Pyruvate as a Potential Beneficial Anion in Resuscitation Fluids

Abstract

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 attention first be paid 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.

Advantages of pyruvate-based fluids in preclinical shock resuscitation-A narrative review

“…Furthermore, a continuous infusion of IV pyruvate (0.1 mmol/kg/min for 6 h) during the extracorporeal membrane oxygenation (ECMO) protocol in an immature swine model confirmed that it enhanced anaplerotic flux (replenishment of tricarboxylic acid (TCA)-cycle substrates) through pyruvate carboxylation and activated fatty acid oxidation, improving mitochondrial nutrients and energy metabolisms in the immature myocardium under conditions emulating ventricular unloading during ECMO (Ledee et al, 2015). Therefore, these extremely high concentrations (2.0 M) and large doses of pyruvate infusion had been known as optimal in preclinical studies and clinical trials (Sharma et al, 2015;Zhou, 2022). Moreover, as an EP alleviation of acute pancreatitis in many studies, a high dose of IV SP (0.25 mg/kg/h for 4 h) infusion vs. NS verified its protection against cerulein-induced acute pancreatitis with a decline of hyperamylasemia and alleviation of histopathological changes in rats (Ziolkowski et al, 2008).…”

“…Furthermore, a high concentration of IV pyruvate (0.1 mmol/kg/min for over 60 min) evidenced its preservation of antiglycation defenses in cerebral protection after cardiac arrest in pigs (Scott et al, 2017). Pyruvate action as an inhibitor of methylglyoxal-induced advanced glycation end products (AGEs), which are one of the triggers in many organ complications of critical illnesses, was subsequently shown in exogenous pyruvate protection against diabetic cataract and diabetic nephropathy (Zhou, 2022). In another study of porcine cardiac arrest with a large dose of IV pyruvate (2.0 M, 0.1 mmol/kg/min for over 60 min with a plasma pyruvate level 4-5 mM), it is worth noting that despite the occurrence of transient hypernatremia after pyruvate infusion, higher blood potassium levels were rapidly maintained close to normal ranges in contrast to NS or 10% NaCl infusion apart from systemic hemodynamics and cerebral function improvements and acidosis correction (Mongan et al, 1999;Cherry et al, 2015).…”

“…Standard and low osmolar WHO-ORS: WHO-ORS consists of four chemicals: sodium bicarbonate, sodium chloride, potassium chloride, and anhydrous glucose with the osmolarity of 331 mOsm/L (WHO-ORS I), which can be easily prepared at home; with the osmolarity of 311 mOsm/L (WHO-ORS II) by equimolar sodium citrate replacement of sodium bicarbonate; and with osmolarity of 245 mOsm/L (WHO-ORS III) in reduced-osmolarity citrate-contained ORS (Pulungsih et al, 2006;Zhou, 2020a;Zhou, 2022). Now, the last one is more popular in clinical use due to its easy absorption from the intestine and a long shelf-life.…”

“…Over the past two decades, pyruvate, as an anion in aqueous solutions of sodium pyruvate, has increasingly shown its unique beneficial bioactive and pharmacological features in the protection of glucometabolic pathways and multiorgan function in various pathogenic insults, such as ischemia-reperfusion injury and/or hemorrhagic, traumatic, and septic shock. Pyruvate may be the optimal expected anion, which is superior to acetate, bicarbonate, chloride, lactate, citrate and even malate, in resuscitation fluids demonstrated in various animal studies on shock treatments, although no clinical resuscitation of shock with pyruvate-based fluids has been yet investigated to date (Zhou, 2020a;Zhou, 2022). Nowadays, the debate on fluids in shock treatments is still ongoing, and the ideal fluid is quite controversial (Zhou, 2022).…”

“…Pyruvate may be the optimal expected anion, which is superior to acetate, bicarbonate, chloride, lactate, citrate and even malate, in resuscitation fluids demonstrated in various animal studies on shock treatments, although no clinical resuscitation of shock with pyruvate-based fluids has been yet investigated to date (Zhou, 2020a;Zhou, 2022). Nowadays, the debate on fluids in shock treatments is still ongoing, and the ideal fluid is quite controversial (Zhou, 2022). This review comprehensively summarized the reports on the inherent advantages of pyruvate-based fluids in preclinical shock resuscitation in the literature.…”