Author: David Richards, MD, FACEP, Denver Health Medical Center, University of Colorado School of Medicine

Editor: Matthew Tews, DO, MS, Medical College of Wisconsin

Objectives

Upon finishing this module, the student will be able to:

• Identify commonly ordered tests in the Emergency Department
• Identify false positive and negative conditions of common conditions
• Know the price for commonly ordered tests
• Identify validated clinical decision rules using post-test probability

Introduction

Laboratory studies are an important part of Emergency Medicine. Laboratory studies should only be ordered in a setting where a specific study combined with the patient’s pretest probability (symptoms, signs, and risk factors), will give a post-test probability of a disease process that will change the management of the patient.  Statistics, likelihood ratio and Bayesian theorem are out of scope of this current discussion with a focus on indications to order, interpretation of, and costs of common emergency department tests.  The selection of the appropriate test for a patient requires consideration of a number of factors including cost, assay performance and epidemiology.

A note about cost

In the following sections, the price listed next to each test indicates the typical cost to perform the test, not the charge to the patient. In many situations the charge to the patient is many times higher. These charges will vary depending on the institution, but the cost to perform provides an idea of what laboratory resources are required to perform the test.

Lab Tests: Indications, Interpretation, Cost

Complete Blood Count (Cost – $9.27)

• WBC – Reference level: 3.5-11 x109/L
  • Requires thoughtful clinical interpretation, neither sensitive nor specific enough to rule in or rule out disease in many circumstances
  • WBC Differential (Cost – $11.14)
  • Leukocytosis – Requires significant clinical correlation for proper interpretation!
    • Neutrophil predominance – may represent bacterial infection, inflammatory, or neoplastic process
    • Lymphocytepredominance – may represent viral (e.g. EBV) bacterial infections (e.g. Pertussis), lymphocytic leukemia
    • Basophilia – Allergic rxns, hypothyroidism, splenectomy, neoplastic (e.g. CML, polycythemia vera)
    • Monocytosis – GI disorders, sarcoid, recovery from marrow suppression
    • Eosinophilia – parasitic infections, allergic diseases, GI diseases, cutaneous diseases
  • Leukopenia
    • Neutropenia – overwhelming bacterial infection, AIDS, hypersplenism, anaphylactic shock, cachexia
    • Lymphopenia – immunodeficiency disorders, adrenocortical hormone excess or corticosteroid treatment, impaired drainage of intestinal lymphatics, chemotherapeutic drugs, advanced lymphomas and carcinomas, infections (e.g. HIV)
  • RBC – Reference level for hematocrit: 31-53%
    • MCV < 80fL, ferritin level <12 ng/mL – both diagnostic of microcytic anemia. Think iron deficiency, iron absorption problems, chronic disease, spherocytoses.
    • MCV >100fL – macrocytic anemia. Think of vitamin B12 and folate deficiencies.  Some anti-retrovirals are associated with a macrocytic anemia.
    • Hematocrit – plasma volume needs 12-24 hours to equilibrate. May not reflect true value in acute bleed. Do not delay transfusion in the patient with an acute bleed!
    • RBC – if patient symptomatic Hb <7mg/dL, transfuse with packed red cells
  • Platelets – Reference level: 140-450 x 109/L
    • Thrombocytopenia – caused by disorders of production, distribution, or destruction
      • Important values:
        • 50-70 x 103 K/μL – associated with clinical evidence of bleeding
        • <10-20 x 103 K/μL – associated with major spontaneous bleeding
        • Consider transfusion of platelets in the setting of acute bleeding with platelets <70 x 103 K/μL or in asymptomatic patients with palteslets <10 x 103 K/μL
      • Thrombocytosis – reactive or myeloproliferative disorder
        • Reactive thrombocytosis rarely >1000 x 103 K/μL
        • Platelets are an acute phase reactant

Basic Metabolic Panel (BMP)/Chem7 (Cost – $12.12)

