobial infections.^1,9

The issue of whether a patient is “symptomatic” might appear trivial, but the clinical practice of checking for UTI in most patients with any type of abdominal pain has important implications. Studies of urine collection and testing in symptomatic patients focus on the classic signs and symptoms of UTI (e.g., urgency, frequency, dysuria, flank pain, costovertebral angle tenderness) and do not include patients with nonspecific abdominal pain. Whether undifferentiated abdominal pain or fever constitutes a “symptom” of UTI has never been studied, and how to apply the results of studies done on patients with classic symptoms to those with nonspecific symptoms is unclear.¹⁰ Patients with classic symptoms need the most careful urine collection method because they have the most riding on the outcome of the test. This group of patients should include those with systemic signs of infection (e.g., fever and chills) who are unable to accurately report their symptoms and patients in whom failure to diagnose asymptomatic bacteriuria would be potentially dangerous (e.g., the immunocompromised, neonates and infants, pregnant patients, diabetics) or for whom urine cultures are going to be necessary because of a history of relapsing, recurrent, complicated, or childhood UTI.^9,11

In cooperative, motivated males and females with symptoms of uncomplicated lower UTI or pyelonephritis who are capable of diligently performing the necessary maneuvers, a midstream clean-catch (MSCC) specimen is as accurate as a catheterized specimen, especially when the possibility of urethral or prostatic trauma and patient discomfort are considered.¹² In patients unable to provide an MSCC specimen, a catheterized specimen is usually warranted.

If no symptoms of UTI are present, the urine examination can be considered a “screening” test. In asymptomatic patients, routine screening for bacteriuria is unwarranted in all but two clinical situations: pregnant women and all patients scheduled for urologic surgery.13,14 If only a urine culture is to be performed, some would argue that any spontaneously voided specimen would suffice since the diagnosis of asymptomatic bacteriuria depends on 10⁵ or more CFUs of a single pathogen per milliliter of urine. With such criteria, contaminants are usually easily identified.⁸ Because performing cultures on all such patients is prohibitively costly, dipstick testing, urinalysis (UA), or both are commonly used for screening.^15,16 With these tests, contamination by bacteria, leukocytes, or erythrocytes results in diagnostic confusion. The advantages of a less contaminated specimen are worth the minimal, extra effort of asking the patient to provide an MSCC sample. The approach in Figure 67-1 covers the vast majority of situations. A few circumstances and techniques deserve special mention.

Urine Dipstick

Urine dipstick tests are available to test 10 separate parameters. The unassuming appearance and commonplace use of the urine dipstick might lead one to mistakenly underestimate its technical sophistication. Each colored square on a urine dipstick involves a biochemically complex assay, and therefore it is essential to meticulously follow the manufacturer’s instructions for storage and use.³⁷ Even with optimal storage and testing conditions, the false-negative and false-positive rates of these tests are problematic. In addition, most of the tests are susceptible to interference from a variety of substances (Table 67-2).

Microscopic UA

Microscopic UA is performed to identify cells, bacteria, and other microbes, as well as formed elements such as casts and crystals (Fig. 67-3). The following discussion focuses on the findings of significance in diagnosing UTI: WBCs, bacteria, and WBC casts. The presence of WBCs with bacteria distinguishes infection from colonization (bacteriuria without pyuria). Some authorities state that significant infection without pyuria occurs in less than 5% of cases, thus making pyuria alone a sensitive marker of infection.^53,55 Other studies do not support reliance on pyuria by itself as an indicator of infection.^2,3,5,27 The presence of WBC casts distinguishes pyelonephritis (“upper UTI”) from cystitis (“lower UTI”).

Microscopic UA is performed by one of five methods. Traditionally, the most common technique has been examination of unstained centrifuged urine. It has the advantage of concentrating formed elements that might otherwise be missed. Its disadvantage is that the presence and quantity of elements in a specimen will depend on many uncontrolled factors: the volume of the specimen, the duration and speed of centrifugation, the fragility of the formed elements, the volume of the “drop” in which the pellet is resuspended, and the size of the microscope’s HPF.14,56,57

Summary of Tests Used in the Diagnosis of UTI

The three tests commonly used to evaluate a patient for the presence or absence of UTI are urine dipstick, microscopic UA, and urine culture. Each represents an increasing degree of expense, delay, and resources.⁶⁴ A brief discussion of their relative strengths and weaknesses ensues.

The Bottom Line

It is well established that female patients with symptoms of uncomplicated lower UTI can be treated without culture since the prevalence of disease is 50% or greater in women with classic urinary symptoms.14,45,69,70 Treatment is generally benign, and 95% of urine cultures that are positive will yield a limited number of organisms with predictable antibiotic susceptibilities. Some authors recommend dipstick or microscopic UA (or both) because a negative test might prompt more careful consideration of alternative diagnoses in this group with a high incidence of sexually transmitted disease.^14,45 If none is found, such patients can be treated empirically. Traditionally, trimethoprim-sulfamethoxazole was recommended, although increasing resistance to this drug has lead to levofloxacin (itself with unacceptably high resistance rates in many locations) being the current choice of empirical antibiotics.^71,72

Urine testing is more likely to influence clinical management in patients with an intermediate pretest probability of infection.¹⁰ Urine microscopy may also help in distinguishing pyelonephritis (WBC casts), vaginitis (absence of pyuria or hematuria in a meticulous MSCC or catheterized specimen), and urethritis (pyuria, rarely hematuria) from cystitis (pyuria and often hematuria).^14,45 In the ED, the ease of performing a dipstick test argues for its use without UA since it is equally sensitive unless formed elements such as casts, crystals, Trichomonas, or other parasites are suspected. In patients with pyelonephritis, urine cultures are warranted because they alter therapy in about 5% of cases.⁷³ In most asymptomatic patients, a negative dipstick or UA result has sufficient negative predictive value to rule out disease unless the patient is pregnant or undergoing urologic surgery. Special clinical considerations in some patients (e.g., the immunocompromised, diabetic females at high risk for UTI) may mandate adjustments to this approach.¹⁵ Recommendations vary regarding infants. Cultures are recommended for all febrile infants younger than 2 months and for children who appear sick or have a high pretest probability of infection.^21,23 In a recent study, combined microscopic and dipstick UA was only 64% sensitive (and 91% specific) for culture-proven UTI in febrile infants younger than 24 months, thus suggesting the use of culture unless an alternative source of infection is clear.⁷⁴

Indications

Blood cultures are indicated when the clinical findings suggest an otherwise unidentifiable bacteremic state (Box 67-2). Twenty-five percent of patients with documented bacteremia have periods without fever.⁹⁷ In the elderly the proportion is even higher, with 50% of bacteremic patients older than 65 having a temperature between 97.1°F (36.2°C) and 100.9° F (38.3°C) and at least 13% with no documented temperature higher than 99.1°F (37.3°C) at any time.^98–101 In the elderly, increasing age, vomiting, altered mental status, urinary incontinence, presence of a Foley catheter, or greater than 6% band forms is predictive of a positive blood culture.^99,102 The subjective impression of “having fever” in adults is not a reliable indicator of the presence of fever, although the subjective impression of “no fever” is much more likely to be accurate.¹⁰³ Prediction models to optimize the use of this costly test have been explored but are cumbersome, add little to educated clinical judgment, and lack widespread validation or acceptance.^104–106 Many studies have shown that blood cultures in patients with uncomplicated pneumonia or pyelonephritis are of very limited clinical value,^107–118 although a recent prospective investigation of patients with upper UTI found that malignancy, an indwelling urinary catheter, and ongoing antimicrobial treatment were clinical conditions that made it significantly more likely that blood cultures would be discordant with urine cultures and that they would reveal clinically important additional information.¹¹⁹ Blood cultures are obtained during 2.8% of all ED visits in the United States, and in a single recent 3-year period this rate increased by 33%.¹²⁰ Since disease prevalence is unlikely to have changed so rapidly, this increase is probably due to changes in practice. These changes have been coincident with regulatory agency–mandated blood cultures in patients being evaluated for pneumonia and have led to calls for more stringent criteria for obtaining blood cultures.

In children, the traditional teaching that blood cultures are indicated for all patients younger than 2 years with fever higher than 38.6°C (>101.5°F) and without an obvious source is being modified by the widespread use of pneumococcal conjugate (PC) and Haemophilus influenzae type b (HIB) vaccines.121,122 In the post-PC and post-HIB vaccine era, the incidence of occult bacteremia in otherwise well-appearing febrile children is probably lower than 1%, thus making the false-positive rate at least four times as high.^121–123 It seems reasonable to withhold blood cultures and empirical antibiotic coverage in otherwise well-appearing febrile children with reliable parents. The risk for bacteremia in a child is positively correlated with the degree of fever, WBC count, and rapidity of onset of the illness. It is inversely proportional to the patient’s age.^124–127 In infants younger than 2 months with temperatures higher than 38°C (>100.5°F), some authorities would recommend blood cultures regardless of the presence or absence of a source, although this approach is subject to modification by experienced clinicians based on the patient’s age and clinical setting. A child with a normal temperature in the ED and a history from the parents of a tactile fever needs to be approached in the same way as a patient with fever documented on physical examination. Parents’ tactile impression of fever is reliable, and bacteremic children, like adults, have intermittent fever, with up to 50% afebrile rates in children with demonstrated bacteremia.^128,129

The Controversy Regarding “Outpatient Blood Cultures”

There is a long-standing debate regarding the utility of outpatient blood cultures (i.e., blood cultures on patients who are discharged from the ED pending results). Arguments for and against outpatient blood cultures are summarized in Box 67-3. Opponents cite medicolegal issues, problems with follow-up, high contamination rates, low rates of positive cultures, and even lower rates of frequency in patients in whom therapy is changed because of culture results.^130–133 Proponents also cite medicolegal concerns, positive rates similar to those seen with inpatient blood cultures, cost savings, and the benefit of diagnosing significant, yet subtle bacteremic states (such as endocarditis).^134,135 They also point out that the high false-positive rates seen in many ED series should be an indictment of poor technique, not of the test itself.

