PHM101 General Medicine I: Interpretation of Laboratory Values 2024 PDF

PHM101 GENERAL MEDICINE I: Interpretation of Laboratory Values S. Yamashita, Pharm.D., FCSHP Clinical Coordinator, Critical Care Department of Pharmacy, SHSC And Assistant Professor (Status) Leslie Dan Faculty of Pharmacy University of Toronto January 2024  Objectives To incr...

PHM101 GENERAL MEDICINE I: Interpretation of Laboratory Values S. Yamashita, Pharm.D., FCSHP Clinical Coordinator, Critical Care Department of Pharmacy, SHSC And Assistant Professor (Status) Leslie Dan Faculty of Pharmacy University of Toronto January 2024  Objectives To increase knowledge and understanding of common laboratory tests that pharmacists may use in their clinical practice Provide a general, practical framework for the assessment of abnormal laboratory values. Apply the framework to the assessment of electrolyte abnormalities Understand how renal and hepatic function are assessed through laboratory monitoring Understand the implications of altered renal and hepatic dysfunction on drug use and dosing Understand the value of drug levels and how to interpret them  Why do I need to know this? As a pharmacist, it is important to: – have an understanding of how lab values are used in the diagnosis of disease – know which abnormal lab values are caused by drug therapy – know which abnormal lab values can be treated with drug therapy – know which lab values will be used in monitoring patients’ responses to drug therapy  Overview of Laboratory tests Common Lab Tests – Electrolytes – Serum Creatinine (Scr) and calculation of Creatinine Clearance – Liver Function Tests (LFT’s) – Complete Blood Count (CBC) Therapeutic Drug Monitoring – Drug levels  Laboratory Values Used in diagnosis (dx) of diseases – CK (creatine kinase), Tn (Troponin) for dx of myocardial infarction (MI, heart attack) – TSH as a screening test for thyroid diseases Used in monitoring diseases – When to initiate therapy PSA (prostate specific antigen) for prostate cancer – Response to therapy WBC (white blood cell) in infection, BG (blood glucose) and HbA1c in diabetes – Relapses/ disease progression PSA, CEA (tumour markers) Used to assess efficacy and toxicity of medications – INR for warfarin, aPTT for heparin – Scr, LFT’s, electrolytes – Drug levels  Pharmacotherapy Work-up (Chapter 6 of Online Pharmaceutical Care Module) Is the problem/laboratory abnormality caused by a drug? Does the problem/abnormality require drug therapy/alter our Care Plan? – If so, is therapy (indicated), effective, safe and will the patient be adherent? Framework for Assessment of Laboratory Abnormalities Is the value abnormal? Is it a clinically significant change? Is management necessary? Look at the patient!!  Pharmacotherapy Work-up Is the problem/laboratory abnormality caused by a drug? – Is the value abnormal? Does the problem/abnormality require drug therapy/alter our Care Plan? – Is it a clinically significant change? – Is management necessary? If so, is therapy (indicated), effective, safe and will the patient be adherent? Framework for Assessment of Laboratory Abnormalities Is the value abnormal? Is it a clinically significant change? Is management necessary? Look at the patient!!  Is the value abnormal? Test specifics Does it make sense? – Understand the physiology – Look at trends in patient’s bloodwork – Interfering substances with lab assay – Timing of sample Clinically Significant Change?  Test Specifics Sensitivity, specificity Reproducibility and Accuracy Lab Error – Calibration of machines “Normal Range”  Sensitivity/ Specificity of Test Sensitivity – Ability of test to detect patients with disease 90% sensitivity: 10% of patients with disease will not be detected (e.g. false negative result) Specificity – Whether test abnormality is restricted to patients with disease 90% specificity: 10% of patients without disease will have an abnormal result (e.g. false positive result)  Test Specifics Sensitivity, specificity Reproducibility and Accuracy Lab Error – Calibration of machines “Normal Range”  Laboratory values: units Traditional (Imperial) units – USA – mg/dL, mcg/mL SI (Systeme international)/Metric units – Rest of the world!! – mmol/L, μmol/L Lab values: Units for normal