• A panel of blood tests used to monitor kidney function, electrolyte, acid/base and fluid balance.
• Na+ – Reference level (135-145 mmol/L)
  • Important in neurological disorders (seizures, trauma)
  • With Na+ abnormalities, calculate serum osmolarity and compare to the measured osmolarity
  • An osmolar gap (>10 mmol/L) indicates presence of other osmotically active substances (e.g. EtOH, methanol, mannitol, glucose)
  • In hyperglycemia, for each 100 mg/dL of glucose above the normal range then laboratory reported sodium decreases by 1.6 mmol/L
  • Hyponatremia:
    • Use clinical exam findings to determine a patient’s volume status
    • Order urine electrolytes to help determine an etiology.
    • Hypovolemic hyponatremia
      • Typically due to GI tract or renal losses
      • Less commonly due to third spacing (pancreatitis) or skin losses (burns)
      • Urine Na < 30 mmol/L, high urine osmolarity
      • Replace fluid at a minimal rate
    • Euvolemic hyponatremia
      • SIADH from medications, pulmonary, or neurologic etiologies
      • Urine not maximally dilute, i.e. Uosm >100mOsm/kg H2O
      • BUN < 10mg/dL
      • Fluid restrict and stop offending agent
    • Hypervolemic – Typically seen with CHF, cirrhosis, CKD
  • Hypernatremia:
    • Reduced water relative to Na+: Diarrhea, lactulose
    • Skin loss: excess sweating and insensible losses from skin and respiratory tract
    • Renal losses (osmotic and loop diuretics), Diabetes insipidus (Li+, demeclocycline), hypercalcemia, hypokalemia
• K+ – Reference level (3.5 -5.1 mmol/L)
  • Important with acid/base abnormalities disorders that can cause electrolyte shifts (e.g. DKA, sepsis, crush injuries, etc.)
  • Hyperkalemia:
    • Pseudohyperkalemia: hemolysis, prolonged tourniquet use during venipuncture, thrombocytosis, leukocytosis
    • Reduced excretion: oliguria & anuria, adrenal insufficiency, aldosterone deficiency (hyporeninisn, type IV RTA)
    • Cellular shifts: Acute acidosis, insulin deficiency, rhabdomyolysis
    • Medications decreasing RAAS (Beta blockers, ACEI, ARBs), K-sparing diuretics (spironolactone, triamterene, amiloride), NSAIDS, cyclosporin, pentamidine
  • Hypokalemia:
    • Inadequate diet: Alcoholism, malnutrition
    • GI & Skin loss: (protracted vomiting, diarrhea, laxative abuse)
    • Renal loss: (Diuresis, RTA, hypomagnesemia, hyperaldosteronism)
    • Cellular shifts: Alkalosis, β -Adrenergic medications (albuterol, epi), Catecholamine excess (Gluco- and mineralocorticoids)
    • Medications: Loop and thiazide diuretics, other drugs promoting K+ loss in distal collecting tubule (carbenicillin, ticarcilin), Catecholamine excess (Gluco- and mineralocorticoids), licorice
• Cl- Reference level (96-106 mmol/L)
  • Important in determining the anion gap
  • Hyperchloremia – non-anion gap metabolic acidosis (e.g. diarrhea, RTA, large volumes of NaCl)
  • Hypochloremia – loss of chloride-containing body fluids (e.g. prolonged vomiting, burns, diuretics, salt-wasting nephropathy) à metabolic alkalosis
  • Urine Chloride:
    • Low (<10mmol/L) – Chloride responsive indicate volume depletion. Treat with fluids
    • High (>20mmol/L) – Chloride resistant indicate mineralocorticoid excess
• CO2 – Reference level (22-29 mmol/L)
