e-ISSN: 2722-3558 Sriwijaya Journal of Surgery [SJS] https://sriwijayasurgery.
Elevated Serum Lactate as an Indicator of Neurometabolic Derangement and its Independent Correlation with Clinical Outcomes in Traumatic Brain Injury Satya Agusmansyah1*.
Anugerah Onie Widhiatmo2.
Theodorus3 1Department of General Surgery.
Dr.
Mohammad Hoesin General Hospital/Faculty of Medicine.
Universitas Sriwijaya.
Palembang.
Indonesia 2Department of Neurosurgery.
Dr.
Mohammad Hoesin General Hospital.
Palembang.
Indonesia 3Faculty of Medicine.
Universitas Sriwijaya.
Palembang.
Indonesia
ARTICLE
INFO
Keywords:
Biomarker Neurometabolism Prognosis Serum lactate Traumatic brain injury *Corresponding author:
Satya Agusmansyah E-mail address:
army13@gmail.
All authors have reviewed and approved the Anal version of the manuscript.
https://doi.
org/10.
37275/sjs.
ABSTRACT
Introduction: Traumatic brain injury (TBI) is a primary cause of global death and disability, where early and accurate prognostication is critical but remains a clinical challenge.
Serum lactate is emerging as a biomarker of the complex neurometabolic derangement following TBI, extending beyond its traditional role as a marker of hypoxia.
This study aimed to determine if serum lactate is an independent predictor of outcomes in TBI patients.
Methods: We conducted a prospective, single-center observational study of 33 TBI patients at Dr.
Mohammad Hoesin General Hospital.
Serial venous serum lactate levels were measured at admission, 24, and 48 hours.
The primary outcome was unfavorable functional status (Glasgow Outcome Scale [GOS] 1-.
at hospital discharge.
Multivariate logistic regression was used to assess lactate as an independent predictor of unfavorable outcome, controlling for age and initial Glasgow Coma Scale (GCS) score.
Survival was analyzed using Kaplan-Meier curves and a Cox proportional hazards model.
Results: The cohort (N=.
was predominantly male .
6%) with a mean age of 37.
91 years.
Higher admission lactate was strongly associated with worse GOS categories .
=0.
After adjusting for age and initial GCS score, admission serum lactate remained a significant independent predictor of unfavorable outcome at discharge.
For every 1 mmol/L increase in lactate, the odds of an unfavorable outcome increased by over twofold (Adjusted Odds Ratio: 2.
95% CI: 1.
p=0.
Similarly, lactate was an independent predictor of in-hospital mortality in the Cox proportional hazards model (Adjusted Hazard Ratio: 1.
95% CI: 1.
p=0.
Conclusion: Elevated admission serum lactate is a strong, independent predictor of unfavorable in-hospital functional outcome and mortality in TBI As a readily available biomarker, it reflects the severity of the underlying neurometabolic crisis and provides crucial prognostic information beyond initial clinical and demographic assessments, aiding in early risk stratification.
Introduction from 2019 indicated approximately 27.
16 million new Traumatic brain injury (TBI) represents a silent cases of TBI worldwide, underscoring its pervasive epidemic and a formidable public health challenge, 2 The devastating consequences of TBI extend constituting a leading cause of mortality and profound far beyond the immediate clinical crisis, imposing an immense socioeconomic burden through exorbitant The sheer scale of its impact is staggering, with healthcare costs, the necessity for prolonged and estimates suggesting over 10 million cases annually intensive rehabilitation, and the tragic loss of human that result in either hospitalization or death.
Data potential and productivity for countless survivors and long-term disability across all age groups their families.
Within the acute setting.
TBI is a such as intoxication or pre-existing conditions.
quintessential neurosurgical emergency, where the Cranial CT scans, while excellent at identifying rapid and precise application of medical and surgical macroscopic structural lesions like hematomas and interventions is paramount to mitigating damage, fractures, often fail to capture the full extent of preserving neurological function, and ultimately, microscopic or metabolic damage, particularly in cases of DAI, where the initial scan can appear deceptively characterized by a biphasic cascade of injury.
