So let's think a little bit more about what's going on. So as I mentioned, it's all about taking your pyruvate or pyruvic acid, the way I've drawn it right over here, this is pyruvic acid.
Pyruvic, pyruvic acid, right over here. Because we have our hydrogen proton, if we lose our hydrogen proton, this is the same thing drawn again, but now we don't have the hydrogen proton here, this oxygen kept that electron, and all of the other hydrogens, all the hydrogens here, they are implicit. So the three hydrogens here, they're implicit on this carbon. I'm just drawing it with a different notation.
And so this one, where we've lost the proton, we would call this pyruvate. And what we have happening is that the pyruvic acid, or the pyruvate is used to oxidize the NADH, take away a hydride, take away an electron from, actually more than just electron but net, you have the NADH losing electrons.
And so if it's losing electrons, it's getting oxidized. So it's oxidized. And when pyruvic acid does this to the NADH, it gets reduced, it gets reduced, it gets reduced, it gains electrons and, if we're thinking about the acid forms, it would turn into this right over here is lactic acid. Lactic, lactic, lactic acid. And that's why we call it lactic acid fermentation, 'cause you're taking that pyruvate, if you had oxygen around, or if you knew how to do it, use the oxygen, you might continue on with cellular respiration and use that for energy.
And let's just now get a better appreciation for all of this happens. So the first thing that I want to show you because a lot of times in biology classes, you just learn NAD, NADH, and it just seems like this somewhat abstract molecule.
But this is a picture of it. This is nicotinamide adenine dinucleotide. And it's kind of a mouthful, but when you break it down, you see these patterns that you see repeatedly in biology. This is, this right over here is what gives us the nicotinamide. This right over here is our good friend adenine.
You have ribose right over here, this is derived from ribose. You have a phosphate group, you have a phosphate group. So, nicotinamide, adenine, you have a nucleotide right over there, you have another nucleotide right over there, so it's nicotine adenine dinucleotide. So the name makes a lot of sense. These researchers highlighted the recognition that the body has the means to rid itself from muscular lactate and that there is ample evidence that such disposal is most efficient under oxidative conditions.
Thus, the dogma of lactate as a muscular product responsible for fatigue and rigor, one that aerobic conditions enhance its disposal, was already well entrenched among scientists at the beginning of the twentieth century. It is still entrenched today among athletes and their coaches. Hill [ 7 , 8 ] went even further than Fletcher by suggesting that the role of oxygen in muscle contracture is twofold, to decrease the duration of heat production and to remove lactate from it.
Hill argued that the measured heat production of lactate oxidation was much lower than the calculated value of its complete combustion. It is somewhat perplexing that a scientist of the stature of Hill would argue that if lactate were a fuel, all the energy of its oxidation would be released as heat. The leading investigators in the field at the time actually concluded that lactate is a separate entity from the one that is oxidized during muscle respiration and which yields energy and CO 2.
Moreover, they held that the energy yielded in respiration is utilized for lactate disposal. By the s [ 28 , 29 ], the central theme of these studies and many others had been muscle tissue and its glycolytic formation of lactate.
The process had been postulated to always be anaerobic and mainly through the breakdown of glycogen. In addition, when aerobic oxidation takes place, it occurs only after the muscle contracts and its main purpose is the removal of accumulated lactate and its accompanied acidosis.
The relationship between lactate and glycogen in muscle and, eventually, in other tissues, including brain, has been a complicating issue in the understanding of glycolysis. While the muscular conversion of glycogen to lactate is still in dispute today [ 30 ], both Nobel laureates had a long-lasting influence on this field of research. Since the majority of scientists in the field of carbohydrate metabolism in those days studied muscle tissue, their interpretation of and opinions about the results of their studies greatly influenced those who studied carbohydrate metabolism of other tissues, especially brain.
Thus, the small scientific community that investigated cerebral glycolysis in the late s and early s adopted the opinions of their peers in the field of muscle glycolysis and accepted the popular dogma, according to which, lactate is a useless end product that the brain eliminates via oxidation.
That concept stood against their own notion that the results of their studies could indicate lactate oxidative utilization by brain tissue.
While Hill and Meyerhof were the leading scientists in the field of muscle carbohydrate metabolism in the s and s, E. Holmes was their counterpart in the field of cerebral carbohydrate metabolism. The latter was joined by his wife, B. First, they showed that brain carbohydrates are not the source of brain lactate; however, the brain is capable of forming lactate from added glucose [ 31 ].
