Elevated Blood Lactate Research Articles

Outcome after veno-arterial extracorporeal membrane oxygenation in elderly patients: A 14-year single-center experience.

Use of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in elderly patients is controversial because of presumed poor outcome. Our primary aim was to determine the influence of advanced age on short- and long-term outcome; the secondary aim was to analyze risk factors for impaired outcome. Between January 2006 and June 2020, 645 patients underwent VA-ECMO implantation in our department. The patients were categorized into four groups:<50, 50-59.9, 60-69.9 and ≥70 years old. Data were retrospectively analyzed for short- and long-term outcome. Risk factors for in-hospital mortality and mortality during follow-up were assessed using multivariate regression analysis. VA-ECMO support duration was comparable in all age groups (median 3 days). Weaning rates were 60.8%/n=104 (<50 years), 51.4%/n=90 (50-59.9 years), 58.8%/n=107 (60-69.9), and 67.5%/n=79 (≥70, p=0.048). Hospital mortality was highest in the patients aged 50-59.9 years (68%/n=119), but not in the elderly patients (60-69.9, ≥70:62.1%/n=113, 58,1%/n=68). At discharge, the cerebral performance category scores were superior in the patients <50 years. Multivariate logistic regression analysis revealed chronic kidney failure requiring hemodialysis, duration of cardiopulmonary resuscitation, and elevated blood lactate levels before VA-ECMO, but not age as predictors of in-hospital mortality. Cox's regression disclosed age as relevant risk factor for death during follow-up. The patients' physical ability was comparable in all age groups. VA-ECMO support should not be declined in patients only because of advanced age. Mortality and neurological status at hospital discharge and during follow-up were comparable in all age groups.

Extracorporeal life support in cardiotoxicant poisoning-A narrative review.

Extracorporeal life support (ECLS) improves circulation in life-threatening cardiac dysfunction or arrest patients. Its benefits in drug-induced cardiovascular complications are debated. Indications and outcomes are poorly established. We performed a narrative review discussing ECLS indications, timing and results in cardiotoxicant-poisoned patients. The review was focused on antiarrhythmic drugs and aluminium phosphide. Literature analysis was limited to the past 30 years in adults. Most reports were single cases and retrospective except one prospective case series of limited size, two of them controlled. ECLS indications and timing were at the discretion of physicians in charge but mostly included persistent cardiovascular failure despite elevated doses of inotropic/vasopressor support associated with elevated blood lactate concentrations (usually, >5mmol/L) and collapsed left ventricular ejection fraction (LVEF; usually, ≤40%). Survival improved using ECLS versus standard care in one study. Survival was ~80% if ECLS was implemented in refractory cardiovascular failure and 25%-66% if implemented in cardiac arrest. In two controlled studies, survival of ECLS-treated aluminium phosphide-poisoned patients was improved versus standard care, if implemented in the presence of systolic blood pressure ≤80 mmHg despite inotropic/vasopressor treatment, arterial pH ≤ 7.0 and LVEF ≤ 40%. Despite low-to-moderate level of evidence, ECLS seems effective to improve survival in selected cardiotoxicant-poisoned patients. Selection criteria need clarification.

Effects Of Transdermal Sodium Bicarbonate Lotion On High-intensity Cycling Performance

Pre-exercise oral ingestion of sodium bicarbonate may lead to improved high-intensity exercise performance in trained individuals. However, this practice often causes gastrointestinal distress, which can mitigate the ergogenic benefits. An alternative method of administration involves the delivery of sodium bicarbonate through applying lotion to the surface of the skin surrounding the working muscles. However, few studies have examined the ergogenic benefits of this practice. PURPOSE: To examine the effects of pre-exercise application of a sodium bicarbonate lotion (SBL) on performance during a series of intermittent high-intensity cycling bouts compared to a placebo (PLA). METHODS: In a randomized cross-over fashion, 7 trained cyclists completed a one-hour cycling performance test on a stationary trainer using their personal road bikes on two separate occasions. This protocol consisted series of maximal 5-second (neuromuscular, NM), 5-minute (maximal aerobic, MAP), 20-minute (functional threshold, FTP), and 1-minute (anaerobic capacity, AC) efforts separated by recovery. Performance was determined by the mean power output during each effort. Thirty minutes prior, subjects applied 0.4 g/kg-bw of either SBL or PLA to the quadriceps, hamstrings, and gastrocnemius. Capillary samples were collected at 1-minute and 3-minutes following the MAP, FTP, and AC tests to measure blood lactate. Differences in power output and lactate responses between conditions were tested using Wilcoxon signed-rank tests. RESULTS: There were no differences in power output during the any of the efforts between conditions. In the SBL condition, participants had higher blood lactate concentrations one-minute following the MAP test compared to PLA (p = 0.01, mean dif. = 4.3 mmol/L). CONCLUSION: Our findings suggest that pre-exercise application of SBL did not influence performance in trained cyclists. The elevated blood lactate response to the MAP effort in SBL could indicate enhanced cellular buffering and lactate clearance. Practically, this suggests that SBL could be beneficial prior to shorter time-trials or intervals performed near maximal aerobic capacity. Once the target sample of 16 cyclists have completed the study, we can provide further insight on the ergogenic effects of SBL application in this population.