The This gap between structural appearance and primary injury is the direct, instantaneous, and functional reality has fueled a sustained search for irreversible mechanical damage inflicted upon the objective, quantitative biological markers .
brain at the moment of impact.
This includes that can provide a more precise and real-time parenchymal contusions, lacerations, tissue shearing assessment of the severity of brain injury and its leading to diffuse axonal injury (DAI), and intracranial metabolic consequences.
7 The ideal biomarker should While this initial event sets the stage, be readily accessible, provide rapid results, and accurately reflect the underlying injury processes.
devastation is driven by the secondary injury cascade.
Serum biomarkers, obtainable through minimally This is a complex, delayed, and potentially preventable invasive blood draws, are particularly attractive for series of deleterious biochemical, metabolic, and their practicality in the acute setting compared to the inflammatory processes that are triggered by the more invasive analysis of cerebrospinal fluid (CSF).
primary insult and evolve over the subsequent hours.
While days, and even weeks.
This cascade is a vortex of released from damaged brain cellsAisuch as S100- beta.
Glial Fibrillary Acidic Protein (GFAP), and The TBI Ubiquitin C-terminal Hydrolase L1 (UCH-L.
Aihas formation of cytotoxic and vasogenic cerebral edema, shown great promise, metabolic biomarkers offer a disruptions to the blood-brain barrier, cerebral unique and complementary window into the functional state and energetic health of the brain.
Among this 4 These processes converge on a final class, serum lactate has emerged as a particularly common pathway: a state of profound cerebral compelling and widely available candidate.
metabolic crisis, which elevates intracranial pressure Historically, (ICP), further compromises cerebral perfusion, and patients was almost exclusively interpreted as a sign promotes widespread neuronal and glial cell death, of anaerobic metabolism resulting from systemic thereby dictating the patient's ultimate functional shock, hypoperfusion, or tissue hypoxia.
8 In TBI, this was often attributed to secondary insults like systemic The complex and heterogeneous nature of TBI hypotension or cerebral ischemia caused by critically makes early and accurate prognostication a significant clinical challenge.
5 For decades, clinicians have relied contemporary understanding of cerebral metabolism on foundational tools like the Glasgow Coma Scale has unveiled a far more complex and nuanced role for (GCS) and structural neuroimaging via Computed Tomography (CT) to gauge injury severity and predict microdialysis studies, has conclusively demonstrated that significant lactate elevation can occur within the limitations of these tools are well-recognized.
The GCS, injured brain even in the presence of normal or a cornerstone of neurological assessment, can be elevated brain tissue oxygen levelsAia phenomenon of confounded by clinically necessary interventions like "aerobic glycolysis" or a Warburg-like effect.
9 This is sedation and intubation, or by patient-specific factors now understood to reflect a state of profound While ICP.
However.
Advanced neurometabolic Methods This investigation was conducted as a prospective, single-center, observational cohort study.
All patient conversion to lactate.
Furthermore, the elegant recruitment and data collection took place at the metabolic coupling described by the astrocyte-neuron Emergency Department lactate shuttle (ANLS) hypothesisAiwhereby astrocytes provide lactate as a primary energy substrate for General Hospital in Palembang.
Indonesia.
As a neuronsAiis provincial tertiary referral center and the primary severe TBI.
Damaged neurons lose their ability to trauma hospital for the region, this institution utilize this astrocyte-derived lactate, leading to its manages a high volume and wide spectrum of TBI cases, providing a suitable environment for recruiting subsequent efflux into the systemic circulation.
a representative cohort.
The study enrollment period Despite was conducted over four consecutive months, from hyperlactatemia to poor outcomes in TBI, its precise May 1st, 2025, to August 31st, 2025.
The single-center role as a dynamic, independent marker of this nature of the study, while ensuring uniformity in underlying metabolic crisis requires more rigorous treatment protocols, is acknowledged as a factor that Many studies have focused on single may influence the external validity of the findings.