On the basis of current data, it seems fiscally extravagant to admit all patients in whom a bacteremic state is possible and injudicious to deny blood cultures solely on the basis of a patient not appearing “toxic enough” to warrant admission. Societal and economic pressures to avoid hospital admission buttress these clinical considerations. Outpatient blood cultures, with due attention to collection technique, patient selection, and arrangements for follow-up, have a place in emergency practice. This approach is reflected by the fact that fully half of ED blood cultures are obtained on patients who are not admitted to the hospital.¹²⁰

Technique for Obtaining Blood for Culture

Studies have demonstrated sources of contamination at every stage of the process of performing and processing blood cultures. In addition to obvious sources of contamination from the patient’s and phlebotomist’s skin, antiseptic agents and gloves have been implicated.136,137 Some authorities have argued that the primary source of contamination is in the laboratory processing of specimens.¹³⁸ The consensus is that the most common source of contamination is the process of phlebotomy and inoculation of blood culture bottles.¹³⁹ Obviously, this is the single step over which emergency clinicians have control, either directly or via protocols of technique for blood culture phlebotomy. Contamination rates are typically between 1.5% and 3%,^121,140,141 although many ED series show much higher rates.^132,142

A high degree of sensitivity is required for blood cultures. Many significant bacteremic illnesses have been documented with as little as 1 CFU/10 mL of blood.143,144 In a cadaver study, human skin has been shown to have a bacterial concentration of between 10³ and 10⁶ CFUs/mL on the forearm and groin, respectively.¹⁴⁵ Designed to detect vanishingly low concentrations of bacteria, the test is clearly susceptible to false-positive results (impaired specificity) when blood must necessarily be obtained by passing a needle through the skin. Eighty percent of the skin flora is transient, superficial, and removable; 20% inhabit the sebaceous ducts and hair follicles and cannot be removed without destroying the skin.^145,146 The former group consists of predominantly gram-positive and gram-negative aerobes and is the target of skin disinfectants.

The primary agents for skin disinfection are iodine compounds, alcohols, chlorhexidine, and hexachlorophene. Iodine solution remains a gold standard and kills bacteria, fungi, protozoa, and viruses but has been replaced in many institutions because of concern about skin burns and allergic reactions. Reports of the former were probably due to the use of 7% solution. The risk for a burn or an allergic reaction is thought to be negligible with the currently available 2% preparation.¹³⁹ The most effective cleansing agent is tincture of iodine, which is a mixture of 2% iodine solution and 70% alcohol.^147,148 Povidone-iodine 10% solution (Betadine) has a much lower free iodine concentration than iodine solution and is therefore less potent. Iodine is superior to hexachlorophene and chlorhexidine in killing gram-negative bacteria. Iodine, like other antiseptic agents, is inhibited by the presence of organic matter and thus requires thorough skin cleansing before the application of any skin disinfectant.

Ethyl or isopropyl alcohol should be used in a 60% to 80% solution. Alcohol prep pads, which generally contain 70% isopropanol, have solved traditional concerns regarding evaporation of alcohol from cotton balls stored in jars. Alcohol is a less powerful germicide than iodine in vitro and kills only 90% of surface bacteria after a full 2 minutes with reapplication to prevent drying.¹⁴⁹ Alcohol foam applicators can avoid premature drying. Alcohol is inactive against fungi, spores, and viruses, but in vivo studies of blood culture contamination rates have shown it to compare favorably with iodine.^147,150 Because iodine solution is often not available and iodophor solutions are less potent, alcohol still has an important place in skin antisepsis. In addition, alcohol is an excellent solvent, so alcohol pads may assist in skin preparation by removing dirt- and microbe-laden skin oils before the application of iodine compounds.

Chlorhexidine (Hibiclens) and hexachlorophene (pHisoHex) are antiseptics that are more effective against gram-positive than gram-negative bacteria. Both agents are absorbed intradermally, thereby offering prolonged antimicrobial activity, which is the basis of their popularity as surgical scrub and operative site preparations. This also makes them preferable agents when indwelling lines, especially central lines, are being placed.¹⁵¹ For routine blood culture phlebotomy, they are not as effective as alcohol and iodine combinations, although they are superior to povidone-iodine solution.¹⁴¹ Most studies show chlorhexidine to be more potent than hexachlorophene, and it has not been associated with induction of seizures in infants.

Box 67-4 presents a skin preparation protocol. Optimal results seem to be obtained with alcohol-iodine mixtures.^{145,148,152,153} The most important concept in skin disinfection is that bacteria do not die at the instant of contact with disinfectant agents. Iodine (2%), which is twice as potent as 10% povidone-iodine, requires at least 90 seconds in contact with the skin to kill 90% of surface bacteria.¹⁴⁹ In many ED patients it will be necessary to use alcohol prep pads to remove gross dirt and debris from phlebotomy sites before initiating the steps of formal skin preparation.

Special Considerations in Obtaining Blood for Culture

Timing of Blood Cultures

In most circumstances the timing of blood cultures is moot in the ED. Patients are sick enough to warrant the initiation of empirical antibiotics or are well enough for discharge, so two or more sets of blood need to be drawn immediately. The timing of blood cultures might become a consideration in a patient requiring admission but in whom the diagnosis of bacteremia is in doubt such that empirical antibiotic therapy is withheld. Contrary to medical lore, true-positive blood cultures are more likely if blood is drawn in the 12 hours before a fever spike.166,167 Furthermore, except for infectious endocarditis, most clinically significant bacteremia is thought to be intermittent, so multiple sets of specimens obtained at one time for culture would heighten the risk for missing the period of bacteremia.¹⁶⁸ For patients admitted to the hospital with the tentative diagnosis of sepsis, it is theoretically advantageous to draw the three sets of blood for culture over the first 12 to 24 hours of admission.¹⁶⁹ If immediate administration of antibiotics is indicated, the two or three sets of blood for culture should be obtained before initiation of antibiotic therapy.

Blood Culture Volumes

How Many Sets of Blood Cultures Are Needed?

A set of blood cultures is the sample obtained from a single site. A 1-mL specimen from a neonate placed in an aerobic bottle and a 30 mL specimen from an adult divided between fungal, aerobic, and anaerobic bottles are both a single set of blood cultures (Fig. 67-5). Two or more sets of blood cultures make up a series.¹⁶⁹ The information derived from the blood culture sets is pooled in such a way to make both the sensitivity and specificity of the series greater than that of the component sets. Sensitivity is enhanced because as discussed earlier, an individual set is typically not more than 80% sensitive.¹⁸⁷ Specificity is improved for microbes that can act as both pathogens and contaminants by determining whether they appear in all sets (pathogen) or in only some (more likely a contaminant).

Although this conceptual process is applied to all blood culture series, the focus of inquiry depends on the infectious process being ruled in or out. For example, in an elderly patient with sepsis and a chronic indwelling Foley catheter, it is extremely unlikely that the causative organism is a typical skin contaminant. The usual causes of “false-positive” blood cultures will therefore be easily recognized, thus lowering the false-positive rate for the series and yielding a test with intrinsically higher specificity. At the same time, with the typical pathogens in this clinical context being nonfastidious organisms, sensitivity is typically around 99% with two sets consisting of 20 mL of blood per set.¹⁷⁸ Conversely, in a patient with a prosthetic heart valve, fever, and signs of septic emboli, many probable pathogens are also skin contaminants, thereby lowering the specificity of each individual blood culture set. Thus, at least two sets of cultures must be positive with such organisms before the overall test (i.e., the series) is considered positive. At the same time, this clinical picture makes the pretest probability of disease very high (diminishing the negative predictive value of a negative set), so an extremely sensitive overall test (i.e., series) will be needed to adequately rule out disease. In this setting, most authorities would recommend four sets of blood culture bottles, with good volumes in each.^168,187 Except in infants, single sets of blood for culture are of insufficient sensitivity or specificity to be of any utility and should not be drawn.^{167,168,187–189} The recommended numbers of sets of blood cultures as they relate to the pretest probability of disease and causative organism are summarized in Table 67-6.

Aerobic versus Anaerobic (versus Other) Bottles

Anaerobic infections tend to occur in poorly perfused tissues or locations and frequently evolve into abscesses. Both characteristics mean that these infections tend to be isolated from the bloodstream, thereby decreasing the likelihood of bacteremia and detection by blood culture. For these reasons it is not surprising that anaerobic isolates account for 0.5% to 12% of positive blood cultures.168,190–192 Blood cultures in general have a typical true-positive rate of about 5%; with 5% or less of positive blood cultures being anaerobic, more than 400 patients need to have a complete series of blood drawn for culture to detect one case of anaerobic bacteremia.^193–197 If more than 50% of anaerobic infections are clinically evident before culture, at least 800 blood culture series are needed to generate a single anaerobic result that would alter clinical management. Anaerobic cultures may also have the unintended consequence of compromising the sensitivity of aerobic cultures in situations in which less than the ideal 20 mL of blood is drawn for a blood culture set.^175,192 Allocation of blood to anaerobic bottles will also diminish the likelihood of detecting fungal infections, which are increasingly common in the rising population of immunocompromised patients.¹⁹⁸ In addition to these pathophysiologic considerations, there was a widely reported decrease in the positive anaerobic blood culture rate in the 1980s and 1990s, although some authors have recently suggested a resurgence of anaerobic bacteremia rates.^{190–192,194,196,199} At the current time, the arguments for selective use of anaerobic blood cultures are compelling, especially if working in an institution where there is a low rate of anaerobic bacteremia. Based on a review of this topic, Table 67-7 suggests a possible approach to the allocation of blood specimens to various blood culture media after phlebotomy.^198–202 Clinical features that place a patient at high risk for anaerobic bacteremia are listed in Box 67-5.