ranges Lab Value SI units Imperial (Canadian) (USA) Albumin 35-50 g/L 3.5 – 5 g/dL Creatinine 53-133 μmol/L 0.6-1.5 mg/dL Glucose 3.9-6.1 mmol/L 70-110 mg/dL Hemoglobin 115-165 g/L 11.5-16.5 g/dL Magnesium 0.7 – 1 mmol/L 1.4 – 2 mEq/L Phenytoin 40-80 μmol/L 10-20 mg/L http://www.amamanualofstyle.com/page/si-conversion-calculator  Watch the units… Loading dose calculation: – LD = desired concentration x volume of distribution (Vd) Phenytoin: – LD = 80 μmol/L x 0.7 L/kg Dose in μmol? – LD = 20 mg/L x 0.7L/kg Dose in mg  Is the value abnormal? Test specifics Does it make sense? – Look at trends in patient’s bloodwork – Understand the physiology – Correlation to symptoms – Interfering substances with lab assay – Timing of sample Clinically Significant Change?  Does it make sense? Look at trends in the bloodwork – wrong patient’s bloodwork Does the pathophysiology make sense? – Hyperkalemia (high potassium) in a patient with normal pH, normal renal function, no drugs Does the labwork correspond to the patient’s symptoms? – High digoxin level in the absence of any ECG or other cardiac abnormalities  Interfering Substances with Laboratory Assay Canrenoate (metabolite of spironolactone) and certain digoxin assay Steroids and cortisol assay Endogenous Digoxin-like Substances (renal and hepatic failure) Cimetidine, trimethoprim, dronedarone and serum creatinine – Interfere with tubular secretion of creatinine  Timing of sample Fasting versus nonfasting values – Glucose, lipids INR after 1st dose warfarin CK’s versus troponins post MI Drug levels: Sample taken too early, relative to distribution period may be artificially high – Digoxin distribution period: 4-6 hours Framework for Assessment of Laboratory Abnormalities Is the value abnormal? Is it a clinically significant change? Is management necessary? Look at the patient!!  Is the abnormality clinically significant? – Reference range potassium of 6 mmol/L (N: 3.5 - 5) vs sodium of 146 mmol/L (N: 135-145) – What physiologic actions does lab value have? Is the patient symptomatic or at risk of symptoms? Framework for Assessment of Laboratory Abnormalities Is the value abnormal? Is it a clinically significant change? Is management necessary? Look at the patient!! Is management necessary? – What are the consequences of not treating? – Are there risks in unnecessary treatment? – Is there any evidence/literature: that treatment is beneficial? of a threshold for treatment?  Drug-induced lab abnormalities Is it caused by a drug? – Consider causality Is it clinically significant? Is management necessary? How does it affect (future) drug therapy?  Drug-induced lab abnormalities Consider causality – Is the drug known to cause the abnormality? Extension of pharmacologic effect – Hypokalemia with diuretics ADR previously reported – Rash with penicillin – Consider differential diagnosis Other medical conditions which cause the abnormality? – Consider temporal relationship – Consider discontinuation and rechallenge Consider clinical significance  Drug-induced lab abnormalities Is it caused by a drug? Does it require drug therapy/intervention? Does it influence drug therapy? – Alteration in renal or hepatic clearance – Choice of drugs in future (ADR, allergy) Electrolyte Disturbances  Electrolytes Na K BUN BG HCO3 Cl Scr 140 4 6 5 24 99 60 Calcium: correction for low albumin (for every 10 g/L drop in albumin, add 0.2 to calcium) Framework for Assessment of Laboratory Abnormalities Is the value abnormal? – Does it make sense? If high, is the cause due to “too much in” or “not enough out”? If low, is the cause due to “not enough in” or “too much out”? Is it a clinically significant change? Is management necessary? Look at the patient!!  