  • Important to help indicate presence of and determine etiology of metabolic acidosis
  • CO2 < 22mmol/L suggests a metabolic acidosis, as HCO3– used as buffer for excess acid production
    • Calculate Anion gap to determine the etiology of metabolic acidosis.
    • Anion gap = Na – (Cl– + CO2) – Reference level (10-12 mmol/L)
      • Increased gap indicates presence of unmeasured ions (e.g. lactic acid, phosphate, sulfate, ketones)
      • Normal gap indicates losses of HCO3– & Cl– (e.g. diarrhea and renal losses)
      • Low anion gap (e.g. hypoalbuminemia, CHF, multiple myeloma)
    • CO2 > 29mmol/L suggests metabolic alkalosis secondary to loss of acid (e.g. vomiting with hypovolemia)
• BUN – Reference level (6-20 mg/dL)
  • Important in determining volume status in conjunction with the creatinine
  • Increases in 3 scenarios:
    • Pre-renal azotemia hypovolemia (e.g. dehydration, CHF, cirrhosis, GI bleed). At low flow rates, renal tubules increases reabsorption of urea (relative to Cr) to increase osmolarity and retain more water.
    • Renal azotemia (BUN/Cr <10). Kidney not excreting urea properly
    • Post-renal. Typically an obstructive uropathy
  • BUN decreased in decreased Urea synthesis (e.g Severe liver disease, malnutrition) and dilutional states (e.g. SIADH, 3rd trimester pregnancy)
• Creatinine – Reference level (0.5-1.2 mg/dL) A product of muscle metabolism. Levels depend on muscle mass, race, age, gender, and diet.
  • Important to assess a patient’s kidney function (important for contrast studies) roles and determine etiology of renal injury (along with BUN)
  • Baseline 5-10% secretion from proximal tubule. Cr secreted increases with GFR decline.
  • Loss of renal function associated with increased creatinine.
  • False elevation in Cr with drugs (e.g. salicylates, H2-blockers, fibrates, etc.)
  • When assessing patient, always want to consider baseline.
• Glucose – Reference level (79-99 mg/dL)
  • Hypoglycemia: <50mg/dL
    • Fasting hypoglycemia
    • Excess insulin or sulfonylurea administration
    • Hepatic, adrenal, or renal insufficiency
    • Insulinomas
  • Hyperglycemia:
    • 2 separate episodes of >126 mg/dL
    • 1 episode of symptoms in patient with glucose >200 mg/dL
• Calcium – Reference level (8.5-10.5 mg/dL)
  • Important in cardiac dysrhythmias and often tied to other electrolyte abnormalities.
  • Total Ca2+ = Protein (Albumin)-bound Ca2+ (40-50%) + Free (Ionized) Ca2+ (50%).
    • Hypercalcemia is 90% off the time due to hyperparathyroidism or malignancy (>13mg/dL especially associated with malignancy)
      • Order PTH and urinary Ca2+ to obtain etiology
    • Hypocalcemia most commonly:
      • Hypoalbuminemia and hypomagnesemia
      • Other etiologies:
        • CKD, Vit D deficiency, hypoparathyroidism, pseudohypoparathyroidism
        • Decreased ionized Ca2+ (Citrate transfusion, acute pancreatitis, rhabdomyolysis)
      • Because Ca2+ bound to albumin, in patients with hypoalbuminemia (e.g. cirrhosis, nephrotic syndrome, malnutrition) correct for missing albumin by either:
        • Order an ionized Ca2+ level (4.65-5.28 mg/dL)
        • Order both Ca2+ and Albumin and calculate ionized level: Corrected Ca = [0.8 x (4.0 mg/dL – patient’s albumin)] + serum Ca