The values without for major Dr.
Mohammad Hoesin confounders, and its interpretation as a direct instruments and consent forms, was submitted to and reflection of cerebral metabolic distress needs to be received full and unconditional approval from the solidified through more robust statistical modeling.
Institutional Ethics Committee of Dr.
Mohammad The primary aim of this study was to meticulously Hoesin General Hospital (Approval No.
investigate the correlation between early, serially DP.
03/D.
XVi.
08/ioo/208/2.
measured serum lactate levels and a spectrum of clinical outcomes in patients with TBI, and to performed in strict adherence to the ethical principles determine if serum lactate serves as an independent outlined in the Declaration of Helsinki and the Council predictor of unfavorable outcome and mortality after for International Organizations of Medical Sciences controlling for established prognostic factors.
The (CIOMS) 2016 guidelines.
Written informed consent novelty of this investigation lies in its rigorous, was obtained from all participants or their legally multivariate approach to validating lactate as a authorized representatives prior to any study-related prognostic tool.
We move beyond simple correlation by For patients who lacked the capacity to interpreting elevated lactate not merely as a surrogate consent due to their altered level of consciousness, for hypoxia, but as a quantifiable indicator of profound consent was obtained from their next of kin or a legally designated surrogate.
The confidentiality and privacy All multivariate regression models to adjust for the powerful confounding effects of initial injury severity throughout the study.
data were anonymized using (GCS) and age, this study seeks to isolate the unique study identifiers to prevent the disclosure of independent predictive value of lactate.
This approach personal health information.
provides a stronger pathophysiological and evidence- The study population consisted of all patients based rationale for its integration into routine clinical presenting to the emergency department with a practice, framing it as a crucial biomarker that reflects suspected diagnosis of traumatic brain injury.
the underlying cellular energy crisis in TBI.
consecutive sampling strategy was employed, whereby all patients who met the eligibility criteria during the study period were invited to participate to minimize hospital arrival were meticulously recorded.
The selection bias.
Patients were formally screened for eligibility based on the predefined inclusion and measurement was 2.
5 hours (Interquartile Range: 1.
exclusion criteria.
Inclusion Criteria: A definitive - 4.
0 hour.
Venous blood samples for serum lactate diagnosis of traumatic brain injury confirmed by a analysis were drawn from all patients at three non-contrast cranial Computed Tomography (CT) scan standardized time points: at admission .
, and at performed within 48 hours of the traumatic event.
24 hours and 48 hours post-admission.
The admission Availability of complete laboratory data, including a lactate level was used as the primary predictor variable serum lactate measurement upon admission to the for all analyses to assess its utility as an early emergency department.
Provision of written informed prognostic marker.
All consent by the patient or their legal representative.
immediately in the hospital's central laboratory using Exclusion Criteria: To isolate the effect of TBI-induced a standard enzymatic colorimetric assay to determine metabolic changes, the following conditions led to exclusion: A pre-existing history of a significant mmol/L.
Throughout their hospital stay, patients were metabolic disease known to independently affect managed according to standardized institutional lactate metabolism, including but not limited to severe neurotrauma care protocols, which are aligned with or uncontrolled diabetes mellitus, established liver international guidelines from organizations like the failure .
, or known mitochondrial disorders.
Brain Trauma Foundation.
This included therapies The presence of concomitant severe multiple traumas, aimed at controlling ICP, maintaining adequate operationally defined as an Injury Severity Score (ISS) cerebral perfusion pressure, and preventing secondary > 15 involving at least one extracranial body region systemic insults.
Data on pre-hospital episodes of .
hest, abdomen, pelvis, or extremities with long bone hypoxia or hypotension were collected but found to be This was done to minimize the confounding inconsistently documented, and were therefore not influence of hemorrhagic shock and peripheral tissue included in the final regression models.
hypoperfusion on systemic lactate levels.