Identifying Contaminants

The emergency clinician may receive calls from the laboratory about the results of positive blood cultures obtained on previous shifts. These may be “true positives” as a result of true contamination or may be caused by the intermittent bacteremia that occurs in normal, healthy people. This situation has been complicated by the increasingly common identification of Staphylococcus epidermidis, Streptococcus viridans, and fungi as real pathogens in blood culture series.203–206 The expense associated with false-positive blood cultures has been estimated to be $900 per episode for discharged patients and more than $5000 per episode for inpatients. These costs emphasize the importance of good technique in obtaining blood for culture.^207,208 Distinguishing contaminants from clinically significant bacteremia is based on both microbiologic information and the patient’s clinical condition. Features of false-positive blood culture results are listed in Box 67-6.^178,187,209 It would probably be prudent to contact discharged patients with positive blood cultures, even when contamination is suspected on a microbiologic basis, to ensure that their condition is improving.

Fungal Cultures

Generally, fungi are difficult to isolate in blood cultures, and it may take 4 to 6 weeks to obtain a positive yield. If fungemia is suspected, it is best to discuss culture media and technique with the laboratory before blood is taken for culture. Cultures of bone marrow are occasionally positive for mycoses when blood cultures are negative.

1. Preparation of the site. The importance of aseptic technique in the preparation of a site to draw blood for culture has been discussed. For hematologic and serum analysis, enough time should be allowed for drying of the alcohol since trace amounts can cause hemolysis. Povidone-iodine can cause errors in several chemistry assays. When used, it should be cleaned off with alcohol, as described in the section on blood cultures.

2. Venous occlusion. Both intracellular and chemical changes start occurring in blood as soon as a tourniquet is applied, not—as is often thought—only after it has passed through a needle into a specimen container. Serum potassium levels may increase by 6% in a vessel that has been occluded for only 3 minutes.²¹³ Venous access sites, if visually identifiable, should be prepared before placement of a tourniquet. After tourniquet application, phlebotomy and sample acquisition should proceed as rapidly as possible, ideally within 30 seconds.²¹⁵ Pumping the fist should be avoided if possible because it increases serum concentrations of potassium, lactate, and phosphate.²¹³

3. Routine phlebotomy. Smaller-gauge needles and higher suction pressure are associated with hemolysis. Overexuberant application of suction on a syringe is doubly counterproductive because in addition to causing hemolysis, the needle is likely to be occluded by the wall of the vein. This increases the likelihood of unsuccessful phlebotomy and iatrogenic injury to the patient. When applying negative or positive pressure to a syringe, a given amount of force on the plunger causes higher pressure within the chamber of a smaller-diameter syringe (pressure is proportional to 1/radius²). Blood drawn into either a standard Vacutainer or a syringe via a butterfly needle and tubing causes similar hemolysis rates (Fig. 67-6).²¹⁵ If a phlebotomy site is tenuous, specimens are obtained in order of clinical priority. In most cases, tubes should be filled in the following order to avoid cross-contamination of chemicals: blood cultures, red, blue, speckled red, green, lavender, gray.²¹³ Consistent with experience, the perception of difficult access or phlebotomy is associated with higher hemolysis rates.^216,217

4. Phlebotomy through a freshly placed IV catheter. Routine phlebotomy typically causes a hemolysis rate of less than 2%.²¹² Reported hemolysis rates in ED patients are often 7% to 15%.^217–219 This may be due to any or all of the reasons considered here, but one contributing factor is the number of blood specimens drawn in the ED through a catheter being placed for therapeutic use (Fig. 67-7). Several studies have shown that this arrangement significantly increases rates of hemolysis.^217,219,220 The popularity of this technique in emergency care is most probably due to limitations of personnel and temporal resources and an attempt to enhance patient comfort by avoiding an extra needlestick. Since tourniquet times are probably longer with catheter placement than with simple phlebotomy, it is likely that this contributes to hemolysis, although it has never been experimentally verified. Perceived ease of blood aspiration, larger-bore catheters, and small aliquots drawn through the catheter are associated with lower rates of hemolysis.^219,220 Laboratory results of specimens obtained in this manner are accurate within clinically acceptable margins of error.

5. Phlebotomy through an established IV catheter. An established IV line appears to be a reliable source of blood for analysis, although success rates are lower and hemolysis rates are higher than for phlebotomy from a fresh site.221,222 Box 67-7 lists common blood tests that are accurate when drawn through an established IV line.^222,223 As with the use of a freshly placed catheter, results are accurate within clinical tolerances.^221,224 If fluids are being administered through the catheter, it should be turned off for at least 3 minutes before the application of a tourniquet for phlebotomy. A typical 18-gauge 30-mm-long plastic IV catheter without a heparin well has a volume of 0.07 mL. The heparin well adds a volume of 0.05 mL to make a combined volume of 0.12 mL. Thus, when using a syringe directly attached to the heparin well (IV tubing detached), just 1 mL of aspirated fluid should have replaced the entire volume of the heparin well at least six times. Most studies have discarded at least three times that volume. Some have suggested a “push-pull” technique (aspirating a small volume into the syringe and reinjecting it before drawing a final 3 mL for discarding) to minimize the likelihood of small sequestered pockets of IV fluid in the heparin well.²²⁵ Use of the standard distal port of the IV tubing (usually 25 cm from the end) is not recommended. The IV tubing has a volume (combined with the heparin well and catheter) of about 1.6 mL, thus making it necessary to discard large volumes of blood, in addition to the risk of contamination from IV fluids entrained in the specimen from the main IV line during aspiration through the port.

6. Disposition of the specimen after phlebotomy. If blood has been drawn into a syringe, it should be promptly decanted into the appropriate containers for the laboratory. If it has already started to clot, it should not be forced since this can cause hemolysis of the specimen. Since cells and platelets are fragile, specimens requiring agitation (all except red and speckled red-topped tubes) should be rocked gently, not shaken. If specimens are sent to the laboratory in pneumatic tubes, they should be surrounded by shock-absorbing material. Artifactual increases in measured HCO₃⁻ occur fairly rapidly at room temperature.²²¹ Progressive hemolysis of blood occurs with prolonged standing, and it is likely that specimens are of little utility after more than 2 to 3 hours of typical ED storage conditions. One study showed that unrefrigerated, nonagitated samples were reliable for up to 8 hours.²²⁶

Detection of Blood in Stool

Bedside fecal blood tests make use of the peroxidase-like activity of Hb. The test card is impregnated with a dye that exhibits a blue color reaction when oxidized. The developer contains 5% hydrogen peroxide and 75% alcohol. The original test used guaiac, but current tests use more sensitive and more reliable quinolone compounds. The addition of hydrogen peroxide developer solution will oxidize the dye to a blue color in the presence of a peroxidase (e.g., Hb).

Testing for occult blood in stool is associated with false-positive and false-negative results, but in its primary role in emergency medical practice the test is usually reliable in detecting significant acute gastrointestinal (GI) hemorrhage (Fig. 67-8).³⁹ Low pH, heat, dry stools, reducing substances (including antioxidants such as vitamin C), and antacids can cause false-negative findings.^227–229 Slow bleeding in the upper GI tract, during which heme can be converted (denatured) to porphyrin during transit through the gut, may not be identified by stool testing. False-positive results have been attributed to the ingestion of partly cooked or large quantities of meat (dietary sources of myoglobin and Hb) and peroxidase-rich food.^229,230 Most vegetables contain peroxidase, including (in decreasing order) broccoli, turnips, cantaloupe, red radishes, horseradish, cauliflower, parsnips, Jerusalem artichokes, bean sprouts, beans, lemon rind, mushrooms, parsley, and zucchini.²³⁰ A simple in vivo study convincingly called into question the possibility of peroxidase passing through the stomach without being denatured.²³¹ False-positive test results can also be caused by the presence of povidone-iodine solution at concentrations of less than 0.1% (a 1% dilution of the 10% solutions commonly available at the bedside), but they are uncommon. A positive test should be considered evidence of the presence of blood until proved otherwise. Routine iron supplementation does cause black stool but does not a cause a positive Hemoccult test result despite early in vitro studies to the contrary.^232,233

Normal GI blood loss is limited to less than 2.5 mL/day, which translates to less than 2 mg of Hb per gram of stool (0.2% by weight).²³⁴ The sensitivity of the Hemoccult test varies both with the concentration of Hb present in stool and with the extent of Hb exposure to the proteolytic effects of the digestive tract. The Hemoccult test is 37% sensitive to stool containing 2.5 mg Hb/g of stool but 95% sensitive when the concentration is 20 mg Hb/g of stool, thus indicating that low to moderate levels of blood may be missed.³⁸ The test is much more likely to detect lower GI hemorrhage than an identical rate of upper GI bleeding because of the 100-fold diminution in the peroxidase activity of blood during transition through the GI tract.⁷¹ Impaired detection of Hb may also occur as a result of dilution because of diarrheal illness.^38,39,235 Recent regulatory attempts in the United States to improve quality control in bedside occult blood testing seem to have had the unintended consequence of discouraging digital rectal examination in patients for whom they are indicated.^236,237 In the event of a trace positive Hemoccult test that is not the source of an emergency illness, notification of the patient and advice regarding further outpatient evaluation should not be overlooked.²²⁸

Testing for Gastric Blood

Heme tests designed for use on stool specimens can be unreliable when applied to gastric juices, with increasing inaccuracies being reported as the pH decreases.238,239 Although a positive test of gastric contents with a fecal Hemoccult card is likely to be accurate, a negative result with the fecal Hemoccult card does not rule out the presence of blood. The Gastroccult card uses a modified guaiac developer containing buffers to neutralize gastric acid, thereby facilitating accurate detection of Hb. The test works on the same basis as the fecal guaiac test in that it uses the properties of Hb as a peroxidase. In product testing, the Gastroccult card was 100% sensitive in detecting specimens with greater than 500 ppm of blood by volume, equivalent to 0.05% or 0.25 mL of blood in 500 mL of gastric contents.

