Clinical Pathology: Cardiovascular Group D

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Clinical Pathology CardiovascularGroup D
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Causes of raised K

• Excessive potassium intake
• potassium supplements
• salt substitutes
• nutritional supplements
• Impaired cellular uptake of potassium
• drug induced ? ß-blockers, digoxin, IV amino
  acids
• Impaired renal potassium excretion
• disease states ? renal impairment,
  hypoaldosteronism, heart failure
• age ? related to changes in renal architecture
• drug induced ? NSAIDs, ACEI, heparin, cyclosporine

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NSAIDS (Meloxicam)

• disturb potassium homeostasis via inhibition of
  renal prostaglandin synthesis especially PGE2 and
  PGI2
• PGI2 stimulates renal synthesis of renin,
  therefore effects the synthesis of aldosterone
• NSAIDs induce a hyporeninemic hypoaldosteronism
  state, reducing renal potassium excretion
• PGE2 and PGI2 ? the number of open
  high-conductance potassium channels and
  facilitate potassium secretion
• NSAIDs interrupt renal potassium secretion by
  reducing the open state of potassium channels
• ? PGE2 and PGI2 synthesis ? ? in preglomerular
  vasodilation and post glomerular constriction,
  which leads to a ? in renal blood flow (RBF) and
  GFR, therefore reduced delivery of sodium and
  water to the site of potassium excretion

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NSAIDS cont

• Risk factors that increase a patients
  vulnerability to NSAID-associated hyperkalaemia
• fluid depletion
• congestive heart failure
• renal insufficiency
• use of potassium sparing diuretics/ ACEI

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Impaired K excretion

• Age
• Impairment of renal potassium excretion
• decline in renal function
• loss of renal mass ? reductions in RBF, GFR,
  tubular transport function
• aging process can result in tubular atrophy and
  intestinal fibrosis which may impair potassium
  secretion
• age associated disturbances in renin-angiotensin-a
  ldosterone system activity
• Heart failure
• reduction in circulatory volume and RBF
• ? in proximal nephron reabsorption of sodium and
  water
• ? in distal sodium and water delivery
• retards potassium secretion

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Model
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Blood Analysis in CHF

• Blood analysis in heart failure patients involves
  measurements of renal function
• Baseline renal function tests include measurement
  of urea and creatinine
• With this patient both urea and creatinine are
  raised

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Urea and Creatinine

• Urea is a waste product formed when protein is
  broken down in the body. It is produced in the
  liver and eliminated from the body in urine.
• A urea test is done to estimate how well the
  kidneys are functioning. If the kidneys are not
  able to remove urea from the blood normally, the
  urea level increases.
• A urea test may be done along with a blood
  creatinine test.
• The level of creatinine in the blood also
  provides information on how well the kidneys are
  working. A high creatinine level may also mean
  the kidneys are not working properly

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Elevated Urea or Creatinine

• Causes of increased levels of both urea and
  creatinine can be divided into three major
  categories
• Prerenal causes include heart disease and shock
• Postrenal causes include urethral obstruction
• True renal disease

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CHF and Renal Function

• Congestive heart failure is associated with two
  major alterations in renal function
• sodium retention early in the course of the
  disease
• a decline in GFR as cardiac function worsens
• A reduced GFR leads to retention of serum urea
  nitrogen and creatinine
• Excess urea and creatinine in the blood is
  referred to as azotaemia

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CHF and Renal Function

• Renal function often deteriorates with chronic
  heart failure due to reduced renal perfusion
  because of diminished cardiac output.
• The normal kidney receives approximately 25 of
  resting cardiac output. Therefore sufficient
  cardiac output is an essential requirement for
  normal renal function. To maintain cardiac
  output, the requirements are sufficient blood
  volume, effective cardiac pump, and appropriate
  peripheral resistance

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CHF and Renal Function

• If renal function is impaired by a decreased
  cardiac output the increase in the concentration
  of urea is more marked than the increase in the
  concentration of creatinine
• This characteristic laboratory finding results
  from avid reabsorption of tubular fluid,
  accompanied by urea which is freely permeable
  through cell membranes, but not creatinine which
  is impermeable to renal tubular cells

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Medications
Other causes of pre renal failure related to this
patient could be medications