Electrolyte Disturbances* “Hypo” – “not enough in” – “too much out” – if low, replace “Hyper” – “too much in” – “not enough out” – if high, get rid of also consider cellular shifts * NOTE: this technique does NOT work for disorders of sodium  Electrolyte Disturbances Hyper (high) Hypo (Low) Other comments “Too much in”; “Not enough in”; “Not enough out” “Too much out” Potassium - excessive oral or IV -GI or renal losses (diuretics) - Also consider intra- replacement -Inadequate replacement cellular/extra-cellular -Cell destruction shifts -Renal failure Calcium -Excessive oral or IV -Binders (phosphate, citrate) - Also consider bone replacement -Renal losses resorption -Bone resorption - ↑PTH Magnesium -Excessive oral or IV -GI or renal losses (diuretics) replacement -Renal failure Phosphate -Excessive oral of IV -Consumption (“refeeding replacement syndrome) -Tumour lysis -Inadequate replacement -Renal failure -Binders (calcium ,aluminum)  Electrolytes Electrolyte Hypo Hyper Potassium Side effect of diuretic; Renal Failure (Nephrology); predispose to arrhythmias side effect of ACEI/ARB… Sodium (Nephrology, Endocrinology) (Nephrology, Endocrinology) Calcium Osteoporosis, Renal Failure (Oncology, Endocrinology) (Nephrology, Endocrinology) Magnesium Side effect of diuretic; Renal Failure (Nephrology) predispose to arrhythmias Phosphate (Critical Care) Renal Failure (Nephrology) Bicarbonate Metabolic Acidosis (Critical Metabolic Alkalosis (Critical Care) Care); side effect of diuretic  Disorders of potassium homeostasis (hypokalemia)  Is the value abnormal? Test specifics Does it make sense? – Look at trends in patient’s bloodwork – Understand the physiology – Interfering substances with lab assay – Timing of sample Clinically Significant Change?  Disorders of Potassium (Normal range 3.5 – 5 mmol/L) Intracellular ion – for every ↓ in serum K+ by 0.3 mmol/L, total body K+ deficit is 100 mmol 1. Intracellular shifts: alkalosis, β agonists, insulin 2. Extracellular shifts: acidosis, α agonists, ? β blockers  Hypokalemia - signs and symptoms Involved in cellular metabolism and maintenance of resting membrane potential Cardiovascular – arrhythmias, hypotension, ischemia Muscular – weakness Metabolic – glucose intolerance, ↓ Mg  Hypokalemia “Not enough In” – usually in conjunction with too much out “Too much out” – Gut – Kidney (distal tubule) Intracellular shift – insulin, alkalosis, β agonists  Diuretic induced hypokalemia Principles of Medical Pharmacology, U of T  Hypokalemia – Is management necessary? What are the consequences of not treating? – can be associated with cardiac arrhythmias, muscle weakness including respiratory distress Is there any evidence that treatment is beneficial? Is there a threshold for treatment? – “↑ risk of cardiac arrhythmias (< 2.7mmol/L), glucose intolerance” – “no treatment if K+>3.0 mmol/L unless symptomatic”  Potassium – Is management necessary? What are the risks of overtreatment? – Potassium replacement: Chloride salt preferred (KCl) Oral vs IV – Considered “hazardous drug” QRS widening, ventricular fibrillation, asystole if too much/too fast (IV) Low risk if continuous ECG monitoring, renal function normal, max dose/rates established Assessment of Renal Function WHAT DOES THE KIDNEY DO?  Function of kidney Clears (water soluble) metabolic waste Fluid/electrolyte balance BP regulation Produces erythropoeitin (stimulates RBC production) HOW CAN YOU ASSESS RENAL FUNCTION? Assessment of Renal Function Measure urine output – Normal 0.5 mL/kg/h Measure serum creatinine (SCr) Calculate Creatinine clearance or eGFR Look for metabolic consequences of renal dysfunction: – Hyperkalemia, metabolic acidosis, fluid overload  Measurement of Renal Function Inulin clearance, radiolabelled markers 24 urine collection: UV P Estimated GFR (eGFR) – (www.mdcalc.com) – CKD-EPI Calculation based on creatinine, age, gender and race – (MDRD) Calculation based on creatinine, age, gender and race U = creatinine concentration in urine, V = urine volume, P = creatinine concentration in plasma, GFR = glomerular filtration rate, MDRD = Modification of Diet in Renal Disease, CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration  Measurement of Renal Function Calculate Creatinine clearance – Cockcroft-Gault: (140-age)(IBW) 50 x SCr (umol/L) In mL/s: multiply x 60 for ml/min Multiple x 0.85 for women Normal 90-120 mL/min IBW = ideal body weight, Scr = serum creatinine Limitations of using Scr to assess renal function Changing renal function Reduction in muscle mass – Elderly, malnourished, spinal cord injury ~10%/decade decline in renal function after age 40! SCr of 30 in an 85 y.o female, 45kg? – Calculated ClCr (in mL/min)? Consider baseline – Doubling of SCr ~ ↓CrCl by 50%  Changing renal function and Baseline SCr Baseline: CrCl > 100 CrCl ~ 50 CrCl ~ 25 mL/min mL/min mL/min Serum creatinine Patient 100 200 400 (normal #1 range: 53-133 umol/L) Patient 20 40 80 #2 CrCl = (140-age)(IBW) 50 x SCr (umol/L)  Increased SCr/ decreased renal function Is it caused by drug therapy? Does it require drug therapy? Does it alter future Care Plans?  