In their second study, they determined that brain lactate levels fall when there was a fall in blood sugar level, which results in shortage of glucose in the brain [ 32 ]. In the third paper of the series, the Holmes found that brain tissue in room temperature or under anaerobic conditions does not exhibit a significant increase in lactate level or a significant fall in glycogen level, but that under aerobic conditions, lactate rapidly disappears, while glycogen level remains unchanged [ 33 ].
Thus, the Holmes established that glucose is the precursor of lactate in the brain and that under aerobic conditions, brain lactate content decreases. Additionally, these investigators showed that brain lactate is formed from glucose supplied by the blood and that its levels rise and fall with blood glucose levels, under both hypo- and hyperglycemic conditions.
Moreover, they showed that the diabetic brain is not different from the normal brain, where lactate formation and its removal under aerobic conditions are concerned [ 34 ]. By , Ashford joined Holmes and the two were able to demonstrate that the disappearance of lactate and the consumption of oxygen are correlated, which, in essence, indicates an aerobic utilization of lactate by brain tissue. Furthermore, these investigators also showed that sodium fluoride NaF , the first known glycolytic inhibitor, blocked both glucose conversion to lactate and oxygen consumption.
Holmes [ 35 ] showed in brain gray matter preparation that oxygen consumption was completely inhibited by NaF in the presence of glucose. However, when lactate was used instead of glucose, oxygen consumption was not inhibited by NaF. Consequently, Holmes concluded that the conversion of glucose to lactate must take place prior to its oxidation by brain gray matter. These results and their straightforward conclusion have been completely ignored for over eight decades.
This ignorance is especially glaring when one considers the fact that by the time the glycolytic pathway was elucidated in , Holmes and Ashford papers were already available for at least a decade [ 35 , 36 ] and should have been taken into account prior to the announcement of that elucidation. Hence, 76 years ago, we could have been presented with somewhat different view of the glycolytic pathway instead of the one in which, depending on the presence or absence of oxygen, ends up with either pyruvate or lactate, respectively.
Krebs and Johnson were careful to place a question mark following their suggestion that pyruvate is the TCA cycle substrate. Thus, the work by the Holmes couple [ 31 — 34 ], Ashford and Holmes [ 36 ] and Holmes and Ashford [ 41 ] on brain carbohydrate metabolism has been ignored and remained obscure even today, due mainly to habit of mind [ 23 ]. PDH is a key enzyme that modulates glucose oxidation, which converts pyruvate to acetyl-CoA. During hypoxia, PDH activity is significantly inhibited and then pyruvate is converted into lactate.
Therefore, PDH activators enable correction of LA because of their ability to accelerate pyruvate oxidation and improve metabolic disturbances.
Dichloroacetate DCA , the representative activator of PDH, has been administered since at least to patients with inborn errors of mitochondrial metabolism and is able to lower lactate concentrations and normalize blood pH. However, a large randomized controlled trial failed to demonstrate its effect on LA, illustrating that DCA increased arterial pH and decreased blood lactate but did not reduce mortality in ICU patients [ 14 , 15 ].
A further study showed that DCA reduced mitochondrial NADH and elevated the incidence of premature ventricular contractions when glucose was the only exogenous fuel in isolated rat hearts during normoxic perfusion, which was mitigated by the addition of PDH substrates such as pyruvate [ 16 ].
In addition, DCA may be harmful because it causes neuropathy [ 17 , 18 ]. Nevertheless, the more rational treatment with appropriate doses of DCA to reduce side effects may need to be further investigated in patients with moderate or early-stage LA. It was reported that phenylbutyrate increased the residual activity of PDH by increasing the proportion of unphosphorylated enzymes and had potential as a therapeutic agent for LA [ 21 ].
DAG, the precursor peptide of ghrelin, could normalize skeletal muscle lactate production and plasma lactate levels elevated by burn injury through the down-regulation of elevated inflammatory cytokines and activation of PDH [ 22 ]. However, the results were not ideal and further study is needed. Many other agents are being investigated to better manage LA. For example, the compound 5-aminohydroxymethylphenyl boronic acid, a phenyl boronic acid derivative, binds lactate and normalizes the blood pH by increasing the consumption of protons via the LDH pathway [ 12 ].
Spermidine, with its activating effect on PDH phosphatase, can also activate PDH, stimulating the decarboxylation of pyruvate and inhibiting lactate accumulation [ 1 ]. Thus, these agents need more research to verify their effects and safety in patients. Resuscitation to support circulation is one of the first steps in treating LA [ 22 ]. Intravenous IV fluids were first administered over years ago [ 23 ] and fluid infusion is considered the mainstay of therapy for critical care patients.