Factors associated with elevated blood lactate levels in patients undergoing maintenance hemodialysis.

Factors associated with chronic elevation of the blood lactate levels in patients undergoing chronic maintenance hemodialysis (hereinafter, hemodialysis patients) have not yet been thoroughly investigated. The purpose of the present study was to clarify factors associated with elevated blood lactate levels in hemodialysis patients. We divided the hemodialysis patients into two groups according the blood lactate levels (the high blood lactate group [> 2mmol/L] and normal blood lactate group), and conducted a retrospective comparison of the following items between the two groups: (1) the creatinine generation rate (%CGR) and the geriatric nutrition risk index (GNRI) as indices of the nutritional status; (2) the left ventricular ejection fraction (LVEF) and E/A, an indicator of diastolic function; (3) the ankle-brachial index (ABI) and transcutaneous partial pressure of oxygen as indices of the adequacy of circulation in the peripheral blood vessels of the lower extremities; (4) the white blood cell count and serum level of C-reactive protein (CRP) before dialysis as markers of an inflammatory state. The mean age and serum CRP level were significantly higher in the high blood lactate group than in the normal blood lactate group. There were no significant differences in the markers of the nutritional status, cardiac function, or adequacy of circulation in the peripheral blood vessels of the lower extremities between the two groups. Advanced age and a state of chronic inflammation appear to be associated with elevated blood lactate levels in patients undergoing chronic maintenance hemodialysis.

Effects of lactate administration on hypertrophy and mTOR signaling activation in mouse skeletal muscle.

Lactate is a metabolic product of glycolysis and has recently been shown to act as a signaling molecule that induces adaptations in oxidative metabolism. In this study, we investigated whether lactate administration enhanced muscle hypertrophy and protein synthesis responses during resistance exercise in animal models. We used male ICR mice (7–8 weeks old) were used for chronic (mechanical overload induced by synergist ablation: [OL]) and acute (high‐intensity muscle contraction by electrical stimulation: [ES]) resistance exercise models. The animals were intraperitoneally administrated a single dose of sodium lactate (1 g/kg of body weight) in the ES study, and once a day for 14 consecutive days in the OL study. Two weeks of mechanical overload increased plantaris muscle wet weight (main effect of OL: p < 0.05) and fiber cross‐sectional area (main effect of OL: p < 0.05), but those were not affected by lactate administration. Following the acute resistance exercise by ES, protein synthesis and phosphorylation of p70 S6 kinase and ribosomal protein S6, which are downstream molecules in the anabolic signaling cascade, were increased (main effect of ES: p < 0.05), but lactate administration had no effect. This study demonstrated that exogenous lactate administration has little effect on the muscle hypertrophic response during resistance exercise using acute ES and chronic OL models. Our results do not support the hypothesis that elevated blood lactate concentration induces protein synthesis responses in skeletal muscle.