Mg2+ (Cost $9.60)

• Can be useful in cardiac dysrhythmias, neuromuscular irritability, and in patients taking medications causing electrolyte abnormalities (loop and thiazide diuretics, digitalis, aminoglycosides, pentamidine, cyclosporin, cisplatin).
• Reference level: 1.7-2.2 mg/dL
• Hypermagnesemia:
  • Excess intake in patient with CKD
  • Addison’s, hypothyroidism, Li intoxication
  • Not symptomatic until 4-6mg/dL
• Hypomagnesemia:
  • Reduced intestinal absorption – malnutrition/malabsorption, chronic diarrhea
  • Increased urinary losses – renal tubular disorders, ketoacidosis
  • Intracellular shifts – hypokalemia, hypocalcemia
  • Ventricular arrhythmias
  • Obtain Spot urine fractional excretion of Mg2+: >2% suggests renal losses

PO42- (Cost $6.79)

• Can be useful in the setting of renal insufficiency or in any condition involving massive cell death (e.g. crush injury, hemolysis, tumor lysis, etc)
• Reference level: 2.5-4.8 mg/dL in adults, 4.0-6.0 mg/dL in kids. Clinically significant < 1.5mg/dL
• Hyperphosphatemia:
  • Most common cause: Renal insufficiency
  • Less common: increased cellular metabolism (e.g. acromegaly, hyperthyroidism, hemolysis, rhabdomyolysis)
• Hypophosphatemia:
  • Decreased intestinal absorption: antacid use
  • Increased renal loss: hyperparathyroidism, renal tubular disease, chronic acidosis
  • Cellular shift across bones: acute respiratory alkalosis, hyperalimentation, TPN, rapid tumor growth, treatment of respiratory failure or DKA

Liver Function Tests (LFTs) (AST/ALT, Alk Phos, Bilirubin – total/direct) (Cost – $22.23)  

• Can be useful in patients with suspected liver inflammation, biliary obstruction, or hemolysis.
• AST/ALT – Reference levels both 6-40 IU/L
  • ALT specific to liver. AST also found in heart, blood, skeletal Mm.
  • General trends (Not foolproof):
    • Marked elevation >15x upper limits of normal is seen with significant necrosis (i.e. acute viral/drug-induced hepatitis, acute biliary obstruction)
    • AST>ALT 2:1 is EtOH. AST rarely >300IU/L
    • ALT>AST Chronic liver disease (e.g. Chronic viral hepatitis, fatty liver, chronic hepatotoxic meds—thionamides)
    • Isolated elevation of AST; consider extrahepatic etiologies (e.g. myocardial or skeletal muscle abnormalities).
  • Alkaline phosphatase – Reference level: 30-120 IU/L
    • Found in liver, bone, intestine, and placenta
  • Bilirubin – Reference level: total (0.1/1 mg/dL) direct (0.1-0.4 mg/dL)
    • Direct=Conjugated, Indirect=Unconjugated
    • Direct+Indirect=Total
    • Most common etiology of unconjugated hyperbilirubinemia – Gilbert’s (5%), hemolysis, recent hematoma, ineffective erythropoiesis.
    • Most common etiology of conjugated hyperbilirubinemia are exocrine hepatic excretion defects – extrahepatic obstruction (e.g. stone), intrahepatic cholestasis, hepatitis, cirrhosis, toxins

Amylase/Lipase (Cost – $9.86)

• Can be useful in patients with suspected pancreatitis.
• Begin increasing 3-6hrs after onset of acute pancreatitis, peaking at 24hrs
• Amylase returns to normal in 3-5d, lipase, in 8-14d
• Amylase also found in salivary glands, and is less specific than lipase
• Highly specific for pancreatitis when: amylase >3x ULN, lipase >5x ULN
• Non-pancreatic etiologies of elevated:
  • Both: Renal failure (20% renal excretion)
  • Lipase: Cholecystitis, perforated peptic ulcer
  • Amylase (inflammatory marker): Intestinal perforation, ischemia, obstruction, DKA, ruptured ectopic

Complete Metabolic Panel (CMP)(Cost – $15.14): Is the BMP plus tests that monitor liver function (See Liver Function Tests (LFT’s) above).

Cardiopulmonary Tests

Troponin (Cost – $46)

• Can be useful in the evaluation of patients where there is concern for myocardial cellular damage. Troponin I is specific to the myocardium and is the latest generation of biomarkers for myocardial cellular damage (earlier tests included CK-MB, LDH, and AST).
• Troponin I is released into the bloodstream within hours of myocardial infarction or ischemic damage. Troponin concentrations can be detected 1-6 hours following onset of chest pain, peaking at 12-16 hours, remaining elevated for 5-9 days
• Reference values: ≤ 0.04 ng/mL, representing the 99th percentile for Troponin level compared to a reference control group.
• Positive troponin result is not synonymous with myocardial infarction.
  • Other conditions can lead to elevated troponin I levels (e.g. myocarditis, cardiac surgery, angina, unstable angina, congestive heart failure, renal failure, pulmonary embolism)
• The kinetics of troponin in MI as well as presence of increased troponin levels in other conditions is why a changes in serial troponin levels strongly supports an acutely evolving cardiac injury (i.e. MI)
• Earlier, less sensitive, and less precise troponin assays required an average of 6 hours before repeat testing could detect a conclusive increase in troponin.
• Recent, higher sensitivity tests can detect changes in troponin levels after as early as 2-3 hours.