Noninvasive Diagnostic Procedures

Invasive Diagnostic Procedures

Several invasive diagnostic bedside procedures can be useful in the assessment of possible drug overdoses. The basic premise of these procedures is that patients who have been exposed to a certain drug or poison will respond in a particular fashion if given a diagnostic challenge dose of another particular drug or true antidote.

Invasive Therapeutic Procedures

The indications and rationale for the use of certain therapeutic procedures in toxicology are often misunderstood.

1. Stamm, WE, Counts, GW, Running, KR, et al. Diagnosis of coliform infection in acutely dysuric women. N Engl J Med. 1982;307:463.

2. Kunin, CM, White, LV, Hua, TH. A reassessment of the importance of “low-count” bacteriuria in young women with acute urinary symptoms. Ann Intern Med. 1993;119:454.

3. Kunin, C, Southall, I, Paquin, AJ. Epidemiology of urinary tract infections. N Engl J Med. 1960;263:817.

4. Nicolle, LE, Bjornson, J, Harding, G, et al. Bacteriuria in elderly institutionalized men. N Engl J Med. 1983;309:1420.

5. Lipsky, BA, Ireton, RC, Fihn, SD, et al. Diagnosis of bacteriuria in men: specimen collection and culture interpretation. J Infect Dis. 1987;155:847.

6. Lohr, JA, Donowitz, LG, Dudley, SM. Bacterial contamination rates for non–clean-catch and clean-catch midstream urine collection in boys. J Pediatr. 1986;109:659.

7. Walter, FG, Knopp, RK. Urine sampling in ambulatory women: midstream clean catch versus catheterization. Ann Emerg Med. 1989;18:166.

8. Immergut, MA, Gilbert, EC, Frensilli, FJ, et al. The myth of the clean catch urine specimen. Urology. 1981;17:339.

9. Stamm, WE, Wagner, KF, Amsel, R, et al. Causes of the acute urethral syndrome in women. N Engl J Med. 1980;303:409.

10. Sultana, RV, Zalstein, S, Cameron, P, et al. Dipstick urinalysis and the accuracy of the clinical diagnosis of urinary tract infection. J Emerg Med. 2001;20:13.

11. Komaroff, AL. Urinalysis and urine culture in women with dysuria. Ann Intern Med. 1986;104:212.

12. Lipsky, BA, Ireton, RC, Fihn, SD, et al. Diagnosis of bacteriuria in men: specimen collection and culture interpretation. J Infect Dis. 1987;155:847.

13. Pels, RJ, Bor, DH, Woolhandler, S, et al. Dipstick urinalysis screening of asymptomatic adults for urinary tract disorders: II Bacteriuria. JAMA. 1989;262:1214.

14. Stamm, WE, Hooton, TM. Management of urinary tract infections in adults. N Engl J Med. 1993;329:1328.

15. Loo, SY, Scottolini, AG, Luangphinith, S, et al. Urine screening strategy employing dipstick analysis and selective culture: an evaluation. Am J Clin Pathol. 1984;81:634.

16. Mariani, AJ, Luangphinith, S, Loo, SY, et al. Dipstick chemical urinalysis: an accurate cost-effective screening test. J Urol. 1984;132:64.

17. Amir, J, Ginzburg, M, Straussberg, R, et al. The reliability of midstream urine cultures from circumcised male infants. Am J Dis Child. 1993;147:969.

18. Boehm, JJ, Haynes, JL. Bacteriology of “midstream catch” urines. Am J Dis Child. 1966;111:366.

19. Taylor, MR, Dillon, M, Keane, CT. Reduction of mixed growth rates in urine by using a finger tap method. Br Med J. 1986;292:990.

20. Shaw, KN, Gorelick, M, McGowan, KL, et al. Prevalence of urinary tract infection in febrile young children in the emergency department. Pediatrics. 1998;102(2):e16.

21. Crain, EF, Gershel, JC. Urinary tract infections in febrile infants younger than eight weeks of age. Pediatrics. 1990;86:363.

22. Hardy, JD, Furnell, PM, Brumfitt, W. Comparison of sterile bag, clean catch, and suprapubic aspiration in the diagnosis of urinary infection in early childhood. Br J Urol. 1976;48:279.

23. Aronson, AS, Gustafson, B, Svenningsen, NW. Combined suprapubic aspiration and clean voided urine examination in infants and children. Acta Paediatr Scand. 1973;62:396.

24. McGillivray, D, Mok, E, Mulrooney, E, et al. A head-to-head comparison: “clean-void” bag versus catheter urinalysis in the diagnosis of urinary tract infection in young children. J Pediatr. 2005;147:451–456.

25. Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. American Academy of Pediatrics. Committee on Quality Improvement. Subcommittee on Urinary Tract Infection. Pediatrics. 1999;103:843–852.

26. Whiting, P, Westwood, M, Bojke, L, et al. Clinical effectiveness and cost-effectiveness of tests for the diagnosis and investigation of urinary tract infection in children: a systematic review and economic model. Health Technol Assess. 2006;10(36):iii–iv. [xi-xiii, 1-154].

27. Hoberman, A, Wald, ER, Penchansky, L, et al. Enhanced urinalysis as a screening test for urinary tract infection. Pediatrics. 1993;91:1196.

28. Grahn, D, Norman, DC, White, ML, et al. Validity of urinary catheter specimen for diagnosis of urinary tract infection in the elderly. Arch Intern Med. 1985;145:1858.

29. Ouslander, JG, Greengold, BA, Silverblatt, FJ, et al. An accurate method to obtain urine for culture in men with external catheters. Arch Intern Med. 1987;147:286.

30. Sullivan, NM, Sutter, VL, Carter, WT, et al. Bacteremia after genitourinary tract manipulation: bacteriological aspects and evaluation of various blood culture systems. Appl Microbiol Biotechnol. 1972;23:1101.

31. Hockberger, RS, Schwartz, B, Connor, J. Hematuria induced by urethral catheterization. Ann Emerg Med. 1987;16:550.

32. Chen, L, Hsiao, AL, Moore, CL, et al. Utility of bedside bladder ultrasound before urethral catheterization in young children. Pediatrics. 2005;115:108–111.

33. Milling, TJ, Jr., Van Amerongen, R, Melville, L, et al. Use of ultrasonography to identify infants for whom urinary catheterization will be unsuccessful because of insufficient urine volume: validation of the urinary bladder index. Ann Emerg Med. 2005;45:510–513.

34. Baumann, BM, McCans, K, Stahmer, SA, et al. Volumetric bladder ultrasound performed by trained nurses increases catheterization success in pediatric patients. Am J Emerg Med. 2008;26:18–23.

35. Pollock, HM. Laboratory techniques for detection of urinary tract infection and assessment of value. Am J Med. 1983;75:79.

36. Kozer, E, Rosenbloom, E, Goldman, D, et al. Pain in infants who are younger than 2 months during suprapubic aspiration and transurethral bladder catheterization: a randomized, controlled study. Pediatrics. 2006;118:e51–e56.

37. Gallagher, EJ, Schwartz, E, Weinstein, R. Performance characteristics of urine dipsticks stored in open containers. Am J Emerg Med. 1990;8:121.

38. Henry JB, ed. Clinical Diagnosis and Management by Laboratory Methods, 19th ed, Philadelphia: Saunders, 1996.

39. Jacobs DS, DeMott WR, Finley PR, et al, eds. Laboratory Test Handbook, 3rd ed, Cleveland, OH: Lexicomp, 1994.

40. Fitzgerald, FT. Hypoglycemia and accidental hypothermia in an alcoholic population. West J Med. 1980;133:105.

41. Fraser, K, Fretter, MC, Mast, RL, et al. Studies with a simplified nitroprusside test for ketone bodies in urine, serum, plasma, and milk. Clin Chim Acta. 1965;11:372.

42. Gelbart, SM, Chen, WT, Reid, R. Clinical trial of leukocyte test strips in routine use. Clin Chem. 1983;29:997.

43. Propp, DA, Weber, D, Ciesla, ML. Reliability of a urine dipstick in emergency department patients. Ann Emerg Med. 1989;18:560.

44. Pfaller, MA, Koontz, FP. Laboratory evaluation of leukocyte esterase and nitrite tests for the detection of bacteriuria. J Clin Microbiol. 1985;21:840.

45. Johnson, JR, Stamm, WE. Urinary tract infections in women. Ann Intern Med. 1989;111:906.

46. Woolhandler, S, Pels, RJ, Bor, DH, et al. Dipstick urinalysis screening of asymptomatic adults for urinary tract disorders. I. Hematuria and proteinuria. JAMA. 1989;262:1214.

