So, what happens clinically when you rev up a system without producing more work? You get heat. This is why patients who overdose on uncouplers can get profoundly hyperthermic. Lots of energy is consumed, but no work is produced — the engine overheats. Clinically this is also one of the ways that aspirin contributes to death. The lack of ATP targets the brain and the heart they are so needy causing the famous life-threatening dyad of a really bad aspirin overdose — cerebral and pulmonary edema.
So I promised I would talk about keeping pH normal and why that is important. First, it is important to mention why salicylate causes acidosis. OK, move on. To be fair we do know a lot about this, but it is complicated.
Steve Curry and Meghan Spyres do a great job discussing this in their chapter on salicylate. The simple version is that under a normal state the hydrogen ions produced when ATP is consumed are balanced by the hydrogen ions used when ATP is made. As long as your metabolic demands are met, you are fine. But as I said above, at high concentrations salicylate is an uncoupler, so you are consuming energy faster than you can make it. This is one of the ways uncouplers cause metabolic acidosis.
Acidosis is a really bad thing in large salicylate overdoses. In a salicylate overdose, we do. This has to do with the dissociation constant of salicylate first mitochondria and now pharmacokinetics. The dissociation constant is the pH at which half of the molecules in a solution are ionized and half are non-ionized.
Things that are ionized, or charged, have a harder time crossing biologic membranes than those that are uncharged, or non-ionized. This means at a normal serum pH of 7. And that is a good thing because only unbound, non-ionized salicylate crosses membranes. Another way of saying this is so long as you keep the pH normal, most salicylate will stay out of the brain and heart. This means that even small changes in pH can have profound changes to the amount of ionized salicylate.
If you drop serum pH from 7. So what does this all mean? It means to keep salicylate out of the heart and brain, where it causes its problems, you need to keep pH normal or even better, alkaline. To make a drip, most of us toxicologists will use three amps of sodium bicarb in 1L of D5W and run a drip at 1.
On a side note, if you can also alkalize the urine then you get the added benefit of excreting more salicylate in the urine. Quick tip : to alkalinize the urine you must keep patients from getting hypokalemic 6 , cause the kidney will preferentially hold on to potassium and dump a proton, preventing the alkalinization.
Another way to maintain arterial pH is to breathe. As you likely recall, salicylates cause patients to hyperventilate. This causes the classic mixed acid-base disorder of respiratory alkalosis with metabolic acidosis test tip: an ABG on a test with a low PCO2 and bicarb is probably a salicylate overdose. Why do salicylates cause people to breath deeper hyperpnea and faster hyperventilation?
We know It is not from cyclooxygenase inhibition. It helps to keep your serum pH normal to alkaline. Why would you do that? Because the patient is sick. As I have already discussed, at high concentrations salicylates uncouple oxidative phosphorylation. This means less ATP being formed in your brain.
We intubate them. This is important, and the whole point of this post. If you are going to intubate a bad salicylate overdose you must keep up their minute ventilation.
Aspirin patients pant in part because their survival depends on them keeping their serum pH alkaline. This is important to remember because many of the deaths that occur with aspirin overdose, do so shortly after they have been intubated. This is why published guidelines on managing salicylate poisoning say:. There is also some clinical and animal data to support this. In one retrospective study, ABGs that were obtained before and after intubation in aspirin overdoses were analyzed.
All the patients post-intubation had significant reductions in pH and several of the patients who died deteriorated shortly after intubation. We recently had three aspirin deaths reported to our center. All of them occurred shortly after the patient was intubated. By now this should all make sense. In animal studies, small decreases in serum pH cause big increases in brain aspirin concentrations. So, what do you do if you need to intubate a sick aspirin patient? As for the vent settings, I am not going to pretend I know anything about ventilators — consult your intensivist.
These patients need repeated checks of arterial pH not a bad indication for an arterial line. EMCrit Blog. Published on April 30, Accessed on November 13th Unless otherwise noted at the top of the post, the speaker s and related parties have no relevant financial disclosures. Hello Thank you for this excellent piece. In an event you have to intubate a massive aspirin overdose if you must , hyperventilation will essentially fail to maintain the pH you want.
In setting of pulmonary edema it will even be more difficult and chances are the heart will go into asystole. We are the EMCrit Project , a team of independent medical bloggers and podcasters joined together by our common love of cutting-edge care, iconoclastic ramblings, and FOAM. Kakuda T. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther.
Carbon monoxide poisoning. Med Clin North Am. Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part I. Biochemical and physiological mechanisms. Br J Pharmacol. J Med Toxicol. Clin Toxicol Phila. This buildup of protons will eventually be enough that the free energy needed to transfer a proton into the intermembrane space from the electron transport chain will not be sufficient to overcome the concentration gradient.
Electron transport is slowed, and working backwards, the chain reaction slows respiration rates in general. Thus there is a direct association between respiration rate and physiological energy need.
Interestingly, there is an exception to this tight coupling of the electron transport chain and formation of ATP. The purpose of brown fat aka brown adipose tissue , which is most often found in newborn and hibernating mammals, is to generate non-shivering non-movement-based heat to keep the animal warm.
This is accomplished by uncoupling the electron transport chain from the ATP synthesis. This uncoupling is a hormonally controlled process based on the presence of a mitochondrial proton channel called thermogenin.
The hormone norepinephrine increases production of free fatty acids, which open the thermogenin channel. This allows protons to ow from the intermembrane space back into the matrix without having to go through ATP synthase.
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