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
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
Lo and behold, the cats with a lower serum pH had diminished blood pressure responses to vasopressor injection (they used epinephrine).
A similarly diminished response was observed for human skeletal muscles when stimulated with phenylephrine at varying pH's

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
As we all learned in physiology class, cardiac output is determined by heart rate, stroke volume, and inotropy (as well as adequate preload).

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

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.

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)

How/why this occurs is unknown but may be due to phosphorylation and subsequent sequestration of the receptor.

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
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?
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

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
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