A known pre-existing, samples were processed The primary dependent variable was the clinical Outcome Scale (GOS).
The 5-point
GOS
Glasgow biochemical picture, such as a primary or metastatic standardized measure of global functional recovery.
brain tumor, active central nervous system infection The GOS was assessed at the time of patient discharge .
eningitis, by a trained neurosurgery resident not directly neuroinflammatory condition.
involved in the patient's primary treatment decisions.
Upon arrival at the emergency department, all The mean length of hospital stay for the cohort was enrolled patients underwent a standardized initial 4 A 12.
1 days.
It is explicitly acknowledged that this assessment according to Advanced Trauma Life
endpoint measures in-hospital outcomes and is Support
subject to temporal bias, as it does not reflect long-
(ATLS)
term recovery, which evolves over months.
For included the determination of the Glasgow Coma Scale analytical purposes, the GOS was dichotomized into (GCS) score by trained emergency or neurosurgery Favorable Outcome (GOS 4-5: Moderate Disability or This initial GCS score was used to classify Good Recover.
and Unfavorable Outcome (GOS 1-3:
the TBI severity as mild (GCS 14-.
, moderate (GCS Dead.
Persistent Vegetative State, or Severe Disabilit.
, or severe (GCS 3-.
Detailed demographic data In-hospital mortality (GOS .
was also analyzed as a .
ge, gende.
and clinical information regarding the distinct endpoint for survival analysis.
mechanism of injury and the time from injury to All statistical analyses were performed using the panel illustrates a notable male predominance, which Statistical Package for the Social Sciences (SPSS) is a well-established epidemiological feature of TBI The data reveal that nearly two-thirds of summarize cohort characteristics.
The distribution of the patients, specifically 63.
6%, were male, while the continuous data was assessed for normality using the 4% were female.
This distribution is One-Sample Kolmogorov-Smirnov test.
As serum lactate levels were not normally distributed .
< 0.
occupational exposures typically observed in male non-parametric populations, providing an important demographic The Kruskal-Wallis H test was used to context for the study's findings.
Moving to the lower- compare median lactate levels across the five GOS left quadrant, the Age Distribution of the cohort is To address the primary aim of the study, a presented using a horizontal bar chart, which multivariate logistic regression model was developed to effectively stratifies the patients into three clinically determine if serum lactate was an independent relevant age categories.
The data highlight that the predictor of unfavorable outcome (GOS 1-.
The vast majority of TBI cases occurred in the adult admission lactate level .
s a continuous variabl.
, population, with 72.
7% of patients falling within the initial GCS score .
, and age .
18 to 59-year age range.
This represents the most were entered as independent variables.
Odds Ratios economically productive years of life, underscoring the (OR) significant societal and personal impact of TBI.
For survival analysis.
Kaplan-Meier curves smaller proportion of patients were in the older adult were generated to visualize survival probability for category (Ou 60 year.
, accounting for 18.
2% of the dichotomized lactate groups, compared using the Log- cohort, while pediatric and adolescent patients (< 18 Rank test.
To determine the independent effect of year.
constituted the smallest group at 9.
This lactate on mortality, a Cox proportional hazards model distribution provides critical insight into the age- was employed, using the same independent variables related epidemiology of the TBI patients treated at the as the logistic regression model.
Hazard Ratios (HR) with 95% CIs were calculated.
A two-tailed p-value of presents a compelling visual breakdown of the TBI < 0.
05 was considered statistically significant for all Severity, as classified by the initial Glasgow Coma Scale (GCS) score upon admission.
A donut chart Descriptive (CI) higher-risk Finally, lower-right elegantly depicts the distribution across the spectrum Results of injury severity.
The largest segment of the cohort Figure 1 provides a comprehensive and synthesized presented with Moderate TBI, accounting for 42.
4% of visualization of the key demographic and clinical all patients.
This was followed closely by patients with characteristics of the 33 patients with Traumatic Brain Mild TBI, who made up 39.