Drug-induced renal dysfunction Direct toxicity – e.g., aminoglycosides, cisplatin, cyclosporine – Often dose-related (cumulative); may be irreversible Changes to renal perfusion – Drugs which interfere with: renin-angiotensin-aldosterone system (ACEI, ARB, DRI) renal prostaglandins (NSAIDS) – Reversible if intervene early  Drug-induced lab abnormalities Consider causality – Consider other causes – Consider temporal relationship – Consider D/C and rechallenge Consider clinical significance Drug-induced increases in serum creatinine Consider causality – Drugs vs disease ACEI/ARB vs heart failure/diabetes? Aminoglycoside vs sepsis? – Consider temporal relationship ↑ SCr before ACEI initiated Consider clinical significance – Use of ACEI in heart failure: expect/accept transient ↑ SCr (no greater than 30%) following initiation of therapy Does the renal dysfunction require drug therapy? Will be covered in PCT 3!! Discontinue offending drugs Dialysis Slow disease progression – Control of hypertension, diabetes Management of chronic complications – Electrolyte disorders, anemia, osteodystrophy  Does it alter future Care Plans? Limit intake of: – Sodium, potassium, magnesium, phosphate (consider drugs, dietary sources) – Fluid, protein Reduce doses of drugs that are renally eliminated Properties of drugs likely to be renally cleared Properties: – water soluble – small molecular weight – low protein/tissue binding – small volume of distribution  Drug Dosing in Renal Dysfunction Dose Drug % renal CrCl >50 CrCl 10-50 CrCl < 10 excretion mL/min mL/min mL/min Allopurinol 30% (toxic 300 mg/day 150 mg/day 50 mg/day (uricosuric for metabolite (100%) (50%) (25%) gout) accumulates) Cefazolin 85% 1g IV q8h 1g IV q12h 1g IV q24- (antibiotic) 48h Digoxin (cardiac 80% 0.125 0.0625 0.0625 mg glycoside for heart mg/day mg/day every other failure/ atrial day arrhythmias)  Drug Dosing in Renal Failure reference http:/kdpnet.louisville.edu/renalbook /adult/  Drug therapy problems in renal disease Drug induced renal dysfunction – NSAIDs, ACE inhibitors (ACEI), Angiotensin Receptor Blockers (ARB), direct renin inhibitors (aliskiren) – aminoglycosides, amphotericin B, cisplatinum, cyclosporine Drug dosing for renal dysfunction – Most beta-lactam antibiotics, digoxin, allopurinol – Replacement doses with dialysis Other considerations in renal dysfunction – Hyperkalemia, hypermagnesemia, hyperphosphatemia, hypocalcemia – Sodium, fluid and protein restrictions Assessment of Hepatic Function WHAT DOES THE LIVER DO?  Function of liver Production of proteins Production of clotting factors Glycogenolysis/gluconeogenesis Detoxification – Production of water soluble metabolites HOW CAN YOU ASSESS HEPATIC FUNCTION?  Assessment of liver function Production of proteins (albumin, protein) Production of clotting factors (INR, aPTT) Glycogenolysis/gluconeogenesis (blood glucose) Detoxification – Production of water soluble metabolites Liver “function” tests  Liver “function” tests (LFTs) Transaminases – Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) – Hepatocyte destruction Viral, toxins (mushrooms) Drug induced: acetaminophen, methotrexate, azole antifungals, statins, isoniazid, phenytoin  Liver function tests Bilirubin and Alkaline phosphatase (ALP) – Cholestatic dysfunction Gallstones Drug-induced: macrolides, neuroleptics  Assessment of liver function INR (international normalized ratio), glucose, albumin, bilirubin Drug dosing in liver dysfunction not well defined  Liver Dysfunction Scales Child-Turcotte-Pugh (CTP) classification (cirrhosis) – Based on bilirubin, INR, ascites, hepatic encephalopathy MELD Score – Used to prognosticate for purposes of transplantation – Based on bilirubin, INR, serum creatinine  Drug dosing in liver dysfunction Lack of guidelines/recommendations for dosage adjustment – If drug is > 60% hepatically metabolized: CTP 8-9: ↓ dose by 25% CTP > 10: ↓ dose by 50% Dosage