Association Between Hyperlactatemia, Perfusional Parameters, and Lymphocyte Mitochondrial Dysfunction in Septic Shock Patients.

INTRODUCTION: In septic shock, mitochondrial dysfunction, and hypoperfusion are the main triggers of multi-organ failure. Little is known about the crosstalk between mitochondrial dysfunction and hemodynamic alterations, especially in the post-resuscitation phase. Here, we assess whether hypoperfusion and lactate levels are associated with oxygen consumption linked to mitochondrial bioenergetic activity in lymphocytes of patients admitted with septic shock. PATIENTS AND METHODS: Prospective cohort study in patients with septic shock defined as the requirement of vasopressors to maintain a mean arterial pressure 65 mm Hg after initial fluid administration. Basal mitochondrial and Complex I respiration was measured to evaluate mitochondrial activity. Both variables and capillary refill time were compared with arterial lactate post-fluid resuscitation. We also compared mitochondrial activity measurements between patients with and without hypoperfusion status. RESULTS: A total of 90 patients were included in analysis. The median arterial lactate at the time of septic shock diagnosis was 2.0 mmol/Dl (IQR 1.3-3.0). Baseline respiration at the time of septic shock diagnosis was correlated with lactate (Spearman -0.388, 95% CI -0.4893 to -0.1021; P = 0.003), as well as Complex I respiration (Spearman -0.403, 95% CI -0.567 to -0.208; P < 0.001). Patients with hypoperfusion status had no difference in basal respiration when compared with patients who did not have hypoperfusion status (P = 0.22) nor in Complex I respiration (P = 0.09). CONCLUSION: Changes in lymphocytic mitochondrial metabolism are associated with post-resuscitation arterial lactate in septic shock; however, they are not associated with the presence of a hypoperfusional status. In this scenario, it is therefore suggested that systemic perfusion and mitochondrial metabolism have different courses.

Understanding critically ill sepsis patients with normal serum lactate levels: results from U.S. and European ICU cohorts.

While serum lactate level is a predictor of poor clinical outcomes among critically ill patients with sepsis, many have normal serum lactate. A better understanding of this discordance may help differentiate sepsis phenotypes and offer clues to sepsis pathophysiology. Three intensive care unit datasets were utilized. Adult sepsis patients in the highest quartile of illness severity scores were identified. Logistic regression, random forests, and partial least square models were built for each data set. Features differentiating patients with normal/high serum lactate on day 1 were reported. To exclude that differences between the groups were due to potential confounding by pre-resuscitation hyperlactatemia, the analyses were repeated for day 2. Of 4861 patients included, 47% had normal lactate levels. Patients with normal serum lactate levels had lower 28-day mortality rates than those with high lactate levels (17% versus 40%) despite comparable physiologic phenotypes. While performance varied between datasets, logistic regression consistently performed best (area under the receiver operator curve 87-99%). The variables most strongly associated with normal serum lactate were serum bicarbonate, chloride, and pulmonary disease, while serum sodium, AST and liver disease were associated with high serum lactate. Future studies should confirm these findings and establish the underlying pathophysiological mechanisms, thus disentangling association and causation.

Prognostic role of perioperative acid-base disturbances on the risk of Clostridioides difficile infection in patients undergoing cardiac surgery.