Brain Natriuretic Peptide (BNP) (Cost $35)

• Is a chemical released by the atria when sufficient stretch occurs (e.g. conditions of volume overload). Most commonly used to distinguish primary pulmonary from cardiac etiologies of dyspnea.
• Reference range: <100pg/mL
• BNP is a peptide released by the atria when sufficient stretch occurs, usually in conditions of volume overload. This test can be particularly used in a patient with acute dyspnea to distinguish heart failure from other etiologies (e.g. COPD, PE, pneumonia)
• BNP >400pg/mL suggest heart failure. Increased BNP values predictive of death or increased cardiovascular events.
• Conditions increasing BNP: Myocardial infarction, atrial fibrillation, pulmonary embolism, pulmonary hypertension, chronic kidney disease, sepsis, age, etc.

D-dimer (Cost – $25)

• Can be used to rule-out DVT or PE in low risk (by Well’s criteria) patients. The PERC criteria can be used to identify “no risk” patients that should not have D-dimer testing.
• D-dimer is the physiological byproducts of fibrin degradation. When found in the blood it can indicate the presence of a large clot or bleeding dyscrasia.
• Reference level: <0.5 mg/L, although studies are ongoing to define different reference levels in certain populations such as pregnant women and the elderly
• D-dimer is produced in the setting of fibrin degradation. It can be used to provide evidence of existence of a clot.
  • False positive: Inflammatory processes, pregnancy

Additional Common Tests

Lactate (Cost – $8.64)

• Can be used both as a confirmatory lab value and a marker of resuscitation for a patient in metabolic acidosis. Lactate is metabolized by the liver. The serum concentration depends both on the rate of production by body tissues and the rate of liver clearance.
• Common indications to order a serum lactate:
  • Tissue hypoxia conditions (e.g., sepsis, shock, hypovolemia, multisystem trauma, heart failure, pulmonary insufficiency)
  • Metabolic disorders (e.g., undifferentiated metabolic acidosis, diabetic ketoacidosis, malignancies)
  • Toxin exposures (e.g. glucophage, ethanol, methanol, salicylates).

Coagulation studies (PT/INR, PTT) (Cost – $8.60, $5.62)

• Can be used to evaluate patients on some anticoagulant therapies, establish a baseline level in an actively bleeding patient, and to evaluate patients with some clotting disorders.
• Reference level: INR (0.9-1.1) PTT (30-50s)
  • The PT is lab specific and the International Normalized Ratio (INR) allows comparison across different laboratories
  • PT prolonged in vitamin K deficiency (e.g. coumadin, fat malabsorption syndromes, recent broad-spectrum antibiotics, premature infants)
  • PTT on heparin for anticoagulation 1.5-2.5x ULN
  • PTT prolonged in 90% of coagulation disorders. Best initial test, but nonspecific.

Arterial Blood Gas (ABG)/Venous Blood Gas (VBG)

• Can be helpful in critically ill patients with suspected acid-base disturbances. In situations where the knowledge of the pO2 is not critical a VBG is often less painful for the patient to obtain and provides almost the same information as an ABG.
• Interpretation is beyond the scope of the brief overview here.

β-HCG (Cost – $10.76)

• Can be useful in evaluating women where pregnancy is suspected or if the presence of a pregnancy would change the management or work-up for the patient. Consideration should be made to use a urine pregnancy test when only a qualitative answer is necessary as it is much cheaper.  Quantitative serum β-HCG concentrations can be helpful in the work-up of early pregnancy, molar pregnancies, or after abortions.
• Produced by the placenta for the first 5 weeks.
• β-hCG levels double every 2-3 days for the first 4-8 weeks of the pregnancy. Serum β-hCG higher than urine levels in first 2 weeks. After 3 weeks urine β-hCG levels are higher.
• Low β-hCG: Failure to double in 48—72 hours suggests ectopic pregnancy or abnormal intrauterine pregnancy
• High β-hCG: Gestational trophoblastic neoplasms (e.g. choriocarcinoma, hydatiform mole)
• Post-partum: levels of β-hCG return to normal in 2 weeks
• Post-abortion: levels of β-hCG return to normal in 3-8 weeks.

