Tromethamine in the Pfizer/BioNTech COVID-19 Vaccine has nothing to do with heart attacks

In my last post, I explained that the Pfizer vaccine for children aged 5 to 11 has been slightly modified with respect to an inactive ingredient: the buffer. Buffers are substances that resist changes to pH (the acidity or alkalinity of a solution). Buffers are a very important component of mRNA vaccines (really all vaccines but mRNA vaccines especially) because mRNA does not tolerate alkaline conditions, which the buffer helps to ensure do not occur in the vial. Specifically, under alkaline conditions, mRNA will undergo a reaction called hydrolysis and rip itself apart. If this happens, our cells don’t get the instructions needed to make the spike protein, which means our immune system doesn’t get to initiate a response against it, and so the vaccine doesn’t work. The shift to a tromethamine (also known as tris or more formally tris(hydroxymethyl)aminomethane) buffer from the original PBS (phosphate-buffered saline) buffer formulation allows the Pfizer/BioNTech COVID-19 vaccine to be stored at standard refrigeration temperatures for up to 10 weeks, whereas before this it had to be stored under ultracold conditions (-80 °C and then -20 °C but for at most 2 weeks). The fact that the buffer was changed and the storage conditions are more relaxed means that the vaccine can be readily given in pediatrician’s offices as they now no longer need to buy very fancy, expensive freezers that are far beyond their budget. Incidentally, this is also the buffer that is used in the Moderna vaccine, as well as for the ERVEBO Ebola vaccine. The old phosphate buffered saline solution (PBS) did the same thing, but Pfizer did additional studies that showed that the mRNA lasted for longer at higher refrigeration temperatures so they switched to that. This is discussed at length in the VRBPAC meeting. There’s really nothing nefarious here. It’s an inactive ingredient- it does not affect the safety or effectiveness of the vaccine- it just makes it easier to give out to people. Unfortunately, this has not stopped some from lying about what its inclusion in the vaccine means.

A screenshot containing misinformation alleging that tromethamine in the Pfizer vaccine is dangerous and also used to treat heart attacks. Essentially no part of this is accurate, as I explain shortly.

The latest I have heard, this change is being taken as an admission that the Pfizer vaccine causes heart attacks, because, per the erroneous claim, tromethamine is given to treat heart attacks (it is not). I have also heard a version in which tromethamine is given to prevent heart attacks, which is also untrue. The claim that the Pfizer/BioNTech vaccine causes heart attacks is a bizarre claim that has quite literally no evidence (in fact if you look at non-COVID-19 causes of death among vaccinees vs. non-vaccinees, vaccinees tend to be much less likely to die), but near as I can tell, it comes from a misreading of the package insert of tromethamine (THAM solution). Anyway, let’s discuss what all the scary parts actually mean and why they aren’t scary.

As I said earlier, tromethamine (in combination with a weak acid like tromethamine hydrochloride as is in the vaccine for Pfizer and Moderna) is a buffer. When you add it to solutions, the solution will resist changes to their pH. The human body is full of buffers, such as the bicarbonate buffer system, phosphate buffer system, and the protein buffer system. However, buffers have limits to their ability to resist pH changes. They can be overwhelmed if too much acid or base is added. Under the indications for the use of THAM solution the package insert states:

Metabolic Acidosis Associated with Cardiac Arrest. Acidosis is nearly always one of the consequences of cardiac arrest and, in some instances, may even be a causative factor in arrest. It is important therefore, that the correction of acidosis should be started promptly with other resuscitative efforts. By correcting acidosis, Tham Solution (tromethamine injection) has caused the arrested heart to respond to resuscitative efforts after standard methods alone had failed…

Cardiac arrest and heart attacks are completely different things. Cardiac arrest is when the heart stops beating. A heart attack is what is formally known as a myocardial infarction, where part of the heart muscle dies because of inadequate blood flow to that part of the heart, usually because of a blood clot in a coronary artery. This is also not myocarditis, which is inflammation of the heart muscle for reasons not related to a lack of oxygen (in severe cases, myocarditis can also cause a cardiac arrest, but in the CDC’s surveillance as has been made clear at the most recent ACIP meeting, the vast majority of vaccine-related cases of myocarditis are mild and resolve rapidly; deaths reported in VAERS to be from myocarditis have been followed up and investigated with none thus far concluded to have been caused by myocarditis, though there are a few that are still under investigation). Untreated, a heart attack can absolutely result in cardiac arrest, but these things are definitely not interchangeable terms. If someone is in cardiac arrest, CPR needs to be initiated immediately. CPR will not help someone who is having a heart attack or myocarditis unless they are also in cardiac arrest. There is a famous mnemonic for reversible causes of cardiac arrest: H’s and T’s. If you can figure out which of the H’s and T’s are responsible for a patient’s cardiac arrest and correct them, you may be able to save their life. One of the H’s in the H’s and T’s is hydrogen ions, or protons, and acidity is itself basically a measure of the concentration of protons in a solution.