The organic acid anions in the fluids can be used as a source of base [ 22 ]. The effectiveness of various organic acids on LA correction is quite different, which is worthy of mention.
Normal saline NS is often used as an initial resuscitation fluid in clinical settings. There is no doubt that NS is a reasonable alternative to restore perfusion if no other fluid is available. However, massive administration of NS often induces hyperchloremic acidosis [ 24 , 25 ].
Recent studies suggest that NS may increase acidosis and the incidence of kidney injury in healthy volunteers or critically ill adults, mainly because of renal microvascular contraction induced by hyperchloremia [ 26 , 27 ].
Therefore, the European guideline on management of major bleeding and coagulopathy following trauma fourth edition suggests that excessive use of NS be avoided Grade 2C , although NS infusion with the potential to restore pH may be advantageous [ 6 ].
Metabolizable anions, such as lactate, acetate and malate, have been included in IV balanced solutions to avoid hyperchloremic acidosis. However, their effects in the treatment of LA vary and have not been compared rigorously. Here, we reviewed the composition of common fluids and their efficiency in LA correction in shock resuscitation.
The IV infusion of LR has been regarded as the standard regime and is widely used in the treatment of ICU patients, especially patients with acute massive hemorrhage. Yuan et al. Despite these advantages, some studies indicated LR-induced inflammation and hepatic apoptosis [ 29 ] and other studies even questioned its effect on acidosis correction [ 30 ].
Recently, it was demonstrated that LR infusion might be detrimental in resuscitation of severe HS in rats [ 31 , 32 ].
In severe HS, lactate metabolism may be disturbed and the accumulated lactate can be further increased by LR infusion [ 32 , 33 ], which aggravates the inhibition of glycolysis and affects organ function. The damaged liver and kidneys will further inhibit gluconeogenesis and cause lactate accumulation. Therefore, LR mainly affords plasma volume expansion, rather than improves acid-base disturbance. Although there is a lack of clinical evidence available, a large amount of LR infusion may exacerbate lactate accumulation in the resuscitation of severe or decompensated shock in ICU patients.
In addition, the plasma lactate level is used as one of the diagnostic parameters in shock severity; thus, LR infusion may interfere with the diagnosis and treatment. Historically, sodium acetate has been used as a fluid bath for hemodialysis [ 34 ].
Recently, AR, whose main component is sodium acetate, has been prevalently used in fluid therapy with both crystalloids and colloids in clinical resuscitation.
It showed a significantly improved outcome prolonged survival and less organ injury in a rat model of severe HS compared with LR [ 33 ]. More importantly, AR showed a positive influence on the acid-base disturbance [ 35 ] because sodium acetate could alkalize plasma as quickly as SB. Acetate can also be converted to bicarbonate in the liver faster than lactate to raise the pHa [ 36 , 37 ]. Furthermore, acetate is mainly degraded in the muscle, which is more ubiquitous than lactate degraded in the liver and kidneys.
The metabolic velocity was the same rate as it was administered [ 38 ], even though the liver was damaged [ 39 ]. In addition, compared with LR, the administration of acetate-buffered solution did not show an elevated lactate concentration in Landrace pigs [ 40 ].
However, impaired cardiac contractile response is a side effect of acetate if a large amount is infused [ 41 ]. Accordingly, AR is also not promising for correcting LA in critical care patients. Malic acid, in the form of its anion malate, is a trigger for the oxidation of acetyl-CoA and could increase the TCA metabolism [ 43 ].
Malate is a key anion in Jonosteril Malat Fresenius Kabi infusion, which is an appropriate primary fluid therapy for critical care in subjects with moderate and severe acidosis to maintain the perioperative fluid balance [ 44 ]. The intragastric administration of malate increased mitochondrial respiration and energy production in rats [ 45 ].
However, malate cannot be metabolized through glycolysis and exhibits no protection of glycolysis under anaerobic metabolism and, thus, no red blood cell RBC protection. It may still not be optimal in the treatment of LA under fatal hypoxic conditions. In all, current fluid therapies can correct LA to some degree, particularly in resuscitation of compensated shock, but the outcome depends on the anion selected in the fluids.
The pathogenesis of LA should be deeply understood to improve the clinical outcomes. As summarized above, activators of PDH play an important role in correcting LA because of their ability to improve metabolic disorders and decrease lactate accumulation, finally correcting severe acidosis. The present agents for the treatment of LA are non-ideal. A therapeutic approach that can simultaneously correct acidosis and improve organ function with few adverse effects is of clinical importance.