• Diuretics
• Beta blockers
• Vasodilators
• NSAIDs
• ACE inhibitors

• Aminoglycosides
• Radio contrast media
• Compound analgesics
• Antiviral agents
• Lithium

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Hydralazine (Alphapress)

• This medication is a vasodilator which can cause
  deterioration of renal function because the renal
  perfusion can be affected by reductions in
  cardiac output from peripheral vasodilatation

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Bisoprolol (Bicor)

• This medication is a beta blocker which has a
  negative inotropic effect
• Bisoprolol also has the potential to impair renal
  function, especially if cardiac output is already
  compromised

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Meloxicam (Mobic)

• This medication is an NSAID which can cause an
  acute, usually reversible, deterioration in renal
  function due to inhibition of renal vasodilatory
  prostaglandins in the kidney leading to
  intrarenal vasoconstriction.
• This decreases the glomerular filtration rate and
  therefore exacerbates salt and water retention in
  patients with congestive heart failure.
• Other risk factors include older age,
  hypertension, pre-existing impaired renal
  function, diabetes, diuretics and volume depletion

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Possible Causes

• The rise in urea and creatinine in this patient
  could be due to
• Prerenal failure caused by congestive heart
  failure, which begins with renal retention of Na
  and water, secondary to decreased renal
  perfusion. As cardiac function deteriorates,
  renal blood flow decreases in proportion to the
  reduced CO, and the GFR falls, which leads to
  retention of serum urea nitrogen and creatinine
• Medications (beta-blocker, vasodilating drug,
  NSAIDs)

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Electrode Structure
Thin-walled glass membrane
Internal reference solution (known concentration)
AgCl-coated silver electrode (internal reference
electrode)
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Potential Difference

• Anion sites are covalently bonded within the
  glass membrane
• Cations can be exchanged with external (sample)
  solution
• SiO-H M ? SiO-M H
• Exchange of ions sets up a potential difference,
  which allows calculation of electrolyte
  concentration in the sample

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Apparatus for Measurement
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Nernst Equation
E Eo RT ln fCt
E Eo nF ln fCi
Where E electrode EMF in V R constant Eo
standard EMF T temperature n e- in
half-reaction F Faradays constant f
activity coefficient Ct ion concentration in
test solution Ci ion concentration in internal
filling solution
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Potential Difference

• P a (at am) (ai am)
• However, assuming the inner and outer activities
  are equal, and the activity of the inner solution
  is constant, this can be simplified further
• P a a

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Ion Selectivity

• Key to selectivity composition of the membrane
• Use of lithium aminosilicate glass makes an
  electrode selective for Na
• Incorporation of valinomycin makes an electrode
  selective for K

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Sources of Error

• Outer surface of membrane may be flamed during
  production ? different structure
• Mechanical and chemical attack on membrane during
  use ? altered composition
• Membrane may be permeable to other ions
• Temperature
• Sample handling
• Measuring volume of the sample solution
• Physiological conditions may alter sample
  composition

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Modern Analysers

• Incorporate multiple electrodes to measure
  different electrolytes in solution
• Results can be available in as little as 6
  minutes
• Flow-dilution system

Can be used for calibration of electrodes as well
as sample analysis
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Apparatus

• Ion selective electrode (ELIT 8230 PVC membrane)
• Reference electrode double junction lithium
  acetate
• Dual electrode head (ELIT 201)
• Standard solution 1000parts per million Na as
  NaCl
• 100mL polypropylene beakers, 100mL volumetric
  flask, pipettes
• Buffers are unsuitable

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Apparatus
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Primary Constituents Na

• Cylindrical tube 5-15mm diameter
• Solid state PVC polymer matrix membrane
• Aim to detect Na in aqueous solution
• Optimal pH range pH3-10 (wide range)
• Temperature range 278-323K (Optimal temperature
  is 25ºC 298K)
• The response time is less than 10s

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Primary Constituents K

• Similarly impregnated PVC Membrane electrode
• Hydrophobic membrane may contain Valinomycin
• Membrane is usually a thin disc
• Aim to detect K in aqueous solution