47. Karras, DJ, Heilpern, KL, Riley, L, et al. Urine dipstick as a screening test for serum creatinine elevation in emergency department patients with severe hypertension. Acad Emerg Med. 2002;9:27.

48. Firestone, DN, Band, RA, Hollander, JE, et al. Use of a urine dipstick and brief clinical questionnaire to predict an abnormal serum creatinine in the emergency department. Acad Emerg Med. 2009;16:699–703.

49. Wenz, B, Lampasso, JA. Eliminating unnecessary urine microscopy. Am J Clin Pathol. 1989;92:78.

50. Moore, GP, Robinson, M. Do urine dipsticks reliably predict micro hematuria? The bloody truth!. Ann Emerg Med. 1988;17:257.

51. Young, SE, Miller, MA, Docherty, M. Urine dipstick testing to rule out rhabdomyolysis in patients with suspected heat injury. Am J Emerg Med. 2009;27:875–877.

52. Messing, EM, Young, TB, Hunt, VB, et al. The significance of asymptomatic microhematuria in men 50 or more years old: findings of a home screening study using urinary dipsticks. J Urol. 1987;137:919.

53. Stamm, WE, Running, K, McKevitt, M, et al. Treatment of the acute urethral syndrome. N Engl J Med. 1981;304:956.

53a. Levin, K, Engström, I. Inadequate hemolysis of erythrocytes at low pH causes false negative readings. Clin Chem. 1984;30:1845.

53b. Niemi, TA, Fischer, RP, Gervin, AS. Povidone iodine: a cause for false-positive dipstick hematuria? Ann Emerg Med. 1984;13:984.

54. Assadi, FK, Fornell, L. Estimation of urine specific gravity in neonates with a reagent strip. J Pediatr. 1986;108:995.

55. Stamm, WE. Measurement of pyuria and its relation to bacteriuria. Am J Med. 1983;75:53.

56. Brumfitt, W. Urinary cell counts and their value. J Clin Pathol. 1965;18:550.

57. Vickers, D, Ahmad, T, Coulthard, MG. Diagnosis of urinary tract infection in children: fresh urine microscopy or culture? Lancet. 1991;338:767.

58. Musher, DM, Thorsteinson, SB, Airola, VM, II. Quantitative urinalysis: diagnosing urinary tract infection in men. JAMA. 1976;236:2069.

59. Gadeholt, H. Quantitative estimation of urinary sediment, with special regard to sources of error. Br Med J. 1964;15:47.

60. Stansfeld, JM. The measurement and meaning of pyuria. Arch Dis Child. 1962;37:257.

61. Shaw, KN, McGowan, KL, Gorelick, MH, et al. Screening for urinary tract infection in infants in the emergency department: which test is best? Pediatrics. 1998;101(6):E1.

62. Jenkins, RD, Fenn, JP, Matsen, JM. Review of urine microscopy for bacteriuria. JAMA. 1986;255:3397.

63. Lohr, JA, Portilla, MG, Geuder, TG, et al. Making a presumptive diagnosis of urinary tract infection by using urinalysis performed in an on-site laboratory. J Pediatr. 1993;122:22.

64. Goldsmith, BM, Campos, JM. Comparison of urine dipstick, microscopy, and culture for the detection of bacteriuria in children. Clin Pediatr (Phila). 1990;29:214.

65. Bonnardeaux, A, Somerville, P, Kaye, M. A study of the reliability of dipstick urinalysis. J Clin Nephol. 1994;41:167.

66. Sewell, DL, Burt, SP, Gabbert, NJ, et al. Evaluation of the Chemstrip 9 as a screening test for urinalysis and urine culture in men. Am J Clin Pathol. 1985;83:740.

67. Gutman, SI, Solomon, RR. The clinical significance of dipstick negative, culture positive urines in a veterans population. Am J Clin Pathol. 1987;88:204.

68. Morrison, MC, Lum, G. Dipstick testing of urine—can it replace urine microscopy? Am J Clin Pathol. 1986;85:590.

69. Kellogg, JA, Manzella, JP, Shaffer, S, et al. Clinical relevance of culture versus screens for the detection of pathogens in urine specimens. Am J Med. 1987;83:739.

70. Fihn, SD. Clinical practice. Acute uncomplicated urinary tract infection in women. N Engl J Med. 2003;349:259–266.

71. Hooton, TM, Besser, R, Foxman, B, et al. Acute uncomplicated cystitis in an era of increasing antibiotic resistance: a proposed approach to empirical therapy. Clin Infect Dis. 2004;39:75–80.

72. Guneysel, O, Onur, O, Erdede, M, et al. Trimethoprim/sulfamethoxazole resistance in urinary tract infections. J Emerg Med. 2009;36:338–341.

73. Thanassi, M. Utility of urine and blood cultures in pyelonephritis. Acad Emerg Med. 1997;4:797.

74. Reardon, JM, Carstairs, KL, Rudinsky, SL, et al. Urinalysis is not reliable to detect a urinary tract infection in febrile infants presenting to the ED. Am J Emerg Med. 2009;27:930–932.

75. Minnerop, MH, Garra, G, Chohan, JK, et al. Patient history and physician suspicion accurately exclude pregnancy. Am J Emerg Med. 2011;29:212–215.

76. Strote, J, Chen, G. Patient self assessment of pregnancy status in the emergency department. Emerg Med J. 2006;23:554–557.

77. Ramoska, EA, Sacchetti, AD, Nepp, M. Reliability of patient history in determining the possibility of pregnancy. Ann Emerg Med. 1989;18:48–50.

78. Mishalani, SH, Seliktar, J, Braunstein, GD. Four rapid serum-urine combination assays of choriogonadotropin compared and assessed. Clin Chem. 1994;40:1944.

79. Fromm, C, Likourezos, A, Haines, L, et al. Substituting whole blood for urine in a bedside pregnancy test. J Emerg Med. 2012;43:478–482.

80. Habboushe, JP, Walker, G. Novel use of a urine pregnancy test using whole blood. Am J Emerg Med. 2011;29:840. [e3-e4].

81. Maymon, R, Shulman, A, Maymon, BB, et al. Ectopic pregnancy, the new gynecologic epidemic disease: review of the modern work up and the non-surgical treatment option. Int J Fertil Womens Med. 1992;37:146.

82. Speroff, L, Glass, RH, Kase, NG. Clinical Gynecological Endocrinology and Infertility, 5th ed. Baltimore: Williams & Wilkins; 1994.

83. Cole, LA, Kardana, A. Discordant results in human gonadotropin assays. Clin Chem. 1992;38:263.

84. Creinin, MD, Meyn, L, Klimashko, T. Accuracy of serum beta-human chorionic gonadotropin cutoff values at 42 and 49 days’ gestation. Am J Obstet Gynecol. 2001;185:966.

85. Levsky, ME, Handler, JA, Suarez, RD, et al. False-positive urine beta-hCG in a woman with a tubo-ovarian abscess. J Emerg Med. 2001;21:407.

86. DeCherney AH. Ectopic pregnancy. American College of Obstetricians and Gynecologists Technical Bulletin No. 150, Dec 1990, p 2.

87. Kadar, N, Caldwell, BU, Romero, RA. A method for screening for ectopic pregnancy and its indications. Obstet Gynecol. 1981;58:162.

88. Kadar, N, Romero, R. Serial human chorionic gonadotropin measurements in ectopic pregnancy. Am J Obstet Gynecol. 1988;158:1239.

89. Bree, RL, Edwards, M, Bohm-Velez, M, et al. Transvaginal sonography in the evaluation of normal early pregnancy: correlation with hCG level. AJR Am J Roentgenol. 1989;153:75.

90. Counselman, FL, Shaar, GS, Heller, RA, et al. Quantitative β-hCG levels less than 1000 mIU/mL in patients with ectopic pregnancy: pelvic ultrasound still useful. J Emerg Med. 1998;16:699.

91. Dart, RG, Kaplan, B, Cox, C. Transvaginal ultrasound in patients with low beta-human chorionic gonadotropin values: how often is the study diagnostic? Ann Emerg Med. 1997;30:135.

92. Dimarchi, JN, Kosasa, TS, Hale, RW. What is the significance of human gonadotropin value in ectopic pregnancy? Obstet Gynecol. 1989;74:851.

93. Romero, RA, Kadar, N, Copel, JA, et al. The effect of different human chorionic gonadotropin assay sensitivity on screening for ectopic pregnancy. Am J Obstet Gynecol. 1985;153:72.

94. Kaplan, BC, Dart, RG, Moskos, M, et al. Ectopic pregnancy: prospective study with improved diagnostic accuracy. Ann Emerg Med. 1996;28:10.

95. Marill, KA, Ingmire, TE, Nelson, BK. Utility of a single beta HCG measurement to evaluate for absence of ectopic pregnancy. J Emerg Med. 1999;17:419.

96. Barnhart, KT, Simhan, H, Kamelle, SA. Diagnostic accuracy of ultrasound above and below the beta-hCG discriminatory zone. Obstet Gynecol. 1999;94:583.

97. Musher, DM, Fainstein, V, Young, EJ, et al. Fever patterns: their lack of clinical significance. Arch Intern Med. 1979;139:1225.

98. Castle, SC, Norman, DC, Yeh, M, et al. Fever response in elderly nursing home residents: are the older truly colder? J Am Geriatr Soc. 1991;39:853.

99. Fontanarosa, PB, Kaeberlein, FJ, Gerson, LW, et al. Difficulty in predicting bacteremia in elderly emergency department patients. Ann Emerg Med. 1992;2:842.

