Does acidosis affect contractility of the neonatal heart? And does bicarbonate help?

I sometimes write posts which are not based on a new publication but to address a clinical issue that I think is important, and may not be clear to everyone. Often triggered by something that has happened in my own practice.

If you are a specialist in the domain you probably already know that the answers to the 2 parts of the question in the title are 1: very little, and 2: probably not.

To give a bit more detail:

The impacts of acidosis on myocardial function were first investigated to my knowledge in the 1960s in several papers published mostly in the American Journal of Physiology, it was shown that acidosis decreased contractility of isolated myocardial strips and ventricular preparations. If you go back to those articles you can find what we would consider medically profound extreme acidosis, pH typically of 6.0, induced often by adding HCl to the fluid surrounding the preparation.

Clearly, hydrochloric acid acidosis is not common in clinical practice, and a pH of 6.0 is usually only found post-mortem.

More recent studies have investigated more clinically important types of acidosis, more reasonable pH ranges, and the relative impacts on adult and neonatal myocardium.

Here is one example, using an isolated perfused adult rabbit heart, with a pH of 7.4 for the controls and pH=7.03 for each of the 3 models of acidosis. (Berger DS, et al. Disparate effects of three types of extracellular acidosis on left ventricular function. Am J Physiol. 1999;276(2):H582-94). As you can see respiratory acidosis had impacts similar to the HCl, leading to a 22% reduction in maximal pressure generation, whereas lactic acidosis only reduced pressure generation by about 8%. Elastance of the ventricle (the inverse of compliance) was not affected by lactic acidosis.

Even in the adult, therefore, organic acidosis has a much more modest effect than inorganic acidosis (there are other studies showing essentially the same thing), and respiratory acidosis is much more potent. Studies of hypercarbia without acidosis, on the other hand, show a smaller effect which is not sustained. The impact, as are most things related to contraction of muscles, seems to be mediated by changes in calcium flux. That becomes important when you start to think of neonatal myocardium, because it is very different.

Excitation of the cardiomyocyte is coupled to contraction by the flux of calcium into the cell which normally stimulates calcium release from the sarcoplasmic reticulum, the link between the sarcolemmal membrane and the SR being the t-tubule. There is also trans-sarcolemmal Na/Ca exchange which kicks in. T-tubules are absent in the newborn and there is very little SR, which basically means that you cannot extrapolate anything about myocardial function from the adult to the newborn. SR is probably still quite important, and recent data show a high concentration of calcium within the relatively sparse SR. However all the mechanisms underlying calcium flux are quantitatively, if not qualitatively, different, and you really need to test any intervention or abnormality in neonatal myocardium before assuming that it applies to the newborn.

This figure, as one example, (Nakanishi T, et al. Effect of acidosis on contractile function in the newborn rabbit heart. Pediatr Res. 1985;19(5):482-8) shows the impact of respiratory acidosis pH=6.8 on the calcium tension relationship in rat hearts, compared ot the adult. There is almost no detectable impact of a very low pH in the newborn.

In the same study, Toshio Nakanishi and his co-workers induced a metabolic acidosis (which was an inorganic acidosis) and found no effect on the neonatal myocardium

At the end of the acidotic period, there was a fall in developed tension (DT, a measure of contractility), which occurred when the acidotic perfusing solution was changed back to a neutral standard solution, containing bicarbonate. (The fall in DT at this point might be relevant, see below).

Despite my comments at the start, even in the 1960s there were studies using medically relevant models of acidosis, such as this one from Yale (Talner NS, et al. Influence of acidemia on left ventricular function in the newborn lamb. Pediatrics. 1966;38(3):457-64)
using an in situ heart preparation in newborn lambs,

SV10 is the stroke volume, MER10 is the mean ejection rate, and you can see that acidosis, which was induced by infusion of lactic acid to a pH of 6.9, had no effect on cardiac function, and no effect on the response to norepinephrine, if anything, the SV response to norepinephrine was greater with acidosis.

Does Bicarbonate improve cardiac function in acidosis?  Bicarbonate plus acidosis, of course, generates CO2 (HCO3- + H+ = H2CO3 = H2O + CO2) which diffuses rapidly across cell membranes and reacts with water to generate carbonic acid, reversing that equation, which releases H+. Bicarbonate administration, therefore, worsens intracellular acidosis when you administer it to acidotic subjects. It doesn’t seem likely that it would improve myocardial function.

Indeed most of the studies confirm the lack of benefit or an adverse effect. In this study for example, (Shapiro JI. Functional and metabolic responses of isolated hearts to acidosis: effects of sodium bicarbonate and Carbicarb. Am J Physiol. 1990;258(6 Pt 2):H1835-9) pH was progressively reduced to 6.8 by using buffers with lower bicarbonate concentrations, and then either saline, bicarbonate or carbicarb (an iso-osmolar mixture of NaHCO3 and Na2CO3 which buffers acid without producing CO2) were added. As you can see, Bicarbonate caused intracellular pH to fall slightly and had no effect on contractility (dp/dt max) whereas carbicarb did the opposite.

I don’t think there are entirely similar studies in the newborn, but there are studies in intact animals which generally show that metabolic acidosis is associated with an increase in dp/dt max, as they are intact animals it may be that there are changes in preload associated with this, so it may not be entirely a contractility change, but there is at least no evidence of a depression of contractility in these models. Basir MA, et al. Effects of Carbicarb and sodium bicarbonate on hypoxic lactic acidosis in newborn pigs. Journal of investigative medicine. 1996;44(2):70-4. Nudel DB, et al. Comparative effects of bicarbonate, tris-(hydroxymethyl)aminomethane and dichloroacetate in newborn swine with normoxic lactic acidosis. Dev Pharmacol Ther. 1993;20(1-2):20-5.

In these models, the increase in cardiac output or dp/dt max occurring with acidosis decreased when bicarbonate was administered.

So to summarize, metabolic acidosis in the newborn has little or no effect on myocardial contractility in several mammalian animal models of isolated myocardial preparations (lambs, rabbits and rats). Even in the mature myocardium, the impact of organic acidosis is relatively modest. And there is no evidence that response to catecholamines in the newborn myocardium is affected by acidosis.

In that context looking for a benefit of bicarbonate in the newborn would be a bit of a lost cause, which may be why there are no relevant studies that I could find. But even in the mature myocardium, the impact of bicarbonate use during acidosis has usually been shown to be a negative effect on contractility. What data there are in the newborn intact mammalian models show that cardiac function in some models is actually increased in acidosis, and decreased by the use of bicarbonate.

About keithbarrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research and tagged , , . Bookmark the permalink.

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