adjustment often not done until significant hepatic impairment is evident CTP = Child Turcotte Pugh  Drug Therapy Problems in Liver Dysfunction Drug-induced liver dysfunction – Hepatitis: acetaminophen, methotrexate, statins, azole antifungals, isoniazid, phenytoin – Cholestasis: macrolides, neuroleptics Drug dosing in liver dysfunction – Lack of guidelines for dosing – Usually only adjust doses when severe dysfunction Other considerations in liver dysfunction – Protein restriction – High risk for bleeding, infection, renal dysfunction Complete Blood Count (CBC) CBC (Complete Blood Count) Hgb WBC plt Hct Hemoglobin (Hgb, Hb) – RBC morphology: MCV Hematocrit (%) – Volume of RBC/unit of whole blood White Blood Cell (WBC) Count Platelet count  Hemoglobin - Anemia Characterized by low hemoglobin – Symptoms include pallor, low energy Normal range: – Men: 130-180 g/L – Women: 115-165 g/L RBC morphology: – Colour: hypochromia (pale) – Size (MCV): macrocytic, microcytic  Etiology of Anemia – Microcytic (↓ Hgb, ↓ MCV): iron deficiency hypochromic Treatment x 3-6 months to replace iron stores (ferritin) – Macrocytic (↓ Hgb, ↑ MCV): folate or B12 deficiency – Normocytic, normochromic (↓ Hgb, normal MCV) : Associated with chronic diseases  Etiology of Anemia (low Hgb) “Not enough in” (decreased production) – Lack of erythropoeitin (renal failure), iron deficiency – BM depression from chronic diseases, drugs (chemotherapy, zidovudine) “Too much out” (increased destruction) – Blood loss, hemolysis  Is management necessary? Consequences of not treating? Symptoms Co-morbid conditions (heart failure, coronary artery disease) – Threshold for treatment Threshold of 70 g/L in critically ill! – TRICC Trial (NEJM 1999) Risks of treatment? – Therapeutic Alternatives: Blood transfusion Erythropoeitin stimulating agents Replacements (iron, folate, B12): oral vs parenteral  WBC (4-11 x109/L) High – Infection, leukemias (and other myelodysplastic syndromes) – Drug-induced: corticosteroids Low – Represents immunocompromised state Monitor fever; seek medical attention – Drug-induced Chemotherapy, clozapine Platelet count (150 – 400 x109/L) Thrombocytopenia may predispose to bleeding – Decreased production: chemotherapy, alcohol – Increased destruction: heparin, autoimmune diseases, sepsis, splenomegaly – Spontaneous bleeds when plt < ~20 Antiplatelet drugs (ASA/NSAIDS/clopidogrel/ ticagrelor) – Interfere with platelet aggregation and may predispose to bleeding – do NOT ↓ plt count – measure effect with Bleeding Time Therapeutic Drug Monitoring  Therapeutic Drug Monitoring Use of serum drug levels to guide drug dosing/ therapy: – Improve/ensure efficacy – Prevent toxicity  Requirements for TDM Readily available assay Correlation between serum drug levels and efficacy or toxicity – eg digoxin (significant overlap b/w efficacy and toxicity) Correlation between concentration in sampled fluid and concentration at site of drug activity – eg tricyclic antidepressants, amiodarone  “Just because you CAN measure a drug in serum, doesn’t mean you should!”  Indications for TDM To assess compliance/absorption To ensure efficacy (provided good correlation b/w levels) To avoid/confirm toxicity To assess for a drug interaction Consider interpatient variability!!  Properties of drugs in which TDM is desirable? Difficult to measure therapeutic response (e.g., antibiotics, seizure prophylaxis) Narrow therapeutic index – e.g., digoxin, theophylline Significant toxicity which is concentration dependent  When to take levels Initiation: – At steady state to see if at therapeutic target Maintenance – Periodically (e.g. “check-up levels q 6 mos) – Suspect toxicity or lack of efficacy  Interpretation of Levels Is the value abnormal? – Does it make sense? Timing of sample relative to dose Timing of sample relative to initiation of therapy (eg steady state) Free vs total level Drug interactions – Decreased absorption – Enzyme induction or inhibition Correlation to symptoms? Is it clinically significant? Does it need management?  Conclusions Interpretation of lab values is becoming an important component of pharmacy practice – Requires common sense, knowledge of test specifics, physiology, pharmacology and pharmacokinetics Questions [email protected]