Pyruvate, a PDH activator and substrate, is capable of modulating blood acidic pH by improving metabolic pathways under hypoxia and thus may be an optimal agent in the correction of LA. Monocarboxylate pyruvate can effectively correct LA, an effect which has been demonstrated in many preliminary experiments.
As early as , Mongan et al. Sharma et al. Petrat et al. Koustova et al. Although clinical data are not available, a case report of Leigh syndrome due to PDH mutation strongly suggests that oral pyruvate even corrects severe LA [ 56 ]. The entire reversal of LA by an administration of regular amount of pyruvate within hours in animal models implies its great clinical significance. The comparative effects of anions in fluid therapy on LA correction are listed in Table 1 [ 28 , 31 , 32 , 33 , 40 , 41 , 42 , 44 , 45 , 46 , 47 , 48 , 49 , 51 , 52 , 53 , 57 ].
The effect of pyruvate on LA correction is not solely a result of its chemical buffering ability as an alkalizer. Therefore, pyruvate may eliminate LA mainly via its biochemical characteristics in the promotion of energy metabolism and improvement of mitochondrial energetics to oxidize accumulated lactate and consume excess protons.
Pyruvate is located in the metabolic center of three major substances in mammals, which connect glycolysis in the cytosol and oxidation in the mitochondria in glucose metabolism. It participates in several important metabolic pathways.
The major acidosis-eliminating effect of exogenous pyruvate Sodium Pyruvate, SP can be illustrated in the following biochemical pathways Fig. Monocarboxylate transporters; PDC. Pyruvate dehydrogenase complex; acetyl-CoA. Acetyl coenzyme A; PC. Oxidized nicotinamide adenine dinucleotide; NADH. Reduced nicotinamide adenine dinucleotide; LDH.
Lactic dehydrogenase; TCA. Under hypoxic or ischemic conditions, PDH activity is inhibited. Notably, exogenous pyruvate can effectively restore the inhibited PDH activity through the decline of pyruvate dehydrogenase kinase activity [ 48 ] and can enhance the anaplerotic pathway replenishment of TCA-cycle substrates by improvement of pyruvate carboxylase PC.
Pyruvate is endogenously produced during glycolysis by breaking down glucose into two three-carbon molecules. Exogenous pyruvate, as a sole substrate, can be spontaneously converted into lactate by LDH, free from energy [ 55 ]. Pyruvate preservation of both the glycolytic pathway and LDH reduction is a unique superior property relative to other anions, including malate, in IV fluids. This beneficial attribute has recently been further argued by comparison of pyruvate-enriched oral rehydration solution ORS with citrate in ORS.
Pyruvate protects multi-organ function in HS, including that of the liver and kidneys, the main organs for gluconeogenesis metabolism. Furthermore, the improved function of heart, liver and kidneys resulting from exogenous pyruvate facilitates tissue oxygenation and lactate clearance. In addition, pyruvate oxidative metabolism has the lowest oxygen consumption per ATP generation compared to other anions.
A side effect of high lactate levels is an increase in the acidity of the muscle cells, along with disruptions of other metabolites. The same metabolic pathways that permit the breakdown of glucose to energy perform poorly in this acidic environment.
On the surface, it seems counterproductive that a working muscle would produce something that would slow its capacity for more work. In reality, this is a natural defense mechanism for the body; it prevents permanent damage during extreme exertion by slowing the key systems needed to maintain muscle contraction.
Contrary to popular opinion, lactate or, as it is often called, lactic acid buildup is not responsible for the muscle soreness felt in the days following strenuous exercise. Rather, the production of lactate and other metabolites during extreme exertion results in the burning sensation often felt in active muscles, though which exact metabolites are involved remains unclear.
This often painful sensation also gets us to stop overworking the body, thus forcing a recovery period in which the body clears the lactate and other metabolites. Researchers who have examined lactate levels right after exercise found little correlation with the level of muscle soreness felt a few days later. This delayed-onset muscle soreness, or DOMS as it is called by exercise physiologists, is characterized by sometimes severe muscle tenderness as well as loss of strength and range of motion, usually reaching a peak 24 to 72 hours after the extreme exercise event.
Though the precise cause of DOMS is still unknown, most research points to actual muscle cell damage and an elevated release of various metabolites into the tissue surrounding the muscle cells.
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