HES: review of pharmacokinetics, dynamics, current products, etc. JVECC 2014

Question 1

What is HES synthesized from?

Answer 1

amylopectin
- natural starch derived from corn/potatoes

Question 2

What are the 3 numbers provided by the HES manufacturer?

Answer 2

average molecular weight (MW)
molecular substitution (MS)
pattern of substitution (C2/C6 ratio)

Question 4

What are the names of HES with molecular substitutions of 0.4, 0.5, 0.6, or 0.7?

Answer 4

• tetrastarch
• pentastarch
• hexastarch
• hetastarch

Question 5

What is the molecular weight of albumin in dogs?

Answer 5

64-67 kDa

Question 5

What do these numbers represent?

Answer 5

Question 6

Name the modified Starling’s equation

Answer 6

Jv = Kf (HPc - HPi) - ohm (COPc - COPg)

JV = net fluid movement across the capillary
Kf = filtration coefficient

Question 7

Why was 6% hetastarch formerly labeled with a lower molecular weight average?

Answer 7

because the weight could be determined more accurately with a newer method (low-angle laser light scattering)

previous method: chromatography

Question 8

What is the glomerular molecular weight filtration threshold?

Answer 8

45-60 kDa

Question 9

If HES molecules’ size is above the glomerular filtration threshold

Answer 9

alpha-amylase breaks larger molecules down –> until small enough to be filtered through the glomerulus

Question 10

What determines how long HES remain in the intravascular space? (MW, MS or C2/C6 ratio)

Answer 10

all
- larger molecules –> must be broken down into smaller parts before excretion
- higher molar substitution –> higher number of sites of substitution (e.g., hetastart compared to hexastarch) –> reduces access of alpha-amylase to the intermoleculalr bonds for degradation
- higher C2/C6 ratio –> HE groups positioned on the C2 atom block alpha-amylase more effectively

Question 11

What characteristic of HES are the most important for determining pharmacokinetics?

Answer 11

molar substitution and pattern of substitution

Question 12

Do dogs or people eliminate HES faster?

Answer 12

dogs - shorter half-life because of higher plasma alpha-amylase concentration

Question 13

What are the mechanisms of HES elimination?

Answer 13

• renal - 70% (the smaller the molecule the faster, because of glomerular filtration)
• transient storage in the reticuloendothelial cells of liver, spleen, lymph nodes, IV and interstitial spaces (increased tissue storafe with increased molar substitution
• bile excretion

Question 14

List 5 reported side effects of HES administration (including in people)

Answer 14

• volume overload
• coagulopathies
• AKI
• proinflammatory effects
• allergic reactions

Question 15

What are the presumed mechanisms of AKI from HES administration?

Answer 15

• HES macromolecule reabsorbtion into proximal renal tubular cells –> osmotic nephrosis (vacuolization and swelling of cells)
• hyperoncotic AKI, i.e., increased intravascular COP reduces glomerular filtration
• backleak of filtrate across damaged tubular epithelium
• dilutional hypoalbuminemia - decreased levels of renoprotective albumin

Question 16

According to a recent Cochrane review, what subcategory of critically ill patients is at a higher risk of AKI from HES administration?

Answer 16

Sepstic patients

Question 17

After administering HES to dogs, what changes may occur on the urine analysis?

Answer 17

increased specific gravity - no changes to osmolality

Question 18

List 4 coagulation abnormalities reported with HES administration

Answer 18

• platelet dysfunction (decreased adhesion)
• decreased vWF
• decreased FVIII
• hyperfibrinolysis

Question 19

How does HES affect platelets?

Answer 19

HES molecules bind to platelet bindings sites (not the fibrinogen one)

Question 20

How do coagulopathic effects of tetrastarch and hetastarch differ?

Answer 20

tetrastarch
* less PLT inhibition
* less vWF-VIII binding (because excreted faster)
* more hyperfibrinolysis

Question 21

How does tetrastarch increased fibrinolysis?

Answer 21

disrupts the thrombin-TAFI relationship

Question 22

What is the initial expansion volume of 450 mL of 6% Hetastarch in healthy normovolemic patients at time 0 and 30 min?

Answer 22

450 min time 0
>650 mL 30 min later

Question 23

How did the initial and delayed plasma expansion compare between 0.9% NaCl and HES in Silverstein et al?

Answer 23

0.9% NaCl caused more plasma volume expansion initially but fell below HES 30 min later

Question 24

What is the normal Colloid osmotic pressure in healthy dogs?

Answer 24

17.5 - 22.7 mm Hg

Question 25

What is the reported colloid osmotic range in hypoalbuminemic dogs?

Answer 25

5.8 - 12.7 mm Hg

Question 26

What are the two theories of how HES administration helps with capillarby hyperpermeability?

Answer 26

• plugging intercellular gaps
• immunomodulators