4% of the group.
Injury (TBI) enrolled in this prospective cohort study.
significant minority of patients, 18.
2%, presented with The Severe TBI, representing the most critically injured prominently displaying the total cohort size of 33 This distribution is crucial for interpreting This fundamental metric underscores the the study's overall outcomes, as it demonstrates that sample from which all subsequent data are derived the cohort comprised a heterogeneous mix of injury and is presented with clarity and emphasis to ground severities, making it a representative sample for the reader.
Adjacent to this, the top-right quadrant investigating a prognostic biomarker like serum details the Gender Distribution within the cohort.
This top-left Figure 1.
Baseline characteristics of the study.
Figure 2 presents a detailed and quantitative Strikingly, an even larger group, 27.
3%, survived but summary of the clinical outcomes observed in the with the most severe form of neurological devastation, cohort of 33 Traumatic Brain Injury (TBI) patients at remaining in a Persistent Vegetative State (GOS .
the time of their hospital discharge.
The data reveal a Together, these two worst-case scenarios account for sobering reality: a significant majority of the patients, over half of the entire cohort, underscoring the life- 6% .
, experienced an Unfavorable Outcome, threatening and life-altering nature of the injuries defined as a GOS score of 1 to 3 .
ncompassing death.
The intermediate and favorable outcomes a persistent vegetative state, or severe disability comprised the remainder of the group.
A smaller requiring daily dependenc.
In contrast, a smaller proportion, 39.
4% .
, achieved a Favorable Disability (GOS .
, conscious but dependent on others Outcome, defined as a GOS score of 4 or 5 .
ndicating for daily care.
The favorable outcomes were divided a return to independence with moderate disability or a between patients who achieved a state of Moderate good recover.
This primary stratification immediately Disability (GOS .
, representing 15.
2% of the cohort, highlights the profound burden of morbidity and and those who made a Good Recovery (GOS .
, mortality associated with TBI within this patient Figure 2 delivers a powerful The data illustrate a bimodal distribution at narrative about the clinical sequelae of TBI in this the extremes of the outcome scale.
A substantial It demonstrates that while a return to a good portion of the cohort, 24.
2%, succumbed to their quality of life is possible, the risk of death or profound, injuries, corresponding to a GOS score of 1 (Dea.
lifelong disability is substantial.
Severe Figure 2.
Clinical outcomes at discharge.
Figure 3 provides a compelling visual synthesis of trend of rising lactate concentrations.
This culminates the primary bivariate findings of the study, graphically in the "Dead" (GOS .
category, where the lactate levels illustrating the powerful and statistically significant are substantially elevated and occupy a distribution relationship between admission serum lactate levels markedly distinct and the subsequent clinical course of patients with graphical representation powerfully conveys that Traumatic Brain Injury (TBI).
Figure 3 presents a higher lactate is not just associated with a binary poor schematic box plot that elegantly visualizes the core outcome, but that its concentration tracks closely with finding from the Kruskal-Wallis test .
= 0.
This plot clearly demonstrates a strong, monotonic dose- reinforcing its role as a sensitive barometer of the response relationship between lactate concentration underlying pathophysiological injury severity.
Figure 3 and the severity of the functional outcome at transitions from functional outcome to the stark Each box represents the interquartile range reality of mortality, presenting the results of the Log- (IQR) of lactate levels for a specific Glasgow Outcome Rank test .
= 0.
This survival plot powerfully Scale (GOS) category, with the bold internal line illustrates the impact of admission hyperlactatemia on marking the median.
The visualization strikingly the probability of survival over time.
The two curves reveals a progressive upward shift in the distribution represent the cumulative survival of patients stratified of lactate levels as the clinical outcome worsens.
into "Low Lactate" and "High Lactate" groups.
The Patients who achieved a "Good Recovery" (GOS .
green line, representing the low-lactate group, remains exhibited the lowest median lactate levels, clustered high and stable, indicating a very high probability of near the physiological baseline.
