1/
Have you ever wondered why patients in shock are refractory to vasopressor support if also severely acidotic?
I always assumed it was b/c cellular stuff just doesn't work well at low pH.
It turns out the answer is slightly more complicated...
#medtwitter #tweetorial
Have you ever wondered why patients in shock are refractory to vasopressor support if also severely acidotic?
I always assumed it was b/c cellular stuff just doesn't work well at low pH.
It turns out the answer is slightly more complicated...
#medtwitter #tweetorial
2/
First we need to establish if acidosis actually leads to vasopressor resistance.
This was first described in 1927 in an experiment involving pithed cats:
- The researchers increased/decreased their respiratory rate to change serum pH
- Responses to vasopressors were measured
First we need to establish if acidosis actually leads to vasopressor resistance.
This was first described in 1927 in an experiment involving pithed cats:
- The researchers increased/decreased their respiratory rate to change serum pH
- Responses to vasopressors were measured
3/
Lo and behold, the cats with a lower serum pH had diminished blood pressure responses to vasopressor injection (they used epinephrine).
Lo and behold, the cats with a lower serum pH had diminished blood pressure responses to vasopressor injection (they used epinephrine).
4/
A similarly diminished response was observed for human skeletal muscles when stimulated with phenylephrine at varying pH's
bit.ly/2oVCdYt
A similarly diminished response was observed for human skeletal muscles when stimulated with phenylephrine at varying pH's
bit.ly/2oVCdYt
5/
To understand why vasopressors don't work as well under acidotic conditions we need to remind ourselves what determines blood pressure, aka Ohm's law:
❤️Cardiac output x systemic vascular resistance = blood pressure
To understand why vasopressors don't work as well under acidotic conditions we need to remind ourselves what determines blood pressure, aka Ohm's law:
❤️Cardiac output x systemic vascular resistance = blood pressure
6/
As we all learned in physiology class, cardiac output is determined by heart rate, stroke volume, and inotropy (as well as adequate preload).
bit.ly/2BmWgBN
As we all learned in physiology class, cardiac output is determined by heart rate, stroke volume, and inotropy (as well as adequate preload).
bit.ly/2BmWgBN
7/
It turns out that reducing pH INSIDE a cardiac myocyte (and vascular smooth cell) has several downstream effects on adrenergic signalling:
👎 Opening of K exporter channels -> hyperpolarization of the cell membrane ->closing of Ca importer channels
bit.ly/2qiOWor
It turns out that reducing pH INSIDE a cardiac myocyte (and vascular smooth cell) has several downstream effects on adrenergic signalling:
👎 Opening of K exporter channels -> hyperpolarization of the cell membrane ->closing of Ca importer channels
bit.ly/2qiOWor
8/
Reduced Ca influx into cells leads to:
👎Reduced binding of calcium to myofibrils
👎Vasodilation of vascular smooth muscle cells and decreased inotropy of cardiac myocytes
This = refractoriness to vasopressor stimulation at low intracellular pH.
bit.ly/31u066C
Reduced Ca influx into cells leads to:
👎Reduced binding of calcium to myofibrils
👎Vasodilation of vascular smooth muscle cells and decreased inotropy of cardiac myocytes
This = refractoriness to vasopressor stimulation at low intracellular pH.
bit.ly/31u066C
9/
But what about the impact of pH OUTSIDE the cell?
Amazingly, extracellular acidosis causes a decrease in the amount of cell-surface beta-adrenergic receptors (at least in ex vivo chick embryo ventricular cells)
bit.ly/35OnXRR
But what about the impact of pH OUTSIDE the cell?
Amazingly, extracellular acidosis causes a decrease in the amount of cell-surface beta-adrenergic receptors (at least in ex vivo chick embryo ventricular cells)
bit.ly/35OnXRR
10/
How/why this occurs is unknown but may be due to phosphorylation and subsequent sequestration of the receptor.
bit.ly/2MpGj45
How/why this occurs is unknown but may be due to phosphorylation and subsequent sequestration of the receptor.
bit.ly/2MpGj45
11/
A natural follow-up question would be if there is a particular serum pH below which vasopressors stop working well?
The answer is we don't know, but the above literature suggested a drop off in response at pH < 7.2
A natural follow-up question would be if there is a particular serum pH below which vasopressors stop working well?
The answer is we don't know, but the above literature suggested a drop off in response at pH < 7.2
12/
Another follow-up question is, if vasopressors don't work well with severe acidosis, should we use alkaline infusions (such as sodium bicarbonate/HCO3) to raise the pH?
Another follow-up question is, if vasopressors don't work well with severe acidosis, should we use alkaline infusions (such as sodium bicarbonate/HCO3) to raise the pH?
13/
This is actually controversial because HCO3 actually DECREASES intracellular pH (probably by being converted to CO2 and creating an H+ ion when reacting with intracellular water).
As we learned before, not something you want to do
bit.ly/2J1e6P9
This is actually controversial because HCO3 actually DECREASES intracellular pH (probably by being converted to CO2 and creating an H+ ion when reacting with intracellular water).
As we learned before, not something you want to do
bit.ly/2J1e6P9
14/
Let's sum up what we've learned:
💡Response to vasopressors⬇️w/ acidosis
💡Intracellular acidosis leads to⬆️K efflux, hyperpolarization,⬇️Ca influx into cardiac/vascular muscle cells
💡Extracellular acidosis also⬇️surface adrenergic receptors
💡HCO3⬇️cell pH = controversial
Let's sum up what we've learned:
💡Response to vasopressors⬇️w/ acidosis
💡Intracellular acidosis leads to⬆️K efflux, hyperpolarization,⬇️Ca influx into cardiac/vascular muscle cells
💡Extracellular acidosis also⬇️surface adrenergic receptors
💡HCO3⬇️cell pH = controversial