100. Gleckman, R, Hilbert, D. Afebrile bacteremia: a phenomenon in geriatric patients. JAMA. 1982;248:1478.

101. Sinclair, D, Svendsen, A, Marrie, T. Bacteremia in nursing home patients. Prevalence among patients presenting to an emergency department. Can Fam Physician. 1998;44:317.

102. Richardson, JP, Hricz, L. Risk factors for the development of bacteremia in nursing home patients. Arch Fam Med. 1995;4:785.

103. Buckley, RG, Conine, M. Reliability of subjective fever in triage of adult patients. Ann Emerg Med. 1996;27:693.

104. Bates, DW, Cook, EF, Goldman, L, et al. Predicting bacteremia in hospitalized patients. A prospectively validated model. Ann Intern Med. 1990;113:495.

105. Yehezkelli, Y, Subah, S, Elhanan, G, et al. Two rules for early prediction of bacteremia: testing in a university and a community hospital. J Gen Intern Med. 1996;11:98.

106. Tokuda, Y, Miyasato, H, Stein, GH. A simple prediction algorithm for bacteraemia in patients with acute febrile illness. QJM. 2005;98:813–820.

107. Hickey, RW, Bowman, MJ, Smith, GA. Utility of blood cultures in pediatric patients found to have pneumonia in the emergency department. Ann Emerg Med. 1996;27:721.

108. Paisley, JW, Lauer, BA. Pediatric blood cultures. Clin Lab Med. 1994;14:17.

109. Waterer, GW, Wunderink, RG. The influence of the severity of community-acquired pneumonia on the usefulness of blood cultures. Respir Med. 2001;95:78.

110. Wing, DA, Park, AS, Debuque, L, et al. Limited clinical utility of blood and urine cultures in the treatment of acute pyelonephritis during pregnancy. Am J Obstet Gynecol. 2000;182:1437.

111. Campbell, SG, Marrie, TJ, Anstey, R, et al. Utility of blood cultures in the management of adults with community acquired pneumonia discharged from the emergency department. Emerg Med J. 2003;20:521–523.

112. Shah, SS, Alpern, ER, Zwerling, L, et al. Risk of bacteremia in young children with pneumonia treated as outpatients. Arch Pediatr Adolesc Med. 2003;157:389–392.

113. Campbell, SG, Marrie, TJ, Anstey, R, et al. The contribution of blood cultures to the clinical management of adult patients admitted to the hospital with community-acquired pneumonia: a prospective observational study. Chest. 2003;123:1142–1150.

114. McMurray, BR, Wrenn, KD, Wright, SW. Usefulness of blood cultures in pyelonephritis. Am J Emerg Med. 1997;15:137–140.

115. Velasco, M, Martinez, JA, Moreno-Martinez, A, et al. Blood cultures for women with uncomplicated acute pyelonephritis: are they necessary? Clin Infect Dis. 2003;37:1127–1130.

116. Mills, AM, Barros, S. Are blood cultures necessary in adults with pyelonephritis? Ann Emerg Med. 2005;46:285–287.

117. Ramanujam, P, Rathlev, NK. Blood cultures do not change management in hospitalized patients with community-acquired pneumonia. Acad Emerg Med. 2006;13:740–745.

118. Kennedy, M, Bates, DW, Wright, SB, et al. Do emergency department blood cultures change practice in patients with pneumonia? Ann Emerg Med. 2005;46:393–400.

119. van Nieuwkoop, C, Bonten, TN, van’t Wout, JW, et al. Risk factors for bacteremia with uropathogen not cultured from urine in adults with febrile urinary tract infection. Clin Infect Dis. 2010;l50(11):e69–e72.

120. McCaig, LF, McDonald, LC, Cohen, AL, et al. Increasing blood culture use at US hospital emergency department visits, 2001 to 2004. Ann Emerg Med. 2007;50:42–48. [48.e1-e2].

121. Alpern, ER, Alessandrini, EA, Bell, LM, et al. Occult bacteremia from a pediatric emergency department: current prevalence, time to detection, and outcome. Pediatrics. 2000;106:505.

122. Sard, B, Bailey, MC, Vinci, R. An analysis of pediatric blood cultures in the postpneumococcal conjugate vaccine era in a community hospital emergency department. Pediatr Emerg Care. 2006;22:295–300.

123. Wilkinson, M, Bulloch, B, Smith, M. Prevalence of occult bacteremia in children aged 3 to 36 months presenting to the emergency department with fever in the postpneumococcal conjugate vaccine era. Acad Emerg Med. 2009;16:220–225.

124. Browne, GJ, Ryan, JM, McIntyre, P. Evaluation of a protocol for selective empiric treatment of fever without localising signs. Arch Dis Child. 1997;76:129.

125. Haddon, RA, Barnett, PL, Grimwood, K, et al. Bacteraemia in febrile children presenting to a paediatric emergency department. Med J Aust. 1999;170:475.

126. Isaacman, DJ, Shults, J, Gross, TK, et al. Predictors of bacteremia in febrile children 3 to 36 months of age. Pediatrics. 2000;106:977.

127. Kuppermann, N, Fleisher, GR, Jaffe, DM. Predictors of occult pneumococcal bacteremia in young febrile children. Ann Emerg Med. 1998;31:679.

128. Banco, VD. Ability of mothers to subjectively assess the presence of fever in their children. Am J Dis Child. 1984;138:976.

129. Kline, MW, Lorin, MI. Bacteremia in children afebrile at presentation to an emergency room. Pediatr Infect Dis J. 1987;6:197.

130. Eisenberg, JM, Rose, JD, Weinstein, AJ. Routine blood cultures from febrile outpatients: use in detecting bacteremia. JAMA. 1976;236:2863.

131. Stair, TO. Outpatient blood cultures: retrospective and prospective audits in one ED. Ann Emerg Med. 1984;13:986.

132. Sturmann, KM, Bopp, J, Molinari, D, et al. Blood cultures in adult patients released from an urban emergency department: a 15-month experience. Acad Emerg Med. 1996;3:768.

133. Howie, N, Gerstenmaier, JF, Munro, PT. Do peripheral blood cultures taken in the emergency department influence clinical management? Emerg Med J. 2007;24:213–214.

134. Epstein, D, Raveh, D, Schlesinger, Y. Adult patients with occult bacteremia discharged from the emergency department: epidemiological and clinical characteristics. Clin Infect Dis. 2001;32:559.

135. Sklar, DP, Rusnak, R. The value of outpatient blood cultures in the emergency department. Am J Emerg Med. 1987;5:95.

136. Berger, SA. Pseudobacteremia due to contaminated alcohol swabs. J Clin Microbiol. 1983;18:974.

137. York, MK. Bacillus species bacteremia traced to gloves used in the collection of blood from patients with acquired immune deficiency syndrome. J Clin Microbiol. 1990;28:2114.

138. Shahar, E, Wohl-Gottesman, B, Shenkman, L. Contamination of blood cultures during venepuncture: fact or myth? Postgrad Med J. 1990;66:1053.

139. Washington, JA. Collection, transport, and processing of blood cultures. Clin Lab Med. 1994;14:59.

140. Everts, RJ, Vinson, EN, Adholla, PO, et al. Contamination of catheter-drawn blood cultures. J Clin Microbiol. 2001;39:3393.

141. Mimoz, O, Karim, A, Mercat, A, et al. Chlorhexidine compared with povidone-iodine as skin preparation before blood culture. A randomized, controlled trial. Ann Intern Med. 1999;131:834.

142. Stalnikowicz, R, Block, C. The yield of blood cultures in a department of emergency medicine. Eur J Emerg Med. 2001;8:93.

143. Henry, NK, McLimans, CA, Wright, AJ, et al. Microbiological and clinical evaluation of the isolator lysis-centrifugation blood culture tube. J Clin Microbiol. 1983;17:864.

144. Kellogg, JA, Manzella, JP, Bankert, DA. Frequency of low-level bacteremia in children from birth to fifteen years of age. J. Clin Microbiol Rev. 2000;38:2181.

145. Selwyn, S, Ellis, H. Skin bacteria and skin disinfection reconsidered. Br Med J. 1972;1:136.

146. Lovell, DL. Preoperative skin preparation with reference to surface bacteria contaminants, and resident flora. Surg Clin North Am. 1946;26:1053.

147. Story, P. Testing of skin disinfectants. Br Med J. 1952;2:1128.

148. Strand, CL, Wajsbort, RR, Sturmann, K. Effect of iodophor versus iodine tincture skin preparation on blood culture contamination rates. JAMA. 1993;269:1004.

149. Harvey, SC. Antiseptics and disinfectants; fungicides and ectoparasiticides. In: Gilman AG, Goodman LS, Rall TW, et al, eds. Goodman and Gilman’s The Pharmacologic Basis of Therapeutics. 7th ed. New York: Macmillan; 1980:959.

150. Lee, S, Schoen, I, Malkin, A. Comparison of use of alcohol with that of iodine for skin antisepsis in obtaining blood cultures. Am J Clin Pathol. 1967;47:646.

151. Maki, DG, Ringer, M, Alvarado, CJ. Prospective randomized trial of povidone-iodine, alcohol, and chlorhexidine for prevention of infection associated with central venous and arterial catheters. Lancet. 1991;338:339.

152. Little, JR, Murray, PR, Traynor, PS, et al. A randomized trial of povidone-iodine compared with iodine tincture for venipuncture site disinfection: effects on rates of blood culture contamination. Am J Med. 1999;107:119.

153. Schifman, RB, Pindur, A. The effect of skin disinfection materials on reducing blood culture contamination. Am J Clin Pathol. 1993;99:536.

