Significado biológico y utilidad clínica del lactato en la sepsis / Biological significance and clinical utility of lactate in sepsis

La sepsis es un problema global de salud y la progresión hacia el shock séptico se asocia con un incremento marcado de la morbimortalidad. En este escenario, el aumento del lactato plasmático demostró ser un indicador de gravedad y un predictor de mortalidad, y suele interpretarse casi exclusivamente como marcador de baja perfusión tisular. Sin embargo, últimamente se produjo un cambio de paradigma en la exégesis del metabolismo y propiedades biológicas del lactato. En efecto, la adaptación metabólica al estrés, aun con adecuado aporte de oxígeno, puede justificar la elevación del lactato circulante. Asimismo, otras consecuencias fisiopatológicas de la sepsis, como la disfunción mitocondrial, se asocian con el desarrollo de hiperlactatemia sin que necesariamente se acompañen de baja perfusión tisular. Interpretar el origen y la función del lactato puede resultar de suma utilidad clínica en la sepsis, especialmente cuando sus niveles circulantes fundamentan las medidas de reanimación.

Sepsis is a global health problem; progression to septic shock is associated with a marked increase in morbidity and mortality. In this setting, increased plasma lactate levels demonstrated to be an indicator of severity and a predictor of mortality, and are usually interpreted almost exclusively as a marker of low tissue perfusion. However, a recent paradigm shift has occurred in the exegesis of lactate metabolism and its biological properties. Indeed, metabolic adaptation to stress, even with an adequate oxygen supply, may account for high circulating lactate levels. Likewise, other pathophysiological consequences of sepsis, such as mitochondrial dysfunction, are associated with the development of hyperlactatemia, which is not necessarily accompanied by low tissue perfusion. Interpreting the origin and function of lactate may be of great clinical utility in sepsis, especially when circulating lactate levels are the basis for resuscitative measures.

A Case of Transient Hyperlactatemia Induced by Intravenous Glycerol Administration in a Patient With Brain Trauma.

Elevated lactate levels are associated with a poor prognosis in patients with sepsis and shock. Intravenous glycerol administration is often used in Japan to treat patients with acute stroke or brain trauma, but such treatment can cause elevated lactate levels. We experienced a case of transient hyperlactatemia induced by intravenous glycerol administration in a patient with brain trauma. A 74-year-old woman underwent decompressive craniotomy because of loss of consciousness and brain edema. Glycerol was administered after the operation for management of the brain edema. Although the patient's hemodynamics remained stable, her lactate level decreased and increased repeatedly. We recognized that the elevation in her lactate level was associated with the administration of intravenous glycerol. This case suggests that intravenous glycerol administration can induce transient hyperlactatemia.

Effects of exogenous lactate on lipid, protein, and glucose metabolism-a randomized crossover trial in healthy males.

Lactate may inhibit lipolysis and thus enhance insulin sensitivity, but there is a lack of metabolic human studies. This study aimed to determine how hyperlactatemia affects lipolysis, glucose- and protein metabolism, and insulin sensitivity in healthy men. In a single-blind, randomized, crossover design, eight healthy men were studied after an overnight fast on two occasions: 1) during a sodium-lactate infusion (LAC) and 2) during a sodium-matched NaCl infusion (CTR). Both days consisted of a 3-h postabsorptive period followed by a 3-h hyperinsulinemic-euglycemic clamp (HEC). Lipolysis rate, endogenous glucose production (EGP), and delta glucose rate of disappearance (ΔRdglu) were evaluated using [9,10-3H]palmitate and [3-3H]glucose tracers. In addition, whole body- and forearm protein metabolism was assessed using [15N]phenylalanine, [2H4]tyrosine, [15N]tyrosine, and [13C]urea tracers. In the postabsorptive period, plasma lactate increased to 2.7 ± 0.5 mmol/L during LAC vs. 0.6 ± 0.3 mmol/L during CTR (P < 0.001). In the postabsorptive period, palmitate flux was 30% lower during LAC compared with CTR (84 ± 32 µmol/min vs. 120 ± 35 µmol/min, P = 0.003). During the HEC, palmitate flux was suppressed similarly during both interventions (P = 0.7). EGP, ΔRdglu, and M value were similar during LAC and CTR. During HEC, LAC increased whole body phenylalanine flux (P = 0.02) and protein synthesis (P = 0.03) compared with CTR; LAC did not affect forearm protein metabolism compared with CTR. Lactate infusion inhibited lipolysis by 30% under postabsorptive conditions but did not affect glucose metabolism or improve insulin sensitivity. In addition, whole body phenylalanine flux was increased. Clinical trial registrations: NCT04710875.NEW & NOTEWORTHY Lactate is a decisive intermediary metabolite, serving as an energy substrate and a signaling molecule. The present study examines the effects of lactate on substrate metabolism and insulin sensitivity in healthy males. Hyperlactatemia reduces lipolysis by 30% without affecting insulin sensitivity and glucose metabolism. In addition, hyperlactatemia increases whole body amino acid turnover rate.