BACKGROUND: It is unclear whether acid-base balance disturbances during the perioperative period may impact Clostridium difficile infection (CDI), which is the third most common major infection following cardiac surgery. We hypothesized that perioperative acid-base abnormalities including lactate disturbances may predict the probability of incidence of CDI in patients after cardiac procedures. METHODS: Of the 12,235 analyzed patients following cardiac surgery, 143 (1.2%) developed CDI. The control group included 200 consecutive patients without diarrhea, who underwent cardiac procedure within the same period of observation. Pre-, intra and post-operative levels of blood gases, as well as lactate and glucose concentrations were determined. Postoperatively, arterial blood was drawn four times: immediately after surgery and successively; 4, 8 and 12 h following the procedure. RESULTS: Baseline pH was lower and PaO2 was higher in CDI patients (p < 0.001 and p = 0.001, respectively). Additionally, these patients had greater base deficiency at each of the analyzed time points (p < 0.001, p = 0.004, p = 0.012, p = 0.001, p = 0.016 and p = 0.001, respectively). Severe hyperlactatemia was also more common in CDI patients; during the cardiac procedure, 4 h and 12 h after surgery (p = 0.027, p = 0.004 and p = 0.001, respectively). Multivariate logistic regression analysis revealed that independent risk factors for CDI following cardiac surgery were as follows: intraoperative severe hyperlactatemia (OR 2.387, 95% CI 1.155-4.933, p = 0.019), decreased lactate clearance between values immediately and 12 h after procedure (OR 0.996, 95% CI 0.994-0.999, p = 0.013), increased age (OR 1.045, 95% CI 1.020-1.070, p < 0.001), emergent surgery (OR 2.755, 95% CI 1.565-4.848, p < 0.001) and use of antibiotics other than periprocedural prophylaxis (OR 2.778, 95% CI 1.690-4.565, p < 0.001). CONCLUSION: This study is the first to show that perioperative hyperlactatemia and decreased lactate clearance may be predictors for occurrence of CDI after cardiac surgery.

Hyperlactatemia during cardiopulmonary bypass: risk factors and impact on surgical results with a focus on the long-term outcome.

INTRODUCTION: Lactate, a product of anaerobic metabolism, is a biomarker and indicator for tissue hypoperfusion and oxygen debt. An elevated blood lactate level has been associated with poor outcome in many clinical conditions, including cardiac surgery. Nevertheless, debate exists regarding which blood lactate concentration is most indicative of poor outcomes. We evaluate the impact of hyperlactatemia, defined as a peak arterial blood concentration ⩾2.0 mmol/L during cardiopulmonary bypass, on surgical results with a focus on long-term outcome. METHODS: We reviewed 1,099 consecutive adult patients who underwent cardiac surgery on pump. The patients were divided into two groups based on the presence or not of hyperlactatemia. Pre- and intraoperative risk factors for hyperlactatemia were identified, and the postoperative outcome of patients with or without hyperlactatemia was compared. RESULTS: Hyperlactatemia was present in 372 patients (33.8%). Factors independently associated with hyperlactatemia were urgent/emergency procedure, cardiopulmonary bypass duration and aortic cross-clamp time. Patients with hyperlactatemia had significantly higher rate of prolonged mechanical ventilation time, in-hospital stay and requirement of inotropes and intra-aortic balloon pump support (p < 0.001). Operative (30-day) mortality was higher in the group of patients with hyperlactatemia (7.8% vs. 1.1%; p < 0.001). Kaplan-Meier curve showed worse long-term survival (mean follow-up: 4.02 ± 1.58 years) in patients with hyperlactatemia. CONCLUSION: Hyperlactatemia during cardiopulmonary bypass has a significant association with postoperative morbidity and mortality. Correction of risk factors for hyperlactatemia, together with prompt detection and correction of this condition, may control complications and improve outcome.

A new perspective of lactatogenesis by isolated adipocytes.

Increased adipose tissue mass exhibited greater capacity of glucose transformation in lactate, highlighting lactatogenesis as a crucial factor in body size. Classically, lactate produced by isolated adipocytes are expressed per million of cells and were never correlated with their size. Spontaneously hypertensive rats (SHR) have a lower body weight and smaller adipocytes when compared to Wistar-Kyoto. We evaluated basal lactate by epididymal 15-weeks-old isolated adipocytes of SHR, Wistar-Kyoto and Wistar. Basal lactate was similar when expressed by one million cells. However, SHR adipocytes were smaller, so we adjusted the results by cell volume and SHR showed higher basal lactate production which was directly endorsed by hyperlactatemia in the presented conditions. Thereby, we suggest a new perspective on lactatogenesis analysis by adipocytes, which could be linked to the receptors density and associate enzymes. Moreover, we showed that the thin and hypertensive rats can be hyperlactemic in fasting conditions.

Base excess is superior to lactate-levels in prediction of ICU mortality after cardiac surgery.