154. Waters, BL. Inoculating blood cultures: recapping needles and contamination rates. JAMA. 1991;265:1685.

155. Leisure, MK, Moore, DM, Schwartzman, JD, et al. Changing the needle when inoculating blood cultures: a no-benefit and high-risk procedure. JAMA. 1990;264:2111.

156. Krumholz, HM, Cummings, S, York, M. Blood culture phlebotomy: switching needles does not prevent contamination. Ann Intern Med. 1990;113:290.

157. Smart, D, Baggoley, C, Head, J, et al. Effect of needle changing and intravenous cannula collection on blood culture contamination rates. Ann Emerg Med. 1993;22:65.

158. Bryant, JK, Strand, CL. Reliability of blood cultures collected from intravenous catheters versus venepuncture. Am J Clin Pathol. 1987;88:113.

159. Tonneson, A, Peuler, M, Lockwood, WR. Culture of blood drawn by catheter versus venepuncture. JAMA. 1976;235:1877.

160. Tafuro, P, Colbourn, D, Gurevich, I, et al. Comparison of blood culture obtained simultaneously by venepuncture and from vascular lines. J Hosp Infect. 1986;7:283.

161. Wormser, GP, Onorato, IM, Preminger, TJ, et al. Sensitivity and specificity of blood cultures obtained through intravenous catheters. Crit Care Med. 1990;18:152.

162. DesJardin, JA, Falagas, ME, Ruthazer, R, et al. Clinical utility of blood cultures drawn from indwelling central venous catheters in hospitalized patients with cancer. Ann Intern Med. 1999;131:641.

163. Mangurten, HH, LeBeau, LJ. Diagnosis of neonatal bacteremia by a microblood culture technique. J Pediatr. 1977;90:990.

164. Knudsen, RP, Alden, ER. Neonatal heel stick blood culture. Pediatrics. 1980;65:505.

165. Orlowski, JP, Porembka, DT, Gallagher, JM, et al. The bone marrow as a source of lab studies. Ann Emerg Med. 1989;18:1348.

166. Bennett, IL, Beeson, PB. Bacteremia: a consideration of some experimental bacteremias. Yale J Biol Med. 1954;226:241.

167. Washington, JA. Collection, transport, and processing of blood cultures. Clin Lab Med. 1994;14:59.

168. Washington, JA. Evolving concepts on the laboratory diagnosis of septicemia. Infect Dis Clin Pract. 1993;1:65.

169. Chandrasekar, PH, Brown, WJ. Clinical issues of blood cultures. Arch Intern Med. 1994;154:841.

170. Hall, MM, Ilstrup, DM, Washington, JA. Effect of volume of blood cultured on detection of bacteremia. J Clin Microbiol. 1976;3:643.

171. Tenney, JH, Reller, LB, Mirrett, S, et al. Controlled evaluation of the volume of blood cultured on detection of bacteremia. J Clin Microbiol. 1982;15:558.

172. Ilstrup, DM, Washington, JA. The importance of volume of blood cultured in the detection of bacteremia and fungemia. Diagn Microbiol Infect Dis. 1983;1:107.

173. Arpi, M, Bentzon, MW, Jenson, J, et al. Importance of blood volume cultured in the detection of bacteremia. Eur J Clin Microbiol Infect Dis. 1989;8:838.

174. Brown, DF, Warren, RE. Effect of sample volume on yield of positive blood cultures for adult patients with hematological malignancy. J Clin Pathol. 1990;43:777.

175. Mermel, LA, Maki, DG. Detection of bacteremia in adults: consequences of culturing an inadequate volume of blood. Ann Intern Med. 1993;119:270.

176. Kellogg, JA, Manzella, JP, Bankert, DA. Frequency of low-level bacteremia in children from birth to fifteen years of age. J. Clin Microbiol Rev. 2000;38:2181.

177. Kellogg, JA. Selection of a clinically satisfactory blood culture system: the utility of anaerobic media. Clin Microbiol Newslett. 1995;17:121.

178. Weinstein, MP, Reller, LB, Murphy, JR, et al. The clinical significance of a positive blood culture: a comprehensive analysis of 500 episodes of bacteremia and fungemia in adults: I Laboratory and epidemiological observations. Rev Infect Dis. 1983;5:35.

179. Washington, JA, Ilstrup, DM. Blood cultures: issues and controversies. Rev Infect Dis. 1986;8:792.

180. Dietzman, DE, Fisher, GW, Schoenknecht, FD. Neonatal Escherichia coli septicemia—bacterial counts in blood. J Pediatr. 1974;85:128.

181. Mangurten, HH, LeBeau, LJ. Diagnosis of neonatal bacteremia by a microblood culture technique. J Pediatr. 1977;90:990.

182. Durbin, WA, Szymczak, EG, Goldman, DA. Quantitative blood cultures in childhood bacteremia. J Pediatr. 1978;92:778.

183. Neal, PR, Kleiman, MB, Reynolds, JK, et al. Volume of blood submitted for culture from neonates. J Clin Microbiol. 1986;24:353.

184. Szymczak, EG, Barr, JT, Durbin, WA, et al. Evaluation of blood culture procedures in a pediatric hospital. J Clin Microbiol. 1979;9:88.

185. Campos, JM. Detection of bloodstream infections in children. Eur J Clin Microbiol Infect Dis. 1989;8:815.

186. Paisley, JW, Lauer, BA. Pediatric blood cultures. Clin Lab Med. 1994;14:17.

187. Aronson, MD, Bor, DH. Blood cultures. Ann Intern Med. 1987;106:246.

188. Novis, DA, Dale, JC, Schifman, RB, et al. Solitary blood cultures: a College of American Pathologists Q-probes study of 132,778 blood culture sets in 333 small hospitals. Arch Pathol Lab Med. 2001;125:1290.

189. Roberts, FJ. The value of the second blood culture. J Infect Dis. 1993;168:795.

190. Dorsher, CW, Rossenblatt, JE, Wilson, WR, et al. Anaerobic bacteremia: decreasing rate over a 15-year period. Rev Infect Dis. 1991;13:633.

191. Murray, PR, Traynor, P, Hopson, D. Critical assessment of blood culture techniques: analysis of recovery of obligate and facultative anaerobes, strict aerobic bacteria, and fungi in aerobic and anaerobic culture bottles. J Clin Microbiol. 1992;30:142.

192. Sharp, SE. Routine anaerobic blood cultures: still appropriate today? Clin Microbiol Newslett. 1991;13:23.

193. Chandler, MT, Morton, ES, Byrd, RP, Jr., et al. Reevaluation of anaerobic blood cultures in a veteran population. South Med J. 2000;93:986.

194. Lombardi, DP, Engleberg, NC. Anaerobic bacteremia: incidence, patient characteristics, and clinical significance. Am J Med. 1992;92:53.

195. Salonen, JH, Eerola, E, Meurman, O. Clinical significance and outcome of anaerobic bacteremia. Clin Infect Dis. 1998;26:1413–1417.

196. Saito, T, Senda, K, Takakura, S, et al. Anaerobic bacteremia: the yield of positive anaerobic blood cultures: patient characteristics and potential risk factors. Clin Chem Lab Med. 2003;41:293–297.

197. Lassmann, B, Gustafson, DR, Wood, CM, et al. Reemergence of anaerobic bacteremia. Clin Infect Dis. 2007;44:895–900.

198. Mylotte, JM, Tayara, A. Blood cultures: clinical aspects and controversies. Eur J Clin Microbiol Infect Dis. 2000;19:157.

199. Geerdes, HF, Ziegler, D, Lode, H, et al. Septicemia in 980 patients at a university hospital in Berlin: prospective studies during four selected years between 1979 and 1989. Clin Infect Dis. 1992;15:991.

200. Zaidi, AK, Knaut, AL, Mirrett, S, et al. Value of routine anaerobic blood cultures for pediatric patients. J Pediatr. 1995;127:263–268.

201. Thomas, JG, Meda, BA. Anaerobic cultures: tailoring their selective use. Clin Microbiol Newslett. 1995;17:125.

202. Morris, AJ, Wilson, ML, Mirrett, S, et al. Rationale for the selective use of anaerobic blood cultures. J Clin Microbiol. 1993;31:2110.

203. DesJardin, JA, Falagas, ME, Ruthazer, R, et al. Clinical utility of blood cultures drawn from indwelling central venous catheters in hospitalized patients with cancer. Ann Intern Med. 1999;131:641.

204. Jarvis, WR, Martone, WJ. Predominant pathogens in hospital infections. J Antimicrob Chemother. 1992;29:19.

205. Silva, HL, Strabelli, TM, Cunha, ER, et al. Nosocomial coagulase negative staphylococci bacteremia: five-year prospective data collection. Braz J Infect Dis. 2000;4:271.

206. Zierdt, CH. Evidence for transient Staphylococcus epidermidis bacteremia in patients and in healthy humans. J Clin Microbiol. 1983;17:628.

207. Bates, DW, Goldman, L, Lee, TH. Contaminant blood cultures and resource utilization: the true consequences of false-positive results. JAMA. 1991;265:365.

208. Segal, GS, Chamberlain, JM. Resource utilization and contaminated blood cultures in children at risk for occult bacteremia. Arch Pediatr Adolesc Med. 2000;154:469.

209. St Geme, JW, III., Bell, LM, Baumgart, S, et al. Distinguishing sepsis from blood culture contamination in young infants with blood cultures growing coagulase-positive staphylococci. Pediatrics. 1990;86:157.

210. Howanitz, PJ. Errors in laboratory medicine: practical lessons to improve patient safety. Arch Pathol Lab Med. 2005;129:1252–1261.