Association between lactic acidosis and multiple organ dysfunction syndrome after cardiopulmonary bypass.

Background: The relationship between hyperlactatemia and prognosis after cardiopulmonary bypass (CPB) is controversial, and some studies ignore the presence of lactic acidosis in patients with severe hyperlactacemia. This study explored the association between lactic acidosis (LA) and the occurrence of multiple organ dysfunction syndrome (MODS) after cardiopulmonary bypass. Methods: This study was a post hoc analysis of patients who underwent cardiac surgery between February 2017 and August 2018 and participated in a prospective study at Taizhou Hospital. The data were collected at: ICU admission (H0), and 4, 8, 12, 24, and 48 h after admission. Blood lactate levels gradually increased after CPB, peaking at H8 and then gradually decreasing. The patients were grouped as LA, hyperlactatemia (HL), and normal control (NC) based on blood test results 8 h after ICU admission. Basic preoperative, perioperative, and postoperative conditions were compared between the three groups, as well as postoperative perfusion and oxygen metabolism indexes. Results: There were 22 (19%), 73 (64%), and 19 (17%) patients in the LA, HL, and NC groups, respectively. APACHE II (24h) and SOFA (24h) scores were the highest in the LA group (P < 0.05). ICU stay duration was the longest for the LA group (48.5 (42.5, 50) h), compared with the HL (27 (22, 48) h) and NC (27 (25, 46) h) groups (P = 0.012). The LA group had the highest incidence of MODS (36%), compared with the HL (14%) and NC (5%) groups (P = 0.015). In the LA group, the oxygen extraction ratio (O2ER) was lower (21.5 (17.05, 32.8)%) than in the HL (31.3 (24.8, 37.6)%) and the NC group (31.3 (29.0, 35.4) %) (P = 0.018). In the univariable analyses, patient age (OR = 1.054, 95% CI [1.003-1.109], P = 0.038), the LA group (vs. the NC group, (OR = 10.286, 95% CI [1.148-92.185], P = 0.037), and ΔPCO2 at H8 (OR = 1.197, 95% CI [1.022-1.401], P = 0.025) were risk factor of MODS after CPB. Conclusions: We speculated that there was correlation between lactic acidosis and MODS after CPB. In addition, LA should be monitored intensively after CPB.

Exploring the relationship between hyperlactatemia and anemia.

Hyperlactatemia and anemia commonly coexist and their crosstalk is a longstanding mystery with elusive mechanisms involved in physical activities, infections, cancers, and genetic disorders. For instance, hyperlactatemia leads to iron restriction by upregulating hepatic hepcidin expression. Increasing evidence also points to lactate as a crucial signaling molecule rather than merely a metabolic byproduct. Here, we discuss the mutual influence between anemia and hyperlactatemia. This opinion calls for a reconsideration of the multifaceted roles of lactate and lactylation in anemia and emphasizes the need to fill knowledge gaps, including the dose dependence of lactate's effects, its sources, and its subcellular localization.

Adverse Impact of Sodium Bicarbonate Administration on Multiple Outcomes in Acute Pancreatitis Patients With Hyperlactatemia.