Urinalysis (Cost – $17.41)

• UA – Urinalysis tests for Glucose, ketones, specific gravity, protein, myoglobin (not hemoglobin), RBC, WBC, Casts
  • A combination of nitrates, leukocytes, WBC, and bacteria indicate urinary tract infection
  • Interpretation of results for acute infection in patients with chronic indwelling catheters in difficult, a urine culture and sensitivities is recommended in this situation

Urine Toxicology (Cost – $180)

• Common drugs screened for include amphetamines, cocaine, benzodiazepines, barbiturates, opiates, marijuana, and PCP.
• Careful interpretation of this test is required. For example, the presence of benzodiazepines in the urine of a patient does not preclude the presence of another, much more serious, cause of altered mental status requiring further work-up and intervention.
• Cutoff points defining positive and negative tests are arbitrary, chosen to maximize sensitivity and specificity rather than correlate with degree of impairment/toxicity
• Urine with drug levels below the cutoff will be reported as negative, even though the drug may be present in the system
• Most drugs typically detectable up to 3 days after use, although this varies (e.g. benzodiazepines and barbituratess can be present for up to 6 weeks after heavy use and up to 11 weeks with marijuana)
• False-negatives and false-positives are well known with this test.

Fecal Occult Blood Test (Cost – $22)

• Used to detect occult (NOT clinically apparent) blood loss in stool. Rectal bleeding per patient history or a grossly bloody rectal exam do not need a FOBT.
• 2 main tests:
  • Detect heme (cheap, less sensitive and specific, fast)
    • Guaiac-based: detect pseudoperoxidase in heme (e.g. Hemoccult, Hemoccult SENSA)
  • Detect globin (expensive, more sensitive and specific, slow)
    • Immunochemical tests to detect globin. Ag-Ab reaction specific for human Hb. Do not react with animal Hb or peroxide-containing foods
  • False negative:
    • Proximal GI lesions allow degradation of heme, not allowing oxidation
    • >250mg/day of Vitamin C or other antioxidants (reducing agents interfere with guiac oxidation)
    • Antacids
  • False positive:
    • Mb/Hb in red meat
    • Peroxidase-rich raw vegetables and fruits if tested immediately after collection (turnips, horseradish, artichokes, mushrooms, radishes, broccoli, beets, apples, oranges, bananas, pears, grapes)
      

References

1. Lab Tests Online. 2005-10-31. Retrieved 2008-09-22. < http://labtestsonline.org/understanding/analytes/cmp/tab/glance >
2. http://www.nlm.nih.gov/medlineplus/ency/article/003477.htm
3. Warner EA, Herold AH. “Interpreting Laboratory Tests.” Rakel: Textbook of Family Medicine, 8th Ed. Copyright © 2011 Saunders, An Imprint of Elsevier Chapter 15 – Interpreting Laboratory Tests. By. 8th ed. N.p.: Saunders, 2011. 176-204. Print.
4. Jiang CF1, Ng KW, Tan SW, Wu CS, Chen HC, Liang CT, Chen YH. Serum level of amylase and lipase in various stages of chronic renal insufficiency. Zhonghua Yi Xue Za Zhi (Taipei). 2002 Feb;65(2):49-54.
5. http://www.nlm.nih.gov/medlineplus/ency/article/003578.htm
6. Hernandez JS. “Cost-effectiveness of laboratory testing.” Arch Pathol Lab Med. 2003 Apr;127(4):440-5.
7. Mahajan VS, Jarolim P. “How to Interpret Elevated Cardiac Troponin Levels.” Circulation.2011; 124: 2350-2354
8. http://emlyceum.com/2013/06/04/troponin-testing-answers/?blogsub=confirming#blog_subscription-4
9. Pricing: http://pathology.ucla.edu/body.cfm?id=382, https://healthcarebluebook.com/page_SearchResults.aspx?CatID=51
10. Additional resources: http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/81767
11. http://www.aafp.org/afp/2011/0315/p719.html