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Pyruvate as a Potential Beneficial Anion in Resuscitation Fluids

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There have been ongoing debates about resuscitation fluids because each of the current fluids has its own disadvantages. The debates essentially reflect an embarrassing clinical status quo that all fluids are not quite ideal in most clinical settings. Therefore, a novel fluid that overcomes the limitations of most fluids is necessary for most patients, particularly diabetic and older patients. Pyruvate is a natural potent antioxidant/nitrosative and anti-inflammatory agent. Exogenous pyruvate as an alkalizer can increase cellular hypoxia and anoxia tolerance with the preservation of classic glycolytic pathways and the reactivation of pyruvate dehydrogenase activity to promote oxidative metabolism and reverse the Warburg effect, robustly preventing and treating hypoxic lactic acidosis, which is one of the fatal complications in critically ill patients. In animal studies and clinical reports, pyruvate has been shown to play a protective role in multi-organ functions, especially the heart, brain, kidney, and intestine, demonstrating a great potential to improve patient survival. Pyruvate-enriched fluids including crystalloids and colloids and oral rehydration solution (ORS) may be ideal due to the unique beneficial properties of pyruvate relative to anions in contemporary existing fluids, such as acetate, bicarbonate, chloride, citrate, lactate, and even malate. Preclinical studies have demonstrated that pyruvate-enriched saline is superior to 0.9% sodium chloride. Moreover, pyruvate-enriched Ringer’s solution is advantageous over lactated Ringer’s solution. Furthermore, pyruvate as a carrier in colloids, such as hydroxyethyl starch 130/0.4, is more beneficial than its commercial counterparts. Similarly, pyruvate-enriched ORS is more favorable than WHO-ORS in organ protection and shock resuscitation. It is critical that pay attention first to improving abnormal saline with pyruvate for ICU patients. Many clinical trials with a high dose of intravenous or oral pyruvate were conducted over the past half century, and results indicated its effectiveness and safety in humans. The long-term instability of pyruvate aqueous solutions and para-pyruvate cytotoxicity is not a barrier to the pharmaceutical manufacturing of pyruvate-enriched fluids for ICU patients. Clinical trials with sodium pyruvate-enriched solutions are urgently warranted.

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Sodium pyruvate is a prospective alkalizer to correct hypoxic lactic acidosis


Type A lactic acidosis resulted from hypoxic mitochondrial dysfunction is an independent predictor of mortality for critically ill patients. However, current therapeutic agents are still in shortage and can even be harmful. This paper reviewed data regarding lactic acidosis treatment and recommended that pyruvate might be a potential alkalizer to correct type A lactic acidosis in future clinical practice. Pyruvate is a key energy metabolic substrate and a pyruvate dehydrogenase (PDH) activator with several unique beneficial biological properties, including anti-oxidant and anti-inflammatory effects and the ability to activate the hypoxia-inducible factor-1 (HIF-1α) - erythropoietin (EPO) signal pathway. Pyruvate preserves glucose metabolism and cellular energetics better than bicarbonate, lactate, acetate and malate in the efficient correction of hypoxic lactic acidosis and shows few side effects. Therefore, application of pyruvate may be promising and safe as a novel therapeutic strategy in hypoxic lactic acidosis correction accompanied with multi-organ protection in critical care patients.

Current non-ideal therapeutic agents

Alkaline agents

The administration of bases (alkalizers) is commonly regarded as the symptomatic treatment to correct metabolic acidosis, but it is unfavorable in LA corrections.

Sodium bicarbonate (SB)

Although it is not recommended in the majority of trauma guidelines, SB has been widely used to correct metabolic acidosis in clinical scenarios. Administration of SB can elevate the bicarbonate ([HCO3]) level and raise the pH in plasma, which benefits patients with decreased serum [HCO3]. However, SB may cause a series of complications. It increases carbon dioxide (CO2) production and decreases serum ionized calcium, which contributes to a decrease in ventricular and vascular contractility and damage to the myocardium. More importantly, SB therapy may induce an intracellular pH (pHi) decline. It was reported that bicarbonate administration led to an average increase in CO2 generation reflected by the need to increase ventilation by 40% to maintain a stable pCO2 [10]. For patients with abnormal respiratory compensation, CO2 generated from SB can rapidly diffuse into cytoplasm, which causes overproduction of intracellular [H+] [10]. The decreased pHi will worsen intracellular acidosis and damage tissues and organs. A randomized crossover study of 14 adults with lactic acidosis ([HCO3] < 17 or base excess < − 10 and lactate nearly 7.8 mmol/L) treated with SB or equimolar sodium chloride demonstrated that SB treatment did not improve hemodynamics in ICU patients who suffered from LA [11]. It also cannot reduce but can even exacerbate the lactate accumulation [1]. Furthermore, SB has several negative side effects, such as altering blood pressure and triggering apoptosis [12]. SB administration requires a functional cardio-respiratory system to exhale the extra CO2 and there is a trend against using it in cardiac arrest patients. Therefore, SB use should be limited with caution to correct LA in critical care patients, i.e., avoiding the administration of SB if the pHa is > 7.10.

Tromethamine (THAM)

THAM is an amino alcohol with acid-buffering capacity [1]. The NH2 in THAM can bind [H+] to modulate both pHa and pHi as well as blood CO2 levels. However, it does not affect lactate accumulation. THAM also has toxic side effects such as respiratory depression and hypoglycemia [13]; thus, it is not suitable for LA treatment [1]. Moreover, except in a few case reports, THAM is no longer available for clinical use in most parts of the world.

The activator of PDH

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 1978 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]. Therefore, when using DCA to correct LA, PDH substrates may be needed. 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.

Other PDH activators, such as phenylbutyrate and desacylghrelin (DAG), are being studied [19, 20]. 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.

Other chemicals

Many other agents are being investigated to better manage LA. For example, the compound 5-amino-2-hydroxymethylphenyl 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]. In addition, NHE1 (a cell-membrane [Na+]/[H+] exchanger) inhibitors may be useful in reverse of LA, but are still in animal studies [23]. Thus, these agents need more research to verify their effects and safety in patients.

Sodium pyruvate inhibits lactate dehydrogenase activity in an MCT1-dependent manner

Millimolar concentrations of exogenous pyruvate induced substrate inhibition of LDH activity in both enzymatic assays ex vivo and in live cells, abrogated glycolytic extracellular acidification rate, and inhibited pyruvate to lactate conversion rates in cells. The extent of exogenous pyruvate-induced inhibition of LDH and glycolytic extracellular acidification rate in live cells was highly dependent on pyruvate influx, functionally mediated by monocarboxylate transporter-1 localized to the plasma membrane.

Overexpression of MCT1 increases the efficiency of sodium pyruvate. MCT1 is a proton-coupled monocarboxylate transporter that translocates a proton through the plasma membrane together with a molecule of sodium pyruvate, so it's like a protonophore.

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