As the outcome survival throughout the observation period, with only deteriorates through "Moderate Disability," "Severe a minimal, single drop.
In dramatic contrast, the red Disability," and "Vegetative State," the corresponding line, representing the high-lactate group, exhibits a box plots ascend systematically, indicating a clear steep and rapid decline, particularly within the first 10 from the other groups.
This to 15 days following injury.
This precipitous drop lactate is not only a marker of mortality but also a graded indicator of morbidity across the full range of mortality for patients presenting with elevated lactate.
TBI outcomes.
The robust statistical significance noted The clear and immediate separation between the two for both analyses, combined with the clear visual curves provides unambiguous visual evidence that a trends, solidifies the conclusion that serum lactate high admission lactate level is a potent and ominous serves as a critical biomarker in the early assessment predictor of death.
Figure 3 offer a comprehensive and of TBI patients.
cohesive narrative.
They demonstrate that serum Figure 3.
Bivariate analysis of lactate and outcome.
Figure 4 presents the central and most critical at admission, the odds of having an unfavorable finding of this investigation: the results of the outcome decreased by 32% .
OR: 0.
95% CI: 0.
This p = 0.
This is visually represented by the green point and its confidence interval, which lie independent predictive value of key clinical variables entirely to the left of the line of no effect.
Crucially, on the likelihood of an unfavorable outcome at Admission Lactate emerges as a powerful and discharge .
efined as a Glasgow Outcome Scale [GOS] statistically significant risk factor, independent of the score of 1-.
The analysis reveals two statistically initial GCS and age.
As depicted by the red point and significant independent predictors.
The Initial Glasgow its confidence interval lying entirely to the right of the Coma Scale (GCS) score, a well-established prognostic line of no effect, higher lactate levels are independently marker, is confirmed to be a strong protective factor.
associated with worse outcomes.
The model quantifies For every one-point increase in a patient's GCS score this risk precisely: for every 1 mmol/L increase in a patient's admission serum lactate, the odds of provides definitive graphical evidence that even after experiencing an unfavorable outcome increased by a accounting for the profound influence of the initial substantial 115% .
OR: 2.
95% CI: 1.
12 - 4.
clinical severity of the brain injury, the admission In contrast.
Age was not found to be a lactate level provides significant, additional, and statistically significant independent predictor in this independent prognostic information.
It moves beyond particular model .
OR: 1.
95% CI: 0.
98 - 1.
simple correlation to establish serum lactate as a key .
, as indicated by its grey confidence interval, independent biomarker of risk in the acute phase of which clearly crosses the line of no effect.
Figure 4 Traumatic Brain Injury.
Figure 4.
Multivariate analysis for predictors of unfavorable outcome.
Figure 5 provides a graphical summary of the 0, which signifies no effect on the hazard of multivariate survival analysis, which was conducted to Each horizontal line corresponds to a identify the independent predictors of in-hospital predictor variable, showing its 95% confidence interval This forest plot visualizes the results of the (CI), with the colored point representing the point Cox proportional hazards model, a statistical method estimate of the adjusted hazard ratio .
HR).
used to investigate the relationship between the confidence interval that does not cross the line of no survival time of patients and several predictor effect indicates that the predictor has a statistically variables simultaneously.
The plot is a standard and significant impact on survival.
An aHR greater than highly effective tool for communicating the results of 0 signifies an increased hazard of death .
risk survival analyses, as it clearly displays the hazard facto.
, while an aHR less than 1.
0 signifies a reduced ratio for each variable, allowing for an immediate hazard .
protective facto.
The analysis confirms the powerful and independent predictive capacity of both influences the risk of death over time.
The central the initial clinical assessment and the admission vertical line on the plot represents a hazard ratio (HR) metabolic state.
The Initial Glasgow Coma Scale (GCS) score is shown to be a significant protective factor.
For This critical finding is depicted by the red point every one-point increase in the admission GCS, the and its confidence interval, which lie entirely to the hazard of in-hospital mortality decreased by a right of the line of no effect.