INTRODUCTION: Cardiac surgery with the use of cardiopulmonary bypass is known to induce distinct metabolic changes. Respective changes in acid-base status including increased systemic lactate levels were previously related to clinical outcomes, but data remain controversial. Therefore, we aim to investigate the relevance of lactate and base excess (BE) levels on ICU-mortality in patients admitted to the ICU after cardiac surgery. MATERIALS AND METHODS: Perioperative data of patients treated in a tertiary care academic center admitted to the ICU after on-pump surgery were analyzed in a retrospective fashion. Receiver operation characteristic (ROC) curves were constructed for admission lactate-levels and BE with calculation of optimal cut-off values to predict ICU mortality. Univariate followed by multivariate regression models were constructed to identify potential outcome-relevant indices. RESULTS: Data from 1,058 patients were included in the analysis. Area under the curves for prediction of ICU mortality were 0.79 for lactate levels at ICU admission (sensitivity 61.9%/ specificity 87.5%; optimal cut-off level 3.9mmol/l), and 0.7 for BE (sensitivity 52.4%/ specificity 93.8%, optimal cut-off level -6.7), respectively. Multivariate regression identified BE < -6.7 as the single metabolic predictor of ICU-mortality (HR 4.78, 95%-CI 1.4-16.33, p = 0.01). Explorative subgroup analyses revealed that the combination of lactate ≤3.9mmol/l and BE ≤ -6.7 has stronger impact on mortality than a combination of lactate of >3.9mmol/l and BE > -6.7 (HR 2.56, 95%-CI 0.18-37.17). CONCLUSIONS: At ICU-admission, severely reduced BE appears superior to hyperlactatemia with regard to prediction of ICU-mortality in patients after cardiac surgery.

Clinical use of plasma lactate concentration. Part 1: Physiology, pathophysiology, and measurement.

OBJECTIVE: To review the current literature with respect to the physiology, pathophysiology, and measurement of lactate. DATA SOURCES: Data were sourced from veterinary and human clinical trials, retrospective studies, experimental studies, and review articles. Articles were retrieved without date restrictions and were sourced primarily via PubMed, Scopus, and CAB Abstracts as well as by manual selection. HUMAN AND VETERINARY DATA SYNTHESIS: Lactate is an important energy storage molecule, the production of which preserves cellular energy production and mitigates the acidosis from ATP hydrolysis. Although the most common cause of hyperlactatemia is inadequate tissue oxygen delivery, hyperlactatemia can, and does occur in the face of apparently adequate oxygen supply. At a cellular level, the pathogenesis of hyperlactatemia varies widely depending on the underlying cause. Microcirculatory dysfunction, mitochondrial dysfunction, and epinephrine-mediated stimulation of Na+ -K+ -ATPase pumps are likely important contributors to hyperlactatemia in critically ill patients. Ultimately, hyperlactatemia is a marker of altered cellular bioenergetics. CONCLUSION: The etiology of hyperlactatemia is complex and multifactorial. Understanding the relevant pathophysiology is helpful when characterizing hyperlactatemia in clinical patients.

Persistent hyperlactatemia-high central venous-arterial carbon dioxide to arterial-venous oxygen content ratio is associated with poor outcomes in early resuscitation of septic shock.

OBJECTIVE: Several studies reported Pv-aCO2/Ca-vO2 ratio as a surrogate of VCO2/VO2 to detect global tissue hypoxia. The present study aimed to evaluate the prognostic value of Pv-aCO2/Ca-vO2 ratio combined with lactate levels during the early phases of resuscitation in septic shock. METHODS: A retrospective study was conducted in 144 septic shock patients in a 30-bed mixed ICU. A Pv-aCO2/Ca-vO2 ratio>1.4 was considered abnormal. Patients were classified into four predefined groups according to lactate levels and Pv-aCO2/Ca-vO2 ratio after the first 6h of resuscitation. Sequential Organ Failure Assessment (SOFA) score at day 3 was assessed. A Kaplan-Meier curve showed the survival probabilities at day 28 using a log-rank test to evaluate the differences between groups. A receiver operating characteristics (ROC) curve evaluated the ability of lactate, Pv-aCO2/Ca-vO2 ratio and Pv-aCO2/Ca-vO2 ratio combined with lactate to predict mortality at day 28. RESULTS: Combination of hyperlactatemia and high Pv-aCO2/Ca-vO2 ratio was associated with poor SOFA scores and low survival rates at day 28 (P<0.001). The Cox multivariate survival analysis demonstrated that Pv-aCO2/Ca-vO2 ratio and lactate at T6 were independent predictors of mortality at day 28. The area under the ROC curve of the Pv-aCO2/Ca-vO2 ratio combined with lactate for predicting mortality at day 28 was highest and superior to that of lactate and Pv-aCO2/Ca-vO2 ratios. CONCLUSION: Combination of Pv-aCO2/Ca-vO2 ratio and lactate at early stages of resuscitation of septic shock can better predict the prognosis of patients. The Pv-aCO2/Ca-vO2 ratio may become a useful parameter supplementary to lactate in the resuscitation of septic shock.