Lymphoma total lesion glycolysis leads to hyperlactatemia and reduction of brain glucose utilization

Clarifying the mechanism of lymphoma-associated hyperlactatemia could help identify patients at risk. Here, 129 non-Hodgkin’s lymphoma patients suspected of blood lactate elevation underwent blood measurement and 18F-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) on the same day. Blood lactate elevation was mild (1.0–2.5 mmol/L) in 60, moderate (2.5–4.0 mmol/L) in 46, and severe (≥ 4.0 mmol/L) in 23 subjects. Subjects with severe lactate elevation had higher lymphoma stage, worse IPI risk, poorer ECOG performance, and higher tumor TLG. Furthermore, there was a linear correlation between blood lactate concentration and lymphoma TLG (Spearman’s r = 0.367; P < 0.0001). Brain FDG uptake was low (SUVave < 4.0) in 81 patients that were older, had greater stage and IPI risk, worse ECOG performance, and higher blood lactate. Brain SUVave showed inverse correlation with blood lactate (Spearman’s r = − 0.564; P < 0.0001) and lymphoma TLG (Spearman’s r = − 0.252; P = 0.0066), as well as with stage, ECOG score, and IPI risk. Multivariable regression analysis confirmed increased blood lactate and lymphoma TLG as significant explanatory variables for reduced brain SUVave (both P < 0.0001). Hence, blood lactate elevation in lymphoma patients is the result of glycolytic tumor burden. Since brain cells prefer lactate over glucose as energy source when blood lactate level is increased, this causes proportional reductions of brain FDG uptake. FDG PET/CT can therefore identify high glycolytic lymphoma burden at risk of hyperlactatemia and may provide estimates of its severity by reductions in brain uptake.

Relationship Between the Anion Gap and Serum Lactate in Hypovolemic Shock.

Background and objectives: Previous studies evaluating patients in the Intensive Care Unit with established lactic acidosis determined that the anion gap is an insensitive screening tool for elevated blood lactate. No prior study has examined the relationship between anion gap and serum lactate within the first hours of the development of lactic acidosis. Design, setting, participants, & measurements: Data were obtained prospectively from a convenience sample of adult trauma patients at a single level 1 trauma center. Venous samples were drawn prior to initiation of intravenous fluid resuscitation. A linear regression model was constructed to assess the relationship between serum lactate and anion gap, and 95% prediction intervals were computed. Logistic regression models were constructed to determine the sensitivity and specificity for several different anion gap and lactate cutpoints. Results: 128 patients with elevated serum lactate levels (>2.1 mmol/L) and 63 patients with normal serum lactate levels (< 2.1 mmol/L) were included. The sensitivity of an elevated anion gap (> 10) to reveal hyperlactatemia was only 43% whereas specificity was 84%. Sensitivity improved if the upper limit of normal anion gap was lowered and with increasing levels of serum lactate. The coefficient of determination between serum lactate level and AG yielded an R2 of 0.30 (p < 0.001) and the slope of this relationship was 2.185 with a 95% confidence interval of 2.011-2.359. The mean 95% prediction interval was + 8.9. Conclusions: Within the first hour of the development of lactic acidosis due to hypovolemic shock, the anion gap was not a sensitive indicator of an elevated serum lactate level, but it was fairly specific. The anion gap increased to a greater extent than the serum lactate, the 95% mean prediction interval was wide and approximately 70% of the change in anion gap could not be explained by increases in serum lactate, suggesting that other anions contribute to the anion gap in lactic acidosis.

Incorporating estuarine-angler behaviour and delayed blood sampling into the rapid assessment of catch-and release angling on the iconic dusky kob Argyrosomus japonicus

Argyrosomus japonicus is arguably South Africa’s most important estuarine recreational and small-scale fishery species. Although juvenile A. japonicus predominate in estuarine environments, where catch-and-release angling is common, limited C&R studies have taken place. The aim of this study was to use angler-behaviour to robustly examine the physiological stress response, reflex impairment and short-term (12–36-hour) survival of A. japonicus following C&R angling. Observations of estuarine recreational angling informed three air exposure treatments based on minimum (10 s), mean (75 s) and maximum (240 s) observed times, for use in a controlled angling experiment. Based on a prior laboratory study, blood sampling was delayed 30–40 min post-capture to allow for peak accumulations of lactate and glucose. Long air exposure (240 s) predicted significantly higher blood glucose concentrations (ANOVA, p = 0.03) than short (10 s) exposure. Similarly, both long (p = 0.01) and moderate (75 s; p = 0.01) air exposure significantly predicted elevated blood lactate concentrations, when compared with short exposure. In terms of physical impairment, long air exposure (240 s) had a significant negative influence on the reflex response (cumulative link model, p = 0.01) of A. japonicus. An observed short-term mortality of 7.7% was primarily attributed to hooking injury. To reduce significant physiological and physical stress, it is proposed that anglers should aim to reduce air exposure times to below the observed mean of 75 s, and ideally to 10 s. For relevant and meaningful future C&R studies, we propound the incorporation of angler behavioural assessments, and the investigation of physiological stress responses, prior to designing field studies.