OBJECTIVE: Hyperlactatemia is likely to occur among patients with acute pancreatitis (AP). Sodium bicarbonate (SB) therapy could be applied to correct potential detrimental acidic disturbances, but the exact impact of SB treatment is unknown. This study aims to investigate the impact of SB on AP patients complicated with hyperlactatemia. METHODS: The study was conducted based on the database named Medical Information Mart for Intensive Care-IV (MIMIC-IV). Propensity matching (PSM) and inverse probability weighting (IPTW) were used to balance the baseline differences. Multivariate regression and marginal structural Cox models were performed to investigate the association between SB and multiple outcomes. RESULTS: Three hundred fifty-three AP patients with hyperlactatemia (initial serum lactate, >2.0 mmol/L) were extracted from the MIMIC-IV database. We found that SB treatment was significantly associated with worse multi-outcomes of AP patients with hyperlactatemia (in-hospital mortality: hazard ratio, 2.46; 95% confidence interval, 1.38-4.39; P < 0.01). Further analysis through marginal structural Cox models showed that SB had adverse impact on in-hospital prognosis of patients with severe lactic acidosis (pH < 7.15,lactate > 2.0 mmol/L). CONCLUSION: Sodium bicarbonate might not be an appropriate treatment for AP patients with hyperlactatemia (lactate > 2.0 mmol/L) or with severe lactic acidosis (pH < 7.15, lactate > 2.0 mmol/L).

Biological significance and clinical utility of lactate in sepsis. / Significado biológico y utilidad clínica del lactato en la sepsis.

Sepsis is a global health problem; progression to septic shock is associated with a marked increase in morbidity and mortality. In this setting, increased plasma lactate levels demonstrated to be an indicator of severity and a predictor of mortality, and are usually interpreted almost exclusively as a marker of low tissue perfusion. However, a recent paradigm shift has occurred in the exegesis of lactate metabolism and its biological properties. Indeed, metabolic adaptation to stress, even with an adequate oxygen supply, may account for high circulating lactate levels. Likewise, other pathophysiological consequences of sepsis, such as mitochondrial dysfunction, are associated with the development of hyperlactatemia, which is not necessarily accompanied by low tissue perfusion. Interpreting the origin and function of lactate may be of great clinical utility in sepsis, especially when circulating lactate levels are the basis for resuscitative measures.

La sepsis es un problema global de salud y la progresión hacia el shock séptico se asocia con un incremento marcado de la morbimortalidad. En este escenario, el aumento del lactato plasmático demostró ser un indicador de gravedad y un predictor de mortalidad, y suele interpretarse casi exclusivamente como marcador de baja perfusión tisular. Sin embargo, últimamente se produjo un cambio de paradigma en la exégesis del metabolismo y propiedades biológicas del lactato. En efecto, la adaptación metabólica al estrés, aun con adecuado aporte de oxígeno, puede justificar la elevación del lactato circulante. Asimismo, otras consecuencias fisiopatológicas de la sepsis, como la disfunción mitocondrial, se asocian con el desarrollo de hiperlactatemia sin que necesariamente se acompañen de baja perfusión tisular. Interpretar el origen y la función del lactato puede resultar de suma utilidad clínica en la sepsis, especialmente cuando sus niveles circulantes fundamentan las medidas de reanimación.

ATAD3A gene variations in a family with Harel-Yoon syndrome. / Harel-Yoon综合征一家系临床表型及ATAD3AåŸºå› å˜å¼‚åˆ†æž.

An 11-day-old female neonate was admitted for cough with mouth foaming and feeding difficulties. The laboratory results indicated hyperlactatemia, elevated markers of myocardial injury and inflammation, and high levels of acylcarnitine octanoylcarnitine and decanoylcarnitine in tandem mass spectrometry. Ultrasonography and MRI suggested cardiac insufficiency and hypertrophic cardiomyopathy. Whole exome sequencing showed that both the proband and her elderly sister had a compound heterozygous variant of c.1492dup (p.T498Nfs*13) and c.1376T>C (p.F459S) in the ATAD3A gene, inherited from their father and mother, respectively. The diagnosis of Harel-Yoon syndrome was confirmed. The proband and her sister were born with clinical manifestations of metabolic acidosis, hyperlactatemia, feeding difficulties, elevated markers of myocardial injury as well as cardiac insufficiency, and both died in early infancy.

Association between initial microcirculation disturbance patients and mortality in patients who are critically ill: A retrospective cohort study.

