Viva G4(ii)c

This viva tests Section G4(ii) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "describe the distribution of blood volume and flow in the various regional circulations and explain the factors that influence them, including autoregulation. These include, but not limited to, the cerebral and spinal cord, hepatic and splanchnic, coronary, renal and uteroplacental circulations."

Specifically, this viva is all about hepatic blood flow.

Describe the blood supply of the liver.

• The liver has a dual blood supply: arterial (30%) and portal venous (70%)
• It contains about 10% of the total blood volume (about 500ml), and in mammals (and possibly also in man) this reservoir can be recruited during serious haemorrhage.
• The total hepatic blood flow is 25% of the total cardiac output, or 1200ml/min
• Arterial supply:
  • The arterial supply of the liver is maintained by the hepatic artery proper,
  • This is a  branch of the common hepatic artery (a short offshoot of the coeliac trunk which also gives rise to the gastroduodenal and right gastric arteries). 
  • Hepatic arterial blood flow is approximately 6% of the total cardiac output (350ml/min, SaO₂= 95%; 40-50% of the DO₂)
• Portal venous supply
  • Portal vein, which is a confluence of mesenteric and splenic veins
  • Valveless, low pressure venous system (8-10 mmHg)
  • Flow here is non-pulsatile
  • Vascular resistance is extremely low
  • 70% of the total blood flow (SvO₂=85%;  50-60% of the DO₂)

Describe the microcirculation of the liver

• Portal venules and hepatic arterioles merge anastomotically into hepatic sinusoids, which then drain into post-sinusoidal venules.
• This is a low resistance system; the pressure gradent is no more than 3-5mmHg under normal conditions and the flow is very slow
• These sinusoids are capillaries which are much wider in diameter than a normal capillary, and with a discontinuous epithelium

How is portal venous blood flow regulated?

• The portal venous circulation responds to a variety of stimuli, some of which can double or halve its resistance.
• The response to endogenous vasopressors is likely related to the liver's apparent role as a blood reservoir, in which case it would make sense to decrease the portal venous volume and "flush" the extra blood into the systemic circulation.
• The portal vein vasodilates in response to a meal, increasing blood flow by 80%

Vasoactive agents which can influence the portal vein include:

Vasoconstrictors	Vasodilators
Phenylephrine Noradrenaline Adrenaline Dopamine Serotonin Histamine Angiotensin Vasopressin CO2	GTN Calcium channel blockers α2-agonists α1-antagonists Serotonin blockers (eg. ketanserin) Glucagon Secretin

What is the "The hepatic arterial buffer response"?

• This is the "hepatic arterial-portal venous semi-reciprocal interrelationship"
• Very simply, when portal venous flow goes down, hepatic arterial flow goes up.
• In other words, hepatic arterial vascular resistance is proportional to portal venous blood flow.
• The mechanism is probably based on adenosine washout:
  • Adenosine is released into the space of Mall, a periportal space which is occupied by the portal vein, hepatic artery and bile duct.
  • It is then trapped there, because the space of Mall is separated from other fluid compartments. In short, it has nowhere else to go, except to diffuse into the vessels to be washed away.
  • The portal vein in this space has the highest flow rate, and therefore if the portal flow is rapid, much of the adenosine is washed out of the space of Mall.
  • As adenosine is a vasodilator, its loss leads to vasoconstriction.
  • As the hepatic artery is the only thing in the space of Mall with even a shred of vascular smooth muscle, it is affected by this the most. 
  • Ergo, portal flow, by adjusting the amount of adenosine in the space of Mall, regulates the vascular resistance of the hepatic artery.

How does the liver compensate for its variable oxygen delivery?

• The oxygen supply to the liver fluctuates considerably.
• In fact it is not tied to the hepatic metabolic rate
• Thus, the liver compensates by altering its oxygen extraction.
• It can extract almost 100% of the delivered oxygen
• In other words, hepatic venous blood can have an SaO2 close to 0%.

What factors influence the perfusion of the liver?

• Extrahepatic factors which increase hepatic perfusion:
  • Increased venous return
    • Spontaneous breathing (inspiration)
  • Increased arterial blood flow
    • Anything that increases cardiac output
  • Increased portal blood flow
    • Splanchnic vasodilation. eg. after a meal
• Extrahepatic factors which decrease hepatic perfusion
  • Decreased venous return
    • Positive pressure ventilation
    • Heart failure, esp. right heart failure
    • Fluid overload states, eg. between regular dialysis sessions
  • Decreased arterial blood flow
    • Anything that decreases cardiac output, eg. heart failure
    • Anything that redistributes splanchnic blood flow, eg. exercise, catecholamine release, stress
  • Decreased portal blood flow
    • Splanchnic vasoconstriction, eg. shock states

How does drug metabolism change with changing hepatic blood flow?

• Hepatic clearance is the product of hepatic blood flow and the hepatic extraction ratio:

  

  where the hepatic extraction ratio here is represented by everything beyond the "×" symbol. 

• Hepatic extraction ratio is the fraction of the drug entering the liver in the blood which is irreversibly removed (extracted) during one pass of the blood through the liver.
• With decreasing hepatic blood flow, hepatic extraction ratio will increase for all drugs.
• What happens to drug metabolism with decreasing liver blood flow depends on the intrinsic hepatic clearance of that drug.
• The higher the intrinsic clearance, the more blood-flow-dependent the clearance of that drug.
• Thus, for drugs with low intrinsic clearance, hepatic clearance will not increase significantly with increasing blood flow.
• For drugs with high intrinsic clearance, hepatic clearance will decrease in a fairly linear fashion, in proportion to hepatic blood flow.