Augmented muscle deoxygenation during repeated sprint exercise with post‐exercise blood flow restriction

Blood flow restriction (BFR) during low‐intensity exercise has been known to be a potent procedure to alter metabolic and oxygen environments in working muscles. Moreover, the use of BFR during inter‐set rest periods of repeated sprint exercise has been recently suggested to be a potent procedure for improving training adaptations. The present study was designed to determine the effect of repeated sprint exercise with post‐exercise BFR (BFR during rest periods between sprints) on muscle oxygenation in working muscles. Eleven healthy males performed two different conditions on different days: either repeated sprint exercise with BFR during rest periods between sets (BFR condition) or without BFR (CON condition). A repeated sprint exercise consisted of three sets of 3 × 6‐s maximal sprints (pedaling) with 24s rest periods between sprints and 5 min rest periods between sets. In BFR condition, two min of BFR (100–120 mmHg) for both legs was conducted between sets. During the exercise, power output and arterial oxygen saturation (SpO2) were evaluated. Muscle oxygenation for the vastus lateralis muscle, exercise‐induced changes in muscle blood flow, and muscle oxygen consumption were measured. During BFR between sets, BFR condition presented significantly higher deoxygenated hemoglobin + myoglobin (p < 0.01) and lower tissue saturation index (p < 0.01) than those in CON condition. However, exercise‐induced blood lactate elevation and reduction of blood pH did not differ significantly between the conditions. Furthermore, power output throughout nine sprints did not differ significantly between the two conditions. In conclusion, repeated sprint exercise with post‐exercise BFR augmented muscle deoxygenation and local hypoxia, without interfering power output.

Severe lactic acidosis and persistent diastolic hypotension following standard dose of intermittent nebulized salbutamol in a child: a case report

BackgroundSalbutamol is a selective β2-receptor agonist widely used to treat asthma in both emergency and outpatient settings. However, it has been associated with a broad spectrum of side effects. Lactic acidosis and diastolic hypotension are rarely reported together following intermittent salbutamol nebulization in children, even less so at standard therapeutic doses.Case presentationWe present the case of a 12-year-old Italian boy, 34 kg body weight, who experienced a serious drug reaction during a moderate asthma exacerbation with associated dehydration (blood urea nitrogen/creatinine 0.25), following intermittent inhaled (0.2 mg at 3-hour intervals—overall 1.4 mg in 24 hours before arrival) and nebulized treatment (3.25 mg at 20-minute intervals in 60 minutes, overall 11.25 mg in our emergency department). The patient developed hyperglycemia (peak concentration 222 mg/dL), hypokalemia (lowest concentration 2.6 mEq/L), electrocardiogram alterations (corrected QT interval 467 ms), long-lasting arterial hypotension despite fluid boluses (lowest value 87/33 mmHg), and elevated blood lactate levels (peak concentration 8.1 mmol/L), following the third nebulized dose. Infections, liver dysfunction, and toxicity following other medications were ruled out. The aforementioned alterations improved within 24 hours after discontinuation of salbutamol.ConclusionsWe reinforce the message that even the use of intermittent nebulized salbutamol for acute moderate asthma can lead to severe transient complications in children. Then, healthcare providers should pay attention not only in emergency settings, to achieve prompt recognition and proper management of this adverse reaction. Careful reassessment could prevent similar reactions.