Impact of microcirculation status from mortality of critically ill population has been investigated for decades, but the prognosis of early initial microcirculation disturbance in critically ill population in the intensive care unit remains to be explored. The cohort study was conducted using the medical information database for intensive care IV. Critically ill adult in intensive care unit have been enrolled and categorized by early microcirculation status. Cox Proportional-Hazards models have been utilized for testing intermediaries and assess the relationship between combined early initial microcirculation disturbance and mortality. Several 2286 patients were initially screened. Some patients with a highest lactate level >2.2 mmol/L on the firstly day of admission (n = 1468) were then extracted for further analysis. 735 patients received in the initial microcirculation disturbance group as well as 733 patients were in the hyperlactatemia group. In those with elevated lactate, the 28-day mortality of early microcirculation disturbance was higher than that of hyperlactatemia alone (7-day mortality [16.19% vs 12.68%; Adjusted hazard ratio 1.35, 95% confidence intervals 1.03 to 1.78, P = .029], 28-day mortality [33.33% vs 27.28%; adjusted HR 1.34, 95% confidence interval 1.11 to 1.67, P = .002]). Early microcirculatory disturbances (increased PV-ACO2/CA-VO2 ratio and higher initial blood lactate level) were more reliable predictors of in-hospital mortality than early isolated lactate elevation.

The Warburg effect in patients with brain tumors: a comprehensive analysis of clinical significance.

PURPOSE: The Warburg Effect, referring to an elevation in serum lactate level attributable to increased tumor metabolism, is present in patients with brain tumors. This study comprehensively analyzes the Warburg effect in patients undergoing brain tumor resection. METHODS: We retrospectively analyzed the baseline intraoperative serum lactate levels of 2,053 patients who underwent craniotomies, including 415 with cerebral aneurysms and 1,638 with brain tumors. The brain tumor group was divided into subgroups based on the tumor pathology (extra-axial and intra-axial tumor) and the WHO tumor grade (high-grade and low-grade). RESULTS: Serum lactate level was significantly higher in the tumor group than in the aneurysm group (1.98 ± 0.97 vs. 1.09 ± 0.57 mmol/L, p < 0.001). The hyperlactatemia incidence (serum lactate level > 2.2 mmol/L) was higher in the tumor group (33.5 vs. 3.1%, p < 0.001). Severe hyperlactatemia (serum lactate level > 4.4 mmol/L) was found in 34 patients (2.1%) of only the tumor group. In patients with intra-axial tumors, serum lactate level was greater in high- than low-grade tumors (2.10 ± 1.05 vs. 1.88 ± 0.92 mmol/L, p = 0.006). Factors predictive of hyperlactatemia included supratentorial tumor location (odds ratio[95%CI] 2.926[2.127-4.025], p < 0.001) and a long tumor diameter (1.071[1.007-1.139], p = 0.028). In high-grade intra-axial brain tumor patients, there was a significant difference in overall survival between patients with hyperlactatemia than those without (p = 0.048). CONCLUSION: Our results show that brain tumor patients exhibit the Warburg effect and serum lactate may be a useful diagnostic and prognostic biomarker in patients with high-grade intra-axial brain tumors.

Relationship between peripheral ischemic microvascular reserve, persistent hyperlactatemia, and its temporal dynamics in sepsis: a post hoc study.

OBJECTIVE: To measure the prognostic value of peripheral ischemic microvascular reserve in the context of persistent sepsis-induced hyperlactatemia and measure its influence on the temporal dynamics of lactate and the strength of association between these variables. METHODS: This post hoc analysis of the peripheral perfusion index/postocclusive reactive hyperemia trial, an observational cohort study that enrolled patients with sepsis who persisted with lactate levels ≥ 2mmol/L after fluid resuscitation (with or without shock). Peripheral ischemic microvascular reserve was evaluated using the association of the peripheral perfusion index and postocclusive reactive hyperemia techniques. The cutoff point of ∆ peripheral perfusion index peak values (%) defined the groups with low (≤ 62%) and high peripheral ischemic microvascular reserve (> 62%). RESULTS: A total of 108 consecutive patients with persistent sepsis-induced hyperlactatemia were studied. The high peripheral ischemic microvascular reserve group showed higher 28-day mortality than the low peripheral ischemic microvascular reserve group (p < 0.01). The temporal dynamics of lactate within the first 48 hours showed a rapid decrease in lactate levels in the low peripheral ischemic microvascular reserve group (p < 0.01). However, this result was not reproduced in the linear mixed effects model. A weak correlation between peripheral ischemic microvascular reserve (%) and lactate level (mmol/L) was observed within the first 24 hours (r = 0.23; p < 0.05). CONCLUSION: The prognostic value of high peripheral ischemic microvascular reserve was confirmed in the context of persistent sepsis-induced hyperlactatemia. Although there was a weak positive correlation between peripheral ischemic microvascular reserve value and lactate level within the first 24 hours of sepsis diagnosis, the low peripheral ischemic microvascular reserve group appeared to have a faster decrease in lactate over the 48 hours of follow-up.