Consistent with the logistic substantial 28% .
HR: 0.
95% CI: 0.
58 - 0.
regression model.
Age was not found to be a This is represented by the green point and its confidence interval, which are located entirely to the mortality in this specific cohort and model .
HR: 1.
left of the line of no effect.
Most importantly, 95% CI: 0.
99 - 1.
p = 0.
, as its confidence Admission Lactate is identified as a significant and interval crosses the line of no effect.
Figure 5 provides independent risk factor for mortality.
After adjusting for the influence of GCS and age, the model admission serum lactate level is not merely associated with mortality but is an independent predictor of a independently associated with a greater hazard of patient's risk of death during their hospital stay.
For every 1 mmol/L increase in admission quantifies the increased hazard conferred by the state serum lactate, the hazard of in-hospital mortality of metabolic derangement, even when the initial increased by 78% .
HR: 1.
95% CI: 1.
05 - 3.
severity of the clinical injury is taken into account.
Figure 5.
Multivariate survival analysis (Cox Mode.
Discussion and independent predictor of unfavorable in-hospital This prospective study was designed to rigorously functional outcome and mortality in patients with TBI, evaluate the prognostic utility of serum lactate in even after accounting for the established prognostic influence of initial injury severity (GCS) and age.
11 Our correlation to assess its value as an independent multivariate analysis demonstrates that for each The principal finding of this investigation mmol/L increase in lactate, the odds of a poor outcome is that elevated admission serum lactate is a strong more than double, and the hazard of death increases by These brain metabolism is framed by the Astrocyte-Neuron statistically adjusted evidence to support the central Lactate Shuttle (ANLS) hypothesis, a model thesis of this study: that serum lactate is not merely a sophisticated metabolic coupling where astrocytes bystander or a simple surrogate for injury severity, but undergo glycolysis to produce lactate, which is then rather a potent, quantitative biomarker reflecting the shuttled to neurons as their preferred energy fuel.
TBI, this elegant system is catastrophically disrupted.
neurometabolic derangement that drives secondary Activated astrocytes, responding to injury signals like brain injury.
12 The interpretation of our findings hinges on understanding the complex role of lactate in traumatic stress.
The brain's exquisite vulnerability to compensatory response.
15 However, neurons suffering any disruption in metabolic homeostasis makes from excitotoxic damage and mitochondrial failure lose lactate a uniquely sensitive reporter of its physiological their ability to take up and utilize this lactate.
This Our results can be explained through the lens of decoupling leads to the accumulation of lactate in the mechanisms that define the secondary injury cascade.
brain's extracellular space, from where it diffuses into The cornerstone of cellular energy production is the systemic circulation.
Consequently, high serum oxidative phosphorylation within the mitochondria.
lactate levels signify a complete breakdown of the Following TBI, a confluence of factors conspires to fundamental metabolic partnership between neurons cripple this vital 'supply-demand This The secondary injury and glia, a marker of physiological disintegration at cascade unleashes a torrent of detrimental processes, the cellular level within the CNS.
A hallmark of including massive intracellular calcium influx and secondary brain injury is excitotoxicity, driven by the oxidative stress, which are profoundly toxic to massive release of glutamate.
16 This leads to a This leads to a state of 'cytopathic sustained influx of calcium ions into neurons, hypoxia,' where cells cannot utilize oxygen effectively activating degradative enzymes that dismantle the cell.
even when it is available, culminating in mitochondrial From a metabolic standpoint, this is disastrous.
This is exacerbated by the opening of the Neurons must expend enormous amounts of ATP to mitochondrial permeability transition pore .
PTP), a power ion pumps in a frantic effort to restore ionic This surge in energy demand occurs at transport chain, collapses the membrane potential, the very moment the cell's energy-producing capacity and halts ATP synthesis.
A critical bottleneck forms at is compromised, forcing a maximal upregulation of the pyruvate dehydrogenase (PDH) complex, which is glycolysis and shunting of pyruvate to lactate.