Pyruvate Dehydrogenase Deficiency: With More Phenotypes Than We Believe

Introduction: The pyruvate dehydrogenase complex (PDC) is a multienzyme complex responsible for catalyzing the oxidative decarboxylation of pyruvate to Acetyl-CoA. A defect in any of its components can interfere with the production of energy on a cellular level; within these disorders we find pyruvate dehydrogenase (PDH) deficiency characterized by clinical neurological and systemic signs of varying severity, highlighting lactic acidosis, neurological and progressive neuromuscular deterioration. Objective: Describe the case of a female, school aged patient with characteristic craniofacial dysmorphology, neurodevelopmental delay and episodes of metabolic decompensation due to infections, with a mutation in the PDHX gene, treated with a ketogenic diet, thiamine, lipoic acid and carnitine. Results: The findings that made it possible to focus the diagnosis were elevated plasma and CSF lactate levels associated with persistent metabolic acidosis with accentuation of hyper intensity in the cortical sulci and in the in the bilateral basal ganglia and lenticular nuclei region of the brain on magnetic resonance imaging. Magnetic resonance imaging with spectroscopy showed a negative peak of lactate. Confirming the diagnosis with an exome of 6000 genes where a homozygous pathogenic variant is found in the PDHX gene position c.1426C&gt; T. Conclusion: PDH deficiency should be considered in cases of neurodevelopmental delay associated with intermittent episodes of neurological deterioration and elevated blood lactate and as well as elevated lactate in magnetic resonance spectroscopy of the brain. Unlike those affected by other subtypes, patients with E3-binding protein deficiency often survive childhood and even adulthood due to the presence of assembly to a certain extent of some of the pyruvate dehydrogenase complex. Prompt diagnosis opens the possibility of starting early supportive management, providing genetic counseling to parents, as well as establishing prognosis.

Prognostic role of elevated lactate in acute pulmonary embolism: A systematic review and meta-analysis

Background Previous studies have shown elevated lactate was a good predictor for the prognosis of pulmonary embolism (PE). However, due to low number of patients and different expression of blood lactate in separate study, these results are inconsistent. Therefore, the aim of this meta-analysis is to evaluate the relationship between increased lactate levels and adverse outcome in acute PE. Method The literatures search was conducted in PubMed, Web of Science, and EMBASE until May 29, 2021. Results Finally, 6 studies with 1706 patients were included in our meta-analysis. High lactate levels were markedly associated with overall mortality both in unselected PE patients (OR 5.13, 95% CI: 3.36–7.86, p &lt; .00,001) and normotensive PE patients (OR 4.54, 95% CI: 2.64–7.80, p &lt; .00,001), and PE-related short-term mortality in patients with elevated lactate was significantly higher than that in patients with normal levels (OR 9.05, 95% CI :4.08–20.10, p &lt; .00,001). The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of lactate for predicting overall mortality in patients with acute PE were 0.67 (95% CI: 0.43–0.85), 0.73 (95% CI: 0.60–0.83), 2.5 (95% CI: 2.0–3.1), and 0.45 (95% CI: 0.26–0.78), respectively. The area under SROC curve (AUC) was 0.76 (95% CI: 0.73–0.80). Conclusion The result of our meta-analysis indicate that elevated blood lactate is a good predictor for overall mortality and short-term mortality in patients with acute PE, and can be routinely measured in risk stratification, but its prognostic role in patients with different risk classes still need to be verified.

M.3685T > C is a novel mitochondrial DNA variant that causes Leigh syndrome.

Variants in the mitochondrial genome can result in dysfunction of Complex I within the electron transport chain, thus causing disruptions in oxidative phosphorylation. Pathogenic variants in the MT-ND1 (NADH:ubiquinone oxidoreductase core subunit 1) gene that result in Complex I dysfunction are a known cause of Leigh syndrome. The patient is a 4-yr-old female who initially presented with generalized tonic–clonic seizures, with other symptoms of Leigh syndrome becoming apparent after the seizures. A three-generation pedigree revealed no family history of mitochondrial disorders. Laboratory studies were remarkable for elevated blood lactate, alanine, and GDF15. T2-weighted magnetic resonance imaging (MRI) revealed bilateral asymmetric signal hyperintensities in the basal ganglia, specifically in the bilateral putamen and right caudate. Magnetic resonance spectroscopy showed regionally elevated glucose and lactate. Mitochondrial respiratory chain enzyme analysis on skin fibroblasts demonstrated slightly reduced Complex I function. A 16-gene dystonia panel and chromosomal microarray analysis did not identify any disease-causing variants. Combined exome and mitochondrial genome sequencing identified the m.3685T > C (MT-ND1 p.Tyr127His) variant with 62.3% heteroplasmy with no alternative cause for the patient's condition. Mitochondrial genome sequencing of the mother demonstrated that the m.3685T > C variant occurred de novo. The m.3685T > C variant is absent from population databases. The tyrosine 127 residue is highly conserved, and several nearby pathogenic variants in the MT-ND1 gene have been previously associated with Leigh syndrome. We propose that the m.3685T > C variant is a novel mitochondrial DNA variant that causes Leigh syndrome, and we classify this variant as likely pathogenic based on currently available information.