The relationship between hyperglycaemia on admission and patient outcome is modified by hyperlactatemia and diabetic status: a retrospective analysis of the eICU collaborative research database.

Both blood glucose and lactate are well-known predictors of organ dysfunction and mortality in critically ill patients. Previous research has shown that concurrent adjustment for glucose and lactate modifies the relationship between these variables and patient outcomes, including blunting of the association between blood glucose and patient outcome. We aim to investigate the relationship between ICU admission blood glucose and hospital mortality while accounting for lactate and diabetic status. Across 43,250 ICU admissions, weighted to account for missing data, we assessed the predictive ability of several logistic regression and generalised additive models that included blood glucose, blood lactate and diabetic status. We found that inclusion of blood glucose marginally improved predictive performance in all patients: AUC-ROC 0.665 versus 0.659 (p = 0.005), with a greater degree of improvement seen in non-diabetics: AUC-ROC 0.675 versus 0.663 (p < 0.001). Inspection of the estimated risk profiles revealed the standard U-shaped risk profile for blood glucose was only present in non-diabetic patients after controlling for blood lactate levels. Future research should aim to utilise observational data to estimate whether interventions such as insulin further modify this effect, with the goal of informing future RCTs of interventions targeting glycaemic control in the ICU.

Association between elevated lactate and clinical outcomes in adults with diabetic ketoacidosis.

PURPOSE: To assess the occurrence of hyperlactatemia among patients admitted to the intensive care unit (ICU) with diabetic ketoacidosis (DKA), and effect on in-hospital mortality. MATERIALS AND METHODS: A retrospective, multicentre, cohort study of adult patients admitted to ICU with a primary diagnosis of DKA in Australia and New Zealand, utilising a pre-existing dataset. The primary exposure variable was lactate, dichotomised into normolactatemia (lactate <2.0 mmol/L) and hyperlactatemia (lactate ≥ 2.0 mmol/L) groups. The primary outcome was in-hospital mortality. Secondary outcomes included ICU and hospital length of stay (LOS), requirement for ventilation, renal replacement therapy (RRT) and inotropes. RESULTS: The final dataset included 9061 patients. Hyperlactatemia was associated with in-hospital mortality (Odds Ratio [OR] 1.785 (95% CI 1.122-2.841, p = 0.014), hospital LOS (Geometric mean ratio [GMR] 1.063, 95% CI 1.025-1.103, p = 0.001), ICU LOS (GMR 1.057, 95% CI 1.026-1.09. p < 0.001), RRT (OR 2.198, 95% CI 1.449-3.334, p < 0.001) and inotropes (OR 1.578, 95% CI 1.311-1.899, p < 0.001). These associations persisted in Type 2 but not Type 1 diabetics. CONCLUSIONS: Hyperlactatemia in patients admitted to ICU with DKA is associated with higher mortality, longer hospital and ICU LOS, and higher rates of mechanical ventilation, RRT and inotropes.

Lactate modulates iron metabolism by binding soluble adenylyl cyclase.

Overproduction of lactate (LA) can occur during exercise and in many diseases such as cancers. Individuals with hyperlactatemia often display anemia, decreased serum iron, and elevated hepcidin, a key regulator of iron metabolism. However, it is unknown whether and how LA regulates hepcidin expression. Here, we show LA binds to soluble adenylyl cyclase (sAC) in normal hepatocytes and affects systemic iron homeostasis in mice by increasing hepcidin expression. Comprehensive in vitro, in vivo, and in silico experiments show that the LA-sAC interaction raises cyclic adenosine monophosphate (cAMP) levels, which activates the PKA-Smad1/5/8 signaling pathway to increase hepcidin transcription. We verified this regulatory axis in wild-type mice and in mice with disordered iron homeostasis. LA also regulates hepcidin in humans at rest and subjected to extensive exercise that produce elevated LA. Our study links hyperlactatemia to iron deficiency, offering a mechanistic explanation for anemias seen in athletes and patients with lactic acidosis.

Targeted therapy using polymyxin B hemadsorption in patients with sepsis: a post-hoc analysis of the JSEPTIC-DIC study and the EUPHRATES trial.