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Advantages

• Ideal for clinical use- serum/ blood
• Simple procedure
• Relatively specific for ions
• Inexpensive/ low cost
• Wide linear range
• Quick response time and reading in 2-3 minutes
• Results unaffected by turbidity/sample colour
• Extremely valuable in monitoring electrolytes
• Measure activity of the ion, not concentration
• One of the few techniques that can measure both
  cations and anions

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Limitations

• Selectivity Many electrodes are not completely
  ion specific and result in the problem of ionic
  interference (Selectivity Coefficient) - e.g.
  Sodium- ion selective electrode selectivity for
  K 0.56
• Accuracy from potentiometric methods is often
  variable but the selectivity of the electrodes
  can be improved
• Crowding at the membrane- high concentrations of
  ions are underestimated
• Extra precautions must be taken to minimise error
  and drifts in values, as minimal error in
  electrode potential will cause significant error
  in concentration of ions
• Ionic strength of the solution effect of all the
  ions in solution High ionic strength samples
  should be analysed using other methods or
  improving methods to avoid error e.g. dilution

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Considerations

• The selectivity of the membrane is dictated by
  the porosity of the membrane
• Electrode Water- insoluble, mechanically stable,
  durable, selective
• Precision (reproducibility) and Accuracy
  (closeness of result to the true value)
• Care must be taken to minimise membrane damage-
  cover to prevent scratches and remove deposits
  with water or alcohol and soak in standard
  solution for several days
• Contamination or blockage of electrodes- rinse by
  spraying with de-ionised water jet and dab dry
• Calibration Start with low to high
  concentrations to minimise cross-contamination

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Direct Potentiometry

• Analysis of low ionic strength samples used to
  detect Na and K
• Calibrate electrodes before use to get a graph
• Components of the solution being tested can be
  removed by precipitation if they disturb the
  primary ion
• Wash and dry electrodes between samples to avoid
  cross-contamination
• Advantage can be used to measure large batches
  of a wide range of concentrations rapidly without
  recalibrating though frequent calibration
  produces more accurate results

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References

• Merck Manual. Merck Research Laboratories New
  York, 17th ed 1999.
• Perazella, M. Drug-induced Hyperkalaemia Old
  Culprits and New Offenders, The American Journal
  of Medicine, vol. 109 (4), September 2000, pp
  307-314.
• Perazella, M., Mahnensmith, R. Rex, L.
  Hyperkalaemia in the Elderly Drugs Exacerbate
  Impaired Potassium Homeostasis, Journal of
  General Internal Medicine, vol. 12 (10), October
  1997, pp. 646-656.
• Rang, H., Dale, M. Ritter, J. Pharmacology.
  Churchill Livingstone London, 1999
• The Merck Manual online
• Saker B. M., Everyday drug therapies affecting
  the kidneys, Australian Prescriber 2000 2317-9
• http//www.liv.ac.uk/agmclen/Medpracs/practical_2
  /theory_2.html
• http//www.healthatoz.com/healthatoz/Atoz/ency/ele
  ctrolyte_tests_pr.html
• http//www.nico2000.net
• http//www.cee.vt.edu/program_areas/environmental/
  teach/smprimer/ise/ise.html

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References

• Monk, Paul M. S. Fundamentals of
  Electroanalytical Chemistry John Wiley and Sons
  ltd. 2001
• Covington, Arthur. K. Ion Selective Electrode
  Methodology Volumes 1 and 2 CRC Press 1979
• http//www.dictionarybarn.com/ION-SELECTIVE-ELECTR
  ODE.php
• Gunter EW, Lewis BG, Koncikowski SM (1996).
  Laboratory procedures used in the Third National
  Health and Nutrition Examination Survey 1988-1994
• Pungor E, Toth K and A. Hrabeczy-Pall.
  Application of ion-selective electrodes in flow
  analysis. Trends in Analytical Chemistry 3(1)
  1984 p.28-30
• Evans A. Potentiometry and ion-selective
  electrodes. ACOL London 1987
• Cammann K. Working with ion-selective electrodes.
  Springer NY 1979
• Rodriguez-Garcia J, Sogo T, Otero S, Paz JM.
  Transferability of results obtained for sodium,
  potassium and chloride ions with different
  analysers. Clinica Chimica Acta 275151-162 1998