Hyperlactatemia

There is overwhelming evidence that sepsis and septic shock are associated with hyperlactatemia (sepsis-associated hyperlactatemia (SAHL)). SAHL is a strong independent predictor of mortality and its presence and progression are widely appreciated by clinicians to define a very high-risk population. Until recently, the dominant paradigm has been that SAHL is a marker of tissue hypoxia. Accordingly, SAHL has been interpreted to indicate the presence of an 'oxygen debt' or 'hypoperfusion', which leads to increased lactate generation via anaerobic glycolysis. In light of such interpretation of the meaning of SAHL, maneuvers to increase oxygen delivery have been proposed as its treatment. Moreover, lactate levels have been proposed as a method to evaluate the adequacy of resuscitation and the nature of the response to the initial treatment for sepsis. However, a large body of evidence has accumulated that strongly challenges such notions. Much evidence now supports the view that SAHL is not due only to tissue hypoxia or anaerobic glycolysis. Experimental and human studies all consistently support the view that SAHL is more logically explained by increased aerobic glycolysis secondary to activation of the stress response (adrenergic stimulation). More importantly, new evidence suggests that SAHL may actually serve to facilitate bioenergetic efficiency through an increase in lactate oxidation. In this sense, the characteristics of lactate production best fit the notion of an adaptive survival response that grows in intensity as disease severity increases. Clinicians need to be aware of these developments in our understanding of SAHL in order to approach patient management according to biological principles and to interpret lactate concentrations during sepsis resuscitation according to current best knowledge.

IntroductionAcute circulatory dysfunction in patients with sepsis can evolve rapidly into a progressive stage associated with high mortality. Early recognition and adequate resuscitation could improve outcome. However, since the spectrum of clinical presentation is quite variable, signs of hypoperfusion are frequently unrecognized in patients just admitted to the emergency department (ED). Hyperlactatemia is considered a key parameter to disclose tissue hypoxia but it is not universally available and getting timely results can be challenging in low resource settings. In addition, non-hypoxic sources can be involved in hyperlactatemia, and a misinterpretation could lead to over-resuscitation in an unknown number of cases. Capillary refill time (CRT) is a marker of peripheral perfusion that worsens during circulatory failure. An abnormal CRT in septic shock patients after ICU-based resuscitation has been associated with poor outcome. The aim of this study was to determine the prevalence of abnormal CRT in patients with sepsis-related hyperlactatemia in the early phase after ED admission, and its relationship with outcome.MethodsWe performed a prospective observational study. Septic patients with hyperlactemia at ED admission subjected to an initial fluid resuscitation (FR) were included. CRT and other parameters were assessed before and after FR. CRT-normal or CRT-abnormal subgroups were defined according to the status of CRT following initial FR, and major outcomes were registered.ResultsNinety-five hyperlactatemic septic patients were included. Thirty-one percent had abnormal CRT at ED arrival. After FR, 87 patients exhibited normal CRT, and 8 an abnormal one. Patients with abnormal CRT had an increased risk of adverse outcomes (88% vs. 20% pConclusionsHyperlactatemic sepsis patients with abnormal CRT after initial fluid resuscitation exhibit higher mortality and worse clinical outcomes than patients with normal CRT.

IntroductionThe clinical significance of elevation of lactate levels within the reference range is not well studied. The objective of this study was to determine the best cutoff threshold for serum lactate within the reference range (0.01 to 2.00 mM) that best discriminated between survivors and nonsurvivors of critical illness and to examine the association between relative hyperlactatemia (lactate above the identified threshold) and mortality.MethodsThis was a retrospective cohort study of adult patients admitted to the medical-surgical intensive care unit (ICU) of a tertiary care academic center. Youden index was calculated to identify the best lactate cutoff threshold that discriminated between survivors and nonsurvivors. Patients with lactate above the identified threshold were defined as having relative hyperlactatemia. Multivariate logistic regression, adjusting for baseline variables, was performed to determine the relationship between the above two ranges of lactate levels and mortality. In addition, a test of interaction was performed to assess the effect of selected subgroups on the association between relative hyperlactatemia and hospital mortality.ResultsDuring the study period, 2,157 patients were included in the study with mean lactate of 1.3 ± 0.4 mM, age of 55.1 ± 20.3 years, and acute physiology and chronic health evaluation (APACHE) II score of 22.1 ± 8.2. Vasopressors were required in 42.4%. Lactate of 1.35 mM was found to be the best cutoff threshold for the whole cohort. Relative hyperlactatemia was associated with increased hospital mortality (adjusted odds ratio (aOR), 1.60, 95% confidence interval (CI) 1.29 to 1.98), and ICU mortality (aOR, 1.66; 95% CI, 1.26 to 2.17) compared with a lactate level of 0.01 to 1.35 mM. This association was consistent among all examined subgroups.ConclusionsRelative hyperlactatemia (lactate of 1.36 to 2.00 mM) within the first 24 hours of ICU admission is an independent predictor of hospital and ICU mortality in critically ill patients.

At rest, glucose serves as the brain's primary oxidative substrate; however, when circulating lactate is elevated, lactate oxidation increases. Whether this glucose-sparing effect differs when lactate is elevated via passive infusion versus exercise remains unknown. To address this, 13 healthy adults (six females) completed protocols of: (1) intravenous sodium lactate infusion (exogenous hyperlactataemia); and (2) cycling exercise (endogenous hyperlactataemia) to matched elevations in arterial lactate concentration (∼4 and ∼8 mmol/l). Radial arterial and internal jugular venous sampling and measures of cerebral blood flow (CBF) were used to calculate cerebral metabolic rates of glucose (CMRGlc), lactate (CMRiLac), and oxygen ( CMRO2${\mathrm{CM}}{{\mathrm{R}}_{{{\mathrm{O}}_2}}}$ ). The exogenous infusion protocol resulted in a higher CBF compared to exercise (P Glc decreased (lactate, P = 0.009; condition, P = 0.373) and CMRiLac increased in a dose-dependent manner (lactate, P < 0.001; condition, P = 0.972). At an arterial concentration of 8 mmol/l, circulating lactate accounted for 24% of total cerebral oxidative metabolism. Elevated circulating lactate leads to preferential lactate oxidation and reduced glucose utilization, irrespective of whether lactate is delivered exogenously or produced endogenously. KEY POINTS: The human brain relies primarily on oxidative glucose metabolism; however, with age and in many pathologies cerebral glucose metabolism declines; therefore, there is interest in investigating alternative fuel sources that can meet the high energetic needs of the brain. The present study investigates whether increased lactate availability exerts a glucose-sparing effect in the healthy human brain, and whether this effect is consistent across physiologically distinct states of exogenous (sodium lactate infusion) and endogenous (exercise-induced) hyperlactataemia. We assessed cerebral uptake and metabolism of glucose and lactate following exercise and lactate infusion, using simultaneous arterial and jugular venous blood samples, and Duplex ultrasound. Despite stark systemic physiological differences between conditions, cerebral glucose metabolism declined in proportion to increased circulating lactate irrespective of whether it is delivered exogenously or produced endogenously. These data provide clear evidence that lactate is preferentially oxidized by the brain when made available, helping preserve glucose for non-energetic roles.