BACKGROUND: Polymyxin B hemadsorption (PMX-HA) reduces blood endotoxin levels, but characteristics of patients with sepsis likely to benefit from PMX-HA are not well known. We sought to identify patient subgroups likely to benefit from PMX-HA. METHODS: We retrospectively identified 1911 patients with sepsis from a retrospective observational study in Japan (the JSEPTIC-DIC study) and 286 patients with endotoxemic septic shock from a randomized controlled trial in North America that restricted patients to those with high endotoxin activity (the EUPHRATES trial). We applied the machine learning-based causal forest model to the JSEPTIC-DIC cohort to investigate heterogeneity in treatment effects of PMX-HA on 28-day survival after adjusting for potential confounders and ascertain the best criteria for PMX-HA use. The derived criteria for targeted therapy by PMX-HA were validated using the EUPHRATES trial cohort. RESULTS: The causal forest model revealed heterogeneity in treatment effects of PMX-HA. Since patients having higher treatment effects were more likely to have severe coagulopathy and hyperlactatemia, we identified the potential treatment targets of PMX-HA as patients with PT-INR > 1.4 or lactate > 3 mmol/L. In the EUPHRATES trial cohort, PMX-HA use on the targeted subpopulation (75% of all patients) was significantly associated with higher 28-day survival (PMX-HA vs. control, 68% vs. 52%; treatment effect of PMX-HA, + 16% [95% CI + 2.2% to + 30%], p = 0.02). CONCLUSIONS: Abnormal coagulation and hyperlactatemia in septic patients with high endotoxin activity appear to be helpful to identify patients who may benefit most from PMX-HA. Our findings will inform enrollment criteria for future interventional trials targeting patients with coagulopathy and hyperlactatemia.

Hyperlactatemia is associated with increased risks of long-term mortality and major adverse cardiovascular events in sepsis survivors.

INTRODUCTION: Serum lactate is a potentially valuable biomarker for risk assessment for patients with sepsis, as hyperlactatemia is associated with elevated short-term mortality risks. However, the associations between hyperlactatemia and long-term clinical outcomes in sepsis survivors remain unknown. The objective of this study was to investigate whether hyperlactatemia at the time of hospitalisation for sepsis was associated with worse long-term clinical outcomes in sepsis survivors. METHODS: In total, of 4983 sepsis survivors aged ≥ 20 years were enrolled in this study between January 1, 2012, and December 31, 2018. They were divided into low (≤18 mg/dL; n = 2698) and high (>18 mg/dL; n = 2285) lactate groups. The high lactate group was then matched 1:1 by propensity-score method to the low lactate group. The outcomes of interest were all-cause mortality, major adverse cardiac events (MACEs), ischaemic stroke, myocardial infarction, hospitalisation for heart failure, and end-stage renal disease. RESULTS: After propensity score matching, the high lactate group had greater risks of all-cause mortality (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.41-1.67), MACEs (HR 1.53, 95% CI 1.29-1.81), ischaemic stroke (HR 1.47, 95% CI 1.19-1.81), myocardial infarction (HR 1.52, 95% CI 1.17-1.99), and end-stage renal disease (HR 1.42, 95% CI 1.16-1.72). Subgroup analyses stratified by baseline renal function revealed almost similarity across groups. CONCLUSION: We found that hyperlactatemia is associated with long-term risks of mortality and MACEs in sepsis survivors. Physicians may consider more aggressive and prompter management of sepsis in patients who present with hyperlactatemia to improve long-term prognoses.

The risk of venous thromboembolism and blood hyperlactatemia is associated with increased mortality among critically ill patients with Covid-19.

INTRODUCTION: Coronavirus disease 2019 (Covid-19) following venous thromboembolism (VTE) and blood hyperlactatemia are associated with higher mortality. However, reliable biomarkers for this association remain to be elucidated. This study investigated the associations of VTE risk and blood hyperlactatemia with mortality among critically ill Covid-19 patients admitted to the intensive care unit (ICU). METHODS: In this single-centre retrospective study, we included 171 patients aged ≥18 years with confirmed Covid-19 admitted to the ICU at a tertiary healthcare clinic in the Eastern region of Saudi Arabia between 1 March 2020 and 31 January 2021. Patients were divided into two groups: survivor and non-survivor. The survivors have been identified as the patients discharged from the ICU alive. The VTE risk was defined using a Padua prediction score (PPS) >4. The blood lactate concentration (BLC) cut-off value >2 mmol/L was used to determine the blood hyperlactatemia. RESULTS: Multi-factor Cox analysis showed that PPS >4 and BLC >2 mmol/L were more likely to be significantly associated with higher odds of ICU mortality in critically ill Covid-19 patients (hazard ratio [HR] = 2.80, 95% confidence interval [CI] = 1.00-8.08, p = 0.050; HR = 3.87, 95% CI = 1.12-13.45, p = 0.033, respectively). The Area under the Curve for VTE and blood hyperlactatemia were 0.62 and 0.85, respectively. CONCLUSION: VTE risk and blood hyperlactatemia have been associated with a higher mortality risk in critically ill Covid-19 patients who are hospitalized in the ICU in Saudi Arabia. According to our findings, these people needed more effective VTE prevention strategies based on a personalized assessment of their risk of bleeding. Moreover, persons without diabetes and other groups with a high risk of dying from COVID-19 may be recognized by measuring glucose as having elevated glucose and lactate jointly.