Update: Clinical Use of Plasma Lactate.

Lactate is an essential, versatile metabolic fuel in cellular bioenergetics. In human emergency and critical care, lactate is used as a biomarker and therapeutic endpoint and evidence is growing in veterinary medicine supporting its clinical utility. Lactate production is a protective response providing ongoing cellular energy during tissue hypoperfusion or hypoxia and mitigating acidosis. Hence, hyperlactatemia is closely associated with disease severity but it is an epiphenomenon as the body attempts to protect itself. This article reviews lactate biochemistry, kinetics, pathophysiology, some practical aspects of measuring lactate, as well as its use in diagnosis, prognosis, and monitoring.

Effects of dexmedetomidine and esmolol on systemic hemodynamics and exogenous lactate clearance in early experimental septic shock.

BACKGROUND: Persistent hyperlactatemia during septic shock is multifactorial. Hypoperfusion-related anaerobic production and adrenergic-driven aerobic generation together with impaired lactate clearance have been implicated. An excessive adrenergic response could contribute to persistent hyperlactatemia and adrenergic modulation might be beneficial. We assessed the effects of dexmedetomidine and esmolol on hemodynamics, lactate generation, and exogenous lactate clearance during endotoxin-induced septic shock. METHODS: Eighteen anesthetized and mechanically ventilated sheep were subjected to a multimodal hemodynamic/perfusion assessment including hepatic and portal vein catheterizations, total hepatic blood flow, and muscle microdialysis. After monitoring, all received a bolus and continuous infusion of endotoxin. After 1 h they were volume resuscitated, and then randomized to endotoxin-control, endotoxin-dexmedetomidine (sequential doses of 0.5 and 1.0 µg/k/h) or endotoxin-esmolol (titrated to decrease basal heart rate by 20 %) groups. Samples were taken at four time points, and exogenous lactate clearance using an intravenous administration of sodium L-lactate (1 mmol/kg) was performed at the end of the experiments. RESULTS: Dexmedetomidine and esmolol were hemodynamically well tolerated. The dexmedetomidine group exhibited lower epinephrine levels, but no difference in muscle lactate. Despite progressive hypotension in all groups, both dexmedetomidine and esmolol were associated with lower arterial and portal vein lactate levels. Exogenous lactate clearance was significantly higher in the dexmedetomidine and esmolol groups. CONCLUSIONS: Dexmedetomidine and esmolol were associated with lower arterial and portal lactate levels, and less impairment of exogenous lactate clearance in a model of septic shock. The use of dexmedetomidine and esmolol appears to be associated with beneficial effects on gut lactate generation and lactate clearance and exhibits no negative impact on systemic hemodynamics.

Hemodilution on cardiopulmonary bypass as a determinant of early postoperative hyperlactatemia.