Therefore, the lactate level serves as a surrogate When pyruvate, the end-product of marker for the severity of ongoing excitotoxicity.
glycolysis, cannot enter the TCA cycle, it is shunted to higher the lactate, the greater the excitotoxic burden lactate via lactate dehydrogenase (LDH).
This reaction and the more futile the cell's struggle, leading is crucial for regenerating NAD , allowing the cell to inevitably to cell death, reflected in the poor GOS continue generating at least a small amount of ATP scores of our patients.
The brain's response to injury post-traumatic Therefore, the hyperlactatemia involves a robust inflammatory cascade, characterized observed in our patients with the worst outcomes is a by the activation of resident immune cells .
direct biochemical manifestation of this mitochondrial These cells can adopt different phenotypes, including the pro-inflammatory "M1" state.
M1 microglia are bioenergetic collapse.
The modern understanding of reprogramming similar to the Warburg effect, where acts as a collection of localized lactate factories, they preferentially utilize glycolysis even in the further contributing to the lactate burden.
The serum presence of oxygen.
18 This "aerobic glycolysis" allows lactate level, therefore, can also reflect the intensity for the rapid production of biosynthetic intermediates and character of the neuroinflammatory response, needed for their inflammatory functions.
The intense with higher levels suggesting a more damaging, pro- M1-skewed inflammatory infiltrate in the injured brain inflammatory state.
Figure 6.
The pathophysiological cascade linking TBI to neurometabolic derangement and clinical outcome.
Figure 6 provides a comprehensive, multi-stage represented by an icon of activated, amoeboid-shaped microglial cells within the brain's silhouette.
These activated resident immune cells undergo a significant traumatic brain injury (TBI) to the ultimate clinical outcomes observed in this study, highlighting the glycolytic state that contributes to the local metabolic central role of serum lactate as a key systemic Stage 1: Traumatic Brain Injury (TBI) The cytotoxic inflammatory mediators.
Stage 3: The entire pathological sequence is initiated by the primary Neurometabolic Crisis The convergent pressures of a mechanical insult to the brain.
This event, depicted by surging energy demand .
rom excitotoxicit.
and a a schematic of a dysfunctional and over-stimulated collapsing energy supply .
rom mitochondrial failur.
brain, encompasses the direct physical forcesAi culminate in a state of profound bioenergetic collapse.
acceleration, deceleration, and rotational stressesAi This metabolic crisis, symbolized by a biohazard icon, that cause immediate structural damage to neurons, forces a desperate and inefficient cellular shift to glia, and the cerebrovasculature.
This primary impact anaerobic glycolysis as the sole means of generating results in parenchymal contusions, lacerations, and ATP.
This results in the massive overproduction of diffuse axonal injury.
While this initial damage is lactate and the generation of intracellular acidosis.
largely irreversible, its most critical consequence is the key consequence of this state is the complete immediate activation of a complex and multifaceted disruption of the elegant Astrocyte-Neuron Lactate secondary injury cascade, a series of delayed and Shuttle.
In this pathological state, damaged neurons potentially preventable pathological processes that are unable to utilize the lactate provided by the now amplify the initial damage and ultimately determine hyper-metabolic the patient's long-term fate.
Stage 2: The Secondary accumulation in the brain's interstitial fluid.
Stage 4:
Injury Cascade This stage illustrates the three Systemic Manifestation and the Measured Biomarker convergent pillars of secondary injury that drive the The lactate that accumulates within the brainAos subsequent metabolic collapse.
These processes do not occur in isolation but are deeply interconnected, blood-brain creating a feed-forward cycle of damage.
First, measurable increase in systemic serum lactate levels, excitotoxicity, represented by a lightning bolt, signifies as depicted by the test tube icon.
This elevated serum lactate is therefore not merely a sign of peripheral neurotransmitter glutamate from damaged neurons.
hypoxia or shock, but a direct, quantifiable echo of the This leads to