Pathogenicity Analysis of a Novel Variant in GTPBP3 Causing Mitochondrial Disease and Systematic Literature Review.

Defect of GTPBP3, the human mitochondrial tRNA-modifying enzyme, can lead to Combined Oxidative Phosphorylation Deficiency 23 (COXPD23). Up to now, about 20 different variants of the GTPBP3 gene have been reported; however, genotype-phenotype analysis has rarely been described. Here, we reported a 9-year-old boy with COXPD23 who presented with hyperlactatemia, hypertrophic cardiomyopathy, seizures, feeding difficulties, intellectual disability and motor developmental delay, and abnormal visual development. Biallelic pathogenic variants of the GTPBP3 gene were identified in this boy, one novel variant c.1102dupC (p. Arg368Profs*22) inherited from the mother and the other known variant c.689A>C (p. Gln230Pro) inherited from father. We curated 18 COXPD23 patients with GTPBP3 variants to investigate the genotype-phenotype correlation. We found that hyperlactatemia and cardiomyopathy were critical clinical features in COXPD23 and the average onset age was 1.7 years (3 months of age for the homozygote). Clinical classification of COXPD23 for the two types, severe and mild, was well described in this study. We observed arrhythmia and congestive heart failure frequently in the severe type with early childhood mortality, while developmental delay was mainly observed in the mild type. The proportion of homozygous variants (71.4%) significantly differed from that of compound heterozygous variants (18.1%) in the severe type. Compared with the variants in gnomAD, the proportion of LOFVs in GTPBP3 was higher in COXPD23 patients (48.6% versus 8.9%, p < 0.0001 ****), and 31% of them were frameshift variants, showing the LOF mechanism of GTPBP3. Additionally, the variants in patients were significantly enriched in the TrmE-type G domain, indicating that the G domain was crucial for GTPBP3 protein function. The TrmE-type G domain contained several significant motifs involved in the binding of guanine nucleotides and Mg2+, the hydrolysis of GTP, and the regulation of the functional status of GTPases. In conclusion, we reported a mild COXPD23 case with typical GTPBP3-related symptoms, including seizures and abnormal visual development seldom observed previously. Our study provides novel insight into understanding the clinical diagnosis and genetic counseling of patients with COXPD23 by exploring the genetic pathogenesis and genotype-phenotype correlation of COXPD23.

Changes in Lactate-related Fecal Microbiome in Hyperlactatemia Diabetic Dogs.

BACKGROUND/AIM: The correlation between the intestinal microbiome and endocrine disorders has recently been drawing attention as an important key for determining their pathology and clinical assessment. In this study, we evaluated the microbiome of dogs with insulin-dependent diabetes mellitus (IDDM) with respect to blood lactate. MATERIALS AND METHODS: Fecal samples were obtained from 17 subjects and real-time quantitative polymerase chain reaction determinations were performed to quantify the gene expression levels of lactate-producing and dysbiosis index-related bacteria. RESULTS: Expression levels of the lactate-producing bacteria Lactobacillus spp., Enterococcus spp., and Bifidobacterium spp., were confirmed in patients with high concentrations of lactate in the blood. The abundance of Enterococcus and Bifidobacterium was higher in diabetic dogs compared to that of non-diabetic dogs. When blood lactate concentrations were high, the abundance of Bifidobacterium also increased. CONCLUSION: Blood lactate levels influence the gut microbiome in dogs with IDDM. This study will help understand the gut microbiota in the context of diabetes in human and veterinary medicine.