OBJECTIVE: The nadir hematocrit (HCT) on cardiopulmonary bypass (CPB) is a recognized independent risk factor for major morbidity and mortality in cardiac surgery. The main interpretation is that low levels of HCT on CPB result in a poor oxygen delivery and dysoxia of end organs. Hyperlactatemia (HL) is a marker of dysoxic metabolism, and is associated with bad outcomes in cardiac surgery. This study explores the relationship between nadir HCT on CPB and early postoperative HL. DESIGN: Retrospective study on 3,851 consecutive patients. MEASUREMENTS AND MAIN RESULTS: Nadir HCT on CPB and other potential confounders were explored for association with blood lactate levels at the arrival in the Intensive Care Unit (ICU), and with the presence of moderate (2.1 - 6.0 mMol/L) or severe (> 6.0 mMol/L) HL. Nadir HCT on CPB demonstrated a significant negative association with blood lactate levels at the arrival in the ICU. After adjustment for the other confounders, the nadir HCT on CPB remained independently associated with moderate (odds ratio 0.96, 95% confidence interval 0.94-0.99) and severe HL (odds ratio 0.91, 95% confidence interval 0.86-0.97). Moderate and severe HL were significantly associated with increased morbidity and mortality. CONCLUSIONS: Hemodilution on CPB is an independent determinant of HL. This association, more evident for severe HL, strengthens the hypothesis that a poor oxygen delivery on CPB with consequent organ ischemia is the mechanism leading to hemodilution-associated bad outcomes.

Hyperlactemia induction modes affect the lactate minimum power and physiological responses in cycling.

The aim of this study was to verify the influence of hyperlactemia and blood acidosis induction on lactate minimum intensity (LMI). Twenty recreationally trained males who were experienced in cycling (15 cyclists and 5 triathletes) participated in this study. The athletes underwent 3 lactate minimum tests on an electromagnetic cycle ergometer. The hyperlactemia induction methods used were graded exercise test (GXT), Wingate test (WAnT), and 2 consecutive Wingate tests (2 × WAnTs). The LMI at 2 × WAnTs (200.3 ± 25.8 W) was statistically higher than the LMI at GXT (187.3 ± 31.9 W) and WAnT (189.8 ± 26.0 W), with similar findings for blood lactate, oxygen uptake, and pulmonary ventilation at LMI. The venous pH after 2 × WAnTs was lower (7.04 ± 0.24) than in (p ≤ 0.05) the GXT (7.19 ± 0.05) and WAnT (7.19 ± 0.05), whereas the blood lactate response was higher. In addition, similar findings were observed for bicarbonate concentration [HCO3] (2 × WAnTs lower than WAnT; 15.3 ± 2.6 mmol·L and 18.2 ± 2.7 mmol·L1, respectively) (p ≤ 0.05). However, the maximal aerobic power and total time measured during the incremental phase also did not differ. Therefore, we can conclude that the induction mode significantly affects pH, blood lactate, and [HCO3] and consequently they alter the LMI and physiological parameters at LMI.

The relationship between hyperlactatemia and microcirculation in the thenar eminence as measured using near-infrared spectroscopy in patients with sepsis.

OBJECTIVE: Near-infrared spectroscopy (NIRS)-derived variables during a vascular occlusion test (VOT) have recently been used to evaluate peripheral circulatory insufficiency in patients with sepsis. We investigated the relationship between NIRS-derived variables and the lactate concentration during sepsis. METHODS: This was a prospective observational study. Forty-one patients with sepsis were divided into two groups according to their blood lactate concentration: a high lactate group (≥2.0 mmol/l; n=15) and a normal lactate group (<2.0 mmol/l; n=26). NIRS was used to evaluate the tissue oxygen index (TOI) at the thenar eminence before and after a VOT. VOT was performed by sphygmomanometer cuff inflation around upper arm for 3 min. The TOI value before VOT was defined as the TOI baseline, the TOI value immediately after VOT was defined as the minimum TOI and the TOI value after releasing the muscle from the VOT was defined as the TOI after VOT. The ΔTOI was defined as the difference between the TOI after VOT and minimum TOI. RESULTS: NIRS-derived variables had significant differences between the normal lactate group and the high lactate group with respect to the TOI baseline (median: 65% vs 55%, p=0.01), TOI after VOT (median: 65% vs 46%, p<0.001) and ΔTOI (median: 19% vs 6%, p<0.001). The lactate concentration was significantly correlated with the TOI after VOT (R=0.594, p<0.001), TOI baseline (R=0.513, p<0.001), ΔTOI (R=0.488, p=0.001) and minimum TOI (R=0.377, p=0.02). CONCLUSIONS: We revealed a significant correlation between NIRS-derived variables and the lactate concentration during sepsis.