Clinical observations of Leber hereditary optic neuropathy with and without neurological symptoms

Three case studies of adults with Leber hereditary optic neuropathy with and without neurological symptoms are presented. An elevated blood lactate level and changes in the activity of the mitochondrial enzymes in peripheral blood lymphocytes were noted. Mutations in the mitochondrial DNA (G3460A in one patient and G11778A in two patients) were found. The patient with a G3460A mutation, in addition to reduced visual acuity, was diagnosed with a cerebellar disorder due to cerebellar vermis hypoplasia. These changes are indications for prescribing energotropic drugs (idebenone, carnitine); carnosine can also be prescribed. These case studies show that patients with optic nerve atrophy should be assessed for Leber hereditary optic neuropathy. Differential diagnosis with multiple sclerosis should be performed, since this condition often presents as optic neuropathy.

Extracellular Lactate Acts as a Metabolic Checkpoint and Shapes Monocyte Function Time Dependently.

Elevated blood lactate levels are frequently found in critically ill patients and thought to result from tissue hypoperfusion and cellular oxygen shortage. Considering the close relationship between immune cell function and intracellular metabolism, lactate is more than a glycolytic waste molecule but able to regulate the immune response. Our aim was to elucidate the temporal and mechanistic effect of extracellular lactate on monocytes. To this end, primary human monocytes and the human monocytic cell line MonoMac6 were stimulated with various toll-like-receptor agonists after priming with Na-L-lactate under constant pH conditions. As readout, cytokine production was measured, real-time assessment of intracellular energy pathways was performed, and intracellular metabolite concentrations were determined. Irrespective of the immunogenic stimulus, short-term Na-lactate-priming strongly reduced cytokine production capacity. Lactate and hexoses accumulated intracellularly and, together with a decreased glycolytic flux, indicate a lactate-triggered impairment of glycolysis. To counteract intracellular hyperglycemia, glucose is shunted into the branching polyol pathway, leading to sorbitol accumulation. In contrast, long-term priming with Na-L-lactate induced cellular adaption and abolished the suppressive effect. This lactate tolerance is characterized by a decreased cellular respiration due to a reduced complex-I activity. Our results indicate that exogenous lactate shapes monocyte function by altering the intracellular energy metabolism and acts as a metabolic checkpoint of monocyte activation.

Physiologic cardiovascular studies in resuscitated normotensive septic shock with persistent hyperlactatemia.

Background: To study effects of increasing vasopressor dosage and fluid resuscitation on ventriculoarterial (VA) coupling and venous return (VR)-related parameters in resuscitated normotensive septic shock patients with persistent hyperlactatemia. Methods: We performed a prospective experimental study in patients with septic shock who was admitted to medical intensive care unit and still had hyperlactatemia even received initial resuscitation to maintain mean arterial pressure (MAP) &gt;65 mmHg. All patients received incremental dose of norepinephrine (NE) to increased MAP, then NE was titrated to baseline dosage and waited for 15 mins, then fluid bolus was given. VA coupling-related parameters [arterial elastance (Ea), left ventricular end-systolic elastance (Ees), left ventricular stroke work (SW), potential energy (PE), stroke volume (SV), and Ea/Ees], and VR-related parameters [central venous pressure (CVP), mean systemic pressure analogue (Pmsa), venous return pressure (Pvr)] were measured at 4 time points including pre-increased NE phase, post-increased NE phase, pre-fluid bolus phase, and post-fluid bolus phase. Primary outcome was average of Ea/Ees. Secondary outcomes were differences in VA coupling-related parameters and VR-related parameters between pre- vs. post- interventions. Results: All 20 patients were normotensive [MAP 74 (66-80) mmHg] with elevated blood lactate [2.7 (2.4-3.6) mmol/L] at enrollment. Average Ea/Ees was 0.89 (0.61-1.16). Compared to pre-increased NE phase, post-increased NE phase had significantly higher MAP, CVP, SV, SW, PE, Pmsa, and Pvr. Likewise, compared to pre-fluid bolus phase, post-fluid bolus raised MAP, CVP, SV, Ees, SW, Pmsa, and Pvr significantly. No difference in Ea/Ees compared between before- vs. after- received both interventions. Conclusions: In resuscitated normotensive septic shock patients with persistent hyperlactatemia, we found an average Ea/Ees of 0.89. Increasing NE dosage or fluid bolus increased most of VA coupling-related parameters and VR-related parameters, but not Ea/Ees. Further large study is warranted to validate these findings.