211. Young, DS. Conveying the importance of the preanalytical phase. Clin Chem Lab Med. 2003;41:884–887.

212. Romero, A, Munoz, M, Ramos, JR, et al. Identification of preanalytical mistakes in the stat section of the clinical laboratory. Clin Chem Lab Med. 2005;43:974–975.

213. Young, DS, Bermes, EW, Haverstick, DM. Specimen collection and processing. In: Burtis CA, Ashwood ER, Bruns DE, eds. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Philadelphia: Saunders, 2006.

214. Bonini, P, Plebani, M, Ceriotti, F, et al. Errors in laboratory medicine. Clin Chem. 2002;48:691–698.

215. Lippi, G, Salvagno, GL, Brocco, G, et al. Preanalytical variability in laboratory testing: influence of the blood drawing technique. Clin Chem Lab Med. 2005;43:319–325.

216. Dugan, L, Leech, L, Speroni, KG, et al. Factors affecting hemolysis rates in blood samples drawn from newly placed IV sites in the emergency department. J Emerg Nurs. 2005;31:338–345.

217. Dwyer, DG, Fry, M, Somerville, A, et al. Randomized, single blinded control trial comparing haemolysis rate between two cannula aspiration techniques. Emerg Med Australas. 2006;18:484–488.

218. Grant, MS. The effect of blood drawing techniques and equipment on the hemolysis of ED laboratory blood samples. J Emerg Nurs. 2003;29:116–121.

219. Cox, SR, Dages, JH, Jarjoura, D, et al. Blood samples drawn from IV catheters have less hemolysis when 5-mL (vs 10-mL) collection tubes are used. J Emerg Nurs. 2004;30:529–533.

220. Kennedy, C, Angermuller, S, King, R, et al. A comparison of hemolysis rates using intravenous catheters versus venipuncture tubes for obtaining blood samples. J Emerg Nurs. 1996;22:566–569.

221. Herr, RD, Bossart, PJ, Blaylock, RC, et al. Intravenous catheter aspiration for obtaining basic analytes during intravenous infusion. Ann Emerg Med. 1990;19:789–792.

222. Mohler, M, Sato, Y, Bobick, K, et al. The reliability of blood sampling from peripheral intravenous infusion lines. Complete blood cell counts, electrolyte panels, and survey panels. J Intraven Nurs. 1998;21:209–214.

223. Corbo, J, Fu, J, Silver, M, et al. Comparison of laboratory values obtained by phlebotomy versus saline lock devices. Acad Emerg Med. 2007;14:23.

224. Zlotowski, SJ, Kupas, DF, Wood, GC. Comparison of laboratory values obtained by means of routine venipuncture versus peripheral intravenous catheter after a normal saline solution bolus. Ann Emerg Med. 2001;38:497–504.

225. Holmes, KR. Comparison of push-pull versus discard method from central venous catheters for blood testing. J Intraven Nurs. 1998;21:282–285.

226. Stahl, M, Brandslund, I. Controlled storage conditions prolong stability of biochemical components in whole blood. Clin Chem Lab Med. 2005;43:210–215.

227. Jaffe, RM, Kasten, B, Young, DS, et al. False-negative stool occult blood tests caused by ingestion of ascorbic acid (vitamin C). Ann Intern Med. 1975;83:824.

228. Mandel, JS, Bond, JH, Church, TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med. 1993;328:1365.

229. Ransohoff, DF, Lang, CA. Screening for colorectal cancer with the fecal occult blood test: a background paper. American College of Physicians. Ann Intern Med. 1997;126:811.

230. Gnauck, R, Macrae, FA, Fleisher, M. How to perform the fecal occult blood test. Cancer. 1984;34:134.

231. Meyer, GW, Komadina, K, Perucca, P. Vegetable peroxidase is denatured by gastric acid: fresh vegetables do not cause false-positive stool Hemoccults in normal subjects. Gastroenterology. 1991;101:871.

232. Anderson, GD, Yuellig, TR, Krone, RE, Jr. An investigation into the effects of oral iron supplementation on in vivo Hemoccult stool testing. Am J Gastroenterol. 1990;85:558.

233. McDonnell, WM, Ryan, JA, Seeger, DM, et al. Effect of iron on the guaiac reaction. Gastroenterology. 1989;96:74.

234. Ahlquist, DA, McGill, DB, Schwartz, S, et al. Fecal blood levels in health and disease. A study using Hemoquant. N Engl J Med. 1985;312:1422.

235. Morris, DW, Hansell, JR, Ostrow, JD, et al. Reliability of chemical tests for fecal occult blood in hospitalized patients. Dig Dis. 1976;21:845.

236. Adams, BD, McHugh, KA, Bryson, SA, et al. The law of unintended consequences: the Joint Commission regulations and the digital rectal examination. Ann Emerg Med. 2008;51:197–201.

237. Cleveland, NJ, Yaron, M, Ginde, AA. The effect of removal of point-of-care fecal occult blood testing on performance of digital rectal examinations in the emergency department. Ann Emerg Med. 2010;56:135–141.

238. Layne, EA, Mellow, MH, Lipman, TO. Insensitivity of guaiac slide tests for detection of blood in gastric juice. Ann Intern Med. 1981;94:774.

239. Holman, JS, Shwed, JA. Influence of sucralfate on the detection of occult blood in simulated gastric fluid by two screening tests. Clin Pharmacol Ther. 1992;11:625.

240. Beuhler, M, Lee, DC, Gerkin, R. The Meixner test in the detection of α-amanitin and false-positive reactions caused by psilocin and 5-substituted tryptamines. Ann Emerg Med. 2004;44:114.

241. Santucci, K, Shah, B. Association of naphthalene with acute hemolytic anemia. Acad Emerg Med. 2000;7:42.

242. Huhn, KM, Rosenberg, FM. Critical clue to ethylene glycol poisoning. CMAJ. 1995;152:193.

243. Hylander, B, Kjellstrand, CM. Prognostic factors and treatment of severe ethylene glycol intoxication. Intensive Care Med. 1996;22:546.

244. McStay, CM, Gordon, PE. Images in clinical medicine. Urine fluorescence in ethylene glycol poisoning. N Engl J Med. 2007;356:611.

245. Wallace, KL, Suchard, JR, Curry, SC, et al. Diagnostic use of physicians’ detection of urine fluorescence in a simulated ingestion of sodium fluorescein–containing antifreeze. Ann Emerg Med. 2001;38:49.

246. Weiner, AL, Ko, C, McKay, CA, Jr. A comparison of two bedside tests for the detection of salicylates in urine. Acad Emerg Med. 2000;7:834.

247. Hlastala, MP. The alcohol breath test—a review. J Appl Physiol. 1998;84:401.

248. Bates, ME, Martin, CS. Immediate, quantitative estimation of blood alcohol concentration from saliva. J Stud Alcohol. 1997;58:531.

249. Bendtsen, P, Hultberg, J, Carlsson, M, et al. Monitoring ethanol exposure in a clinical setting by analysis of blood, breath, saliva, and urine. Alcohol Clin Exp Res. 1999;23:1446.

250. Keim, ME, Bartfield, JM, Raccio-Robak, N. Blood ethanol estimation: a comparison of three methods. Acad Emerg Med. 1996;3:85.

251. Henretig, FM, Gribetz, B, Kearney, T, et al. Interpretation of color change in blood with varying degree of methemoglobinemia. J Toxicol Clin Toxicol. 1988;26:293.

252. Doyon, S, Roberts, JR. Reappraisal of the “coma cocktail.” Dextrose, flumazenil, naloxone, and thiamine. Emerg Med Clin North Am. 1994;12:301.

253. Hoffman, JR, Schriger, DL, Luo, JS. The empiric use of naloxone in patients with altered mental status: a reappraisal. Ann Emerg Med. 1991;20:246.

254. Hoffman, RS, Goldfrank, LR. The poisoned patient with altered consciousness. Controversies in the use of a “coma cocktail. JAMA. 1995;274:562.

255. Basile, AS, Hughes, RD, Harrison, PM, et al. Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure. N Engl J Med. 1991;325:473.

256. Gyr, K, Meier, R, Haussler, J, et al. Evaluation of the efficacy and safety of flumazenil in the treatment of portal systemic encephalopathy: a double-blind, randomised, placebo-controlled multicentre study. Gut. 1996;39:319.

257. Laccetti, M, Manes, G, Uomo, G. Flumazenil in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double-blind, randomized, placebo-controlled study. Dig Liver Dis. 2000;32:335.

258. Beaver, KM, Gavin, TJ. Treatment of acute anticholinergic poisoning with physostigmine. Am J Emerg Med. 1998;16:505.

259. Burns, MJ, Linden, CH, Graudins, A, et al. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med. 2000;35:374.

260. Oakley, P. Physostigmine versus diazepines for anticholinergic poisoning. Ann Emerg Med. 2001;37:239.

261. Siff, JE, Meldon, SW, Tomassoni, AJ. Usefulness of the total iron binding capacity in the evaluation and treatment of acute iron overdose. Ann Emerg Med. 1999;33:73.

262. Wax, P, Hoffman, R. Sodium bicarbonate. Contemp Manage Crit Care. 1991;1:81.

263. Brent, J, McMartin, K, Phillips, S, et al. Fomepizole for the treatment of methanol poisoning. N Engl J Med. 2001;344:424.

264. Megarbane, B, Borron, SW, Trout, H, et al. Treatment of acute methanol poisoning with fomepizole. Intensive Care Med. 2001;27:1370.

265. Brent, J, McMartin, K, Phillips, S, et al. Fomepizole for the treatment of ethylene glycol poisoning. Methylpyrazole for Toxic Alcohols Study Group. N Engl J Med. 1999;340:832.