One of the key functions of the heart is to supply all of our cells with oxygen through its contraction to circulate blood throughout the body. In the process, that circulation delivers blood to the kidneys and lungs to remove metabolic wastes. If the heart suddenly stops, our cells consume their supply of oxygen. The key reason oxygen is so important is because it is absolutely required for our cells to make energy via aerobic metabolism. However, we do have an alternative option: anaerobic metabolism. This is used when the oxygen demands of our cells are not being met, such as during periods of intense exercise (or when your heart is stopped and so your cells consume their supply of oxygen but still need energy). Aerobic metabolism is much more efficient than anaerobic metabolism, as it yields far more energy upon completion of the metabolic cycles involved, but it takes far longer. Thus, though the yield of anaerobic metabolism is smaller, it works well for short bursts of energy. A byproduct of our anaerobic metabolism is lactic acid, which also makes the body more acidic. Ordinarily, that wouldn’t be an issue because you could clear the excess acid via the kidneys, lungs, and a number of other mechanisms, but that doesn’t work well when blood can’t flow to those organs to pass the lactic acid to them and all of the cells in the body start to resort to anaerobic metabolism at the same time. The molecules that we rely on to function cannot work when the pH is that low (i.e. when the body is overly acidified). For that reason, virtually every body fluid is extensively buffered. Arterial blood pH for example has a normal range of 7.35 to 7.45, and deviations from those values in either direction can make us incredibly sick (in general values less than 6.8 or greater than 7.8 are not compatible with human life- which is why alkaline diets and the like have no scientific basis; you cannot alkalinize your body with your diet). When arterial blood pH is below 7.35 it is known as acidemia and when it is above 7.45 it is known as alkalemia; more generally, the terms acidosis and alkalosis are used often interchangeably with these but do not specify the blood as the compartment being examined. If the heart is not beating, significant acidosis will occur within about 30 to 60 seconds. Furthermore, acidosis itself can cause cardiac arrest. Hence the indications for THAM solution note that it can be given during cardiac arrest to prevent the blood pH from dropping to dangerous levels. THAM is rarely used today for this purpose in most parts of the world; a bicarbonate solution would be used instead in most situations as the AHA link on H’s and T’s notes.

The other piece being misrepresented in the claims are the risks of tromethamine. As far as the vaccine, with the pediatric dose, there are 0.06 mg tromethamine and 0.4 mg tromethamine hydrochloride. The package insert describes a 500 mL solution of tromethamine containing, in total, 18 g of tromethamine (3.6 g per 100 mL), or 60,000 times as much tromethamine and 2500 times as much fluid in the solution total. The 500 mL solution is adjusted to have a pH of 8.6, which is more alkaline than the human body, which is precisely what you want if the body starts to become more acidic than it is supposed to be. Still, the dose makes the poison. Because the solution is alkaline, if it is administered in inappropriately high doses, it can suppress our impulses to breathe, as this is regulated by sensors in the brain’s medulla that work by sensing the concentration of hydrogen ions (protons), which are depleted if the body becomes too alkaline. The quantity of tromethamine in this solution cannot plausibly affect your body’s pH or that of a child.

Also because the THAM solution is a fluid, if you give it to someone who has significant kidney disease (and therefore cannot regulate their fluid volume), you might run into problems there- hence there is a warning on the insert not to give it to anuric patients (those who cannot make urine) or uremic patients (those with an elevated level of urea in the blood, indicative of impaired kidney function). Another risk cited by some is the risk of perivascular infiltration. This doesn’t have anything to do with the medication per se- this is a potential problem with IV administration which is how THAM is administered. As the package insert writes:

Care must be exercised to prevent perivascular infiltration since this can cause inflammation, necrosis and sloughing of tissue. Venospasm and intravenous thrombosis, which may occur during infusion, can be minimized by insuring [sic] that the injection needle is well within the largest available vein and that solutions are slowly infused. Intravenous catheters are recommended. If perivascular infiltration occurs, institute appropriate countermeasures.

In other words, when you give infusions of THAM solution, be sure to place the IV well. This risk does not apply to vaccines as they are not given IV.

There is also a warning that the infusion of tromethamine may very briefly lower blood sugar- which makes sense because you are diluting the blood with the infusion. Again, not applicable to the vaccine because it’s not given IV and there’s a grand total of 0.2 mL of fluid with the vaccine as opposed to the 500 mL the package insert references.

There is also a warning on the package insert of THAM not to give it via an umbilical catheter for concern of causing hepatic necrosis (liver cells dying). The vaccine is not given via an umbilical catheter. See where I’m going with this?

In short, between the route of administration and the dosage, none of the stated risks of THAM solution apply to the vaccine. And it has nothing to do with heart attacks.