The Role of Acidosis in the Pathogenesis of Severe Forms of COVID-19.

Simple SummaryRecently, several studies have shown that acidosis, which is increased acidity in the blood and other body tissues, is often associated with severe COVID-19. In this article, we look at the mechanisms and consequences of acidosis that can lead to an exacerbation of COVID-19. We want to draw the attention of readers to the threshold values of such disease characteristics as hypoxia and acidosis, which are associated with a sharp deterioration in the patient’s condition. Hypoxia and acidosis mutually reinforce each other according to the principle of a vicious cycle (that is, they are involved in a system of positive feedbacks). Elevated blood lactate (lactic acid) levels are associated with poor clinical outcomes in COVID patients. As a practical recommendation, we propose to pay more attention to the prevention of acidosis, including in the early stages of the disease, when the adjustment of homeostasis requires less effort and is less risky.COVID-19 has specific characteristics that distinguish this disease from many other infections. We suggest that the pathogenesis of severe forms of COVID-19 can be associated with acidosis. This review article discusses several mechanisms potentially linking the damaging effects of COVID-19 with acidosis and shows the existence of a vicious cycle between the development of hypoxia and acidosis in COVID-19 patients. At the early stages of the disease, inflammation, difficulty in gas exchange in the lungs and thrombosis collectively contribute to the onset of acidosis. In accordance with the Verigo-Bohr effect, a decrease in blood pH leads to a decrease in oxygen saturation, which contributes to the exacerbation of acidosis and results in a deterioration of the patient’s condition. A decrease in pH can also cause conformational changes in the S-protein of the virus and thus lead to a decrease in the affinity and avidity of protective antibodies. Hypoxia and acidosis lead to dysregulation of the immune system and multidirectional pro- and anti-inflammatory reactions, resulting in the development of a “cytokine storm”. In this review, we highlight the potential importance of supporting normal blood pH as an approach to COVID-19 therapy.

ATPAF1 deficiency impairs ATP synthase assembly and mitochondrial respiration

ATP11p and ATP12p are two nuclear-encoded mitochondrial chaperone proteins required for assembling the F1Fo-ATP synthase F1 sector. ATPAF1 and ATPAF2 are the mammalian homologs of ATP11p and ATP12p. However, the biochemical and physiological relevance of ATPAF1 and ATPAF2 in animal tissues with high energy-dependence remains unclear. To explore the in vivo role of ATP assembly and the effects of ATP synthase deficiency in animals, we have generated knockout (KO) mouse models of these assembly factors using CRISPR/Cas9 technology. While the Atpaf2-KO mice were embryonically lethal, Atpaf1-KO mice grew to adulthood but with smaller body sizes and elevated blood lactate later in life. We specifically investigated how ATPAF1 deficiency may affect ATP synthase biogenesis and mitochondrial respiration in the mouse heart, an organ highly energy-dependent. Western blots and Blue-Native electrophoresis (BN-PAGE) demonstrated a decreased F1 content and ATP synthase dimers in the Atpaf1-KO heart. Mitochondria from ATPAF1-deficient hearts showed ultrastructural abnormalities with condensed degenerated mitochondria, loss of cristae, and impaired respiratory capacity. ATP synthase deficiency also leads to impaired autophagy and mitochondrial dynamic. Consequently, decreased cardiac function was exhibited in adult Atpaf1-KO mice. The results provide strong support that ATPAF1 is essential for ATP synthase assembly and mitochondrial oxidative phosphorylation, thus playing a crucial role in maintaining cardiac structure and function in animals.

The role of lactate in sepsis and COVID-19: Perspective from contracting skeletal muscle metabolism.

New Findings What is the topic of this review? Lactate is considered an important substrate for mitochondria in the muscles, heart and brain during exercise and is the main gluconeogenetic precursor in the liver and kidneys. In this light, we review the (patho)physiology of lactate metabolism in sepsis and coronavirus disease 2019 (COVID‐19). What advances does it highlight? Elevated blood lactate is strongly associated with mortality in septic patients. Lactate seems unrelated to tissue hypoxia but is likely to reflect mitochondrial dysfunction and high adrenergic stimulation. Patients with severe COVID‐19 exhibit near‐normal blood lactate, indicating preserved mitochondrial function, despite a systemic hyperinflammatory state similar to sepsis. In critically ill patients, elevated plasma lactate is often interpreted as a sign of organ hypoperfusion and/or tissue hypoxia. This view on lactate is likely to have been influenced by the pioneering exercise physiologists around 1920. August Krogh identified an oxygen deficit at the onset of exercise that was later related to an oxygen ‘debt’ and lactate accumulation by A. V. Hill. Lactate is considered to be the main gluconeogenetic precursor in the liver and kidneys during submaximal exercise, but hepatic elimination is attenuated by splanchnic vasoconstriction during high‐intensity exercise, causing an exponential increase in blood lactate. With the development of stable isotope tracers, lactate has become established as an important energy source for muscle, brain and heart tissue, where it is used for mitochondrial respiration. Plasma lactate > 4 mM is strongly associated with mortality in septic shock, with no direct link between lactate release and tissue hypoxia. Herein, we provide evidence for mitochondrial dysfunction and adrenergic stimulation as explanations for the sepsis‐induced hyperlactataemia. Despite profound hypoxaemia and intense work of breathing, patients with severe coronavirus disease 2019 (COVID‐19) rarely exhibit hyperlactataemia (> 2.5 mM), while presenting a systemic hyperinflammatory state much like sepsis. However, lactate dehydrogenase, which controls the formation of lactate, is markedly elevated in plasma and strongly associated with mortality in severe COVID‐19. We briefly review the potential mechanisms of the lactate dehydrogenase elevation in COVID‐19 and its relationship to lactate metabolism based on mechanisms established in contracting skeletal muscle and the acute respiratory distress syndrome.

Blood Lactate Level Evolution during Lung Transplantation

<h3>Purpose</h3> Lactic acidosis has been recently propose as independently associated with longer intubation times and length of stay in lung transplantation(1). However, there is no data on the association between elevated blood lactate concentration (BLC) and grade 3 primary graft dysfunction at day 3 after lung transplantation (PGD3). The purpose of the study was to investigate the profile of BLC during double-lung transplantation and it association with PGD3. <h3>Methods</h3> We performed a retrospective observational study of all bilateral lung transplantations at the Foch Hospital from January 2012 to December 2019, excluding those on bridge-to-transplantation, under cardiopulmonary bypass, and multiple-organ transplantation. BLC was measured at every key time of the invention: initially, at every pulmonary artery clamping or declamping, and at end-surgery stage. The ethical committee of the French Society of Anesthesia and Critical Care (SFAR) approved the study. The evolution of intraoperative BLC was evaluated with a paired T-test with Holm correction to compare lactate. AUC was constructed to determine Sp and Se. The optimal threshold of lactates variable used for separation of PGD3 was calculated using the Youden-index. <h3>Results</h3> Over 478 patients were included, 83 (17.3%) had a PGD3. BLC evolution during surgery is illustrated in figure 1. The median of BLC at end-surgery was 2 [1.5 - 3.1] and 3.3 [2.4 - 4.9] mmol/L in no PGD3 and PGD3 groups respectively, p = 0.02. BLC kinetic illustrated by its variability was the best predictive factor of PGD3 (AUC=0.84, Se=77.03, Sp=79.82%). <h3>Conclusion</h3> Hyperlactatemia reflects anaerobic metabolism during peroperative hemodynamic unstable conditions and poor oxygen exchange after implantation of the grafts. Blood lactate variability during surgery is associated with PGD3.1. Worrell SG, et al. Is Lactic Acidosis After Lung Transplantation Associated With Worse Outcomes The Annals of Thoracic Surgery. 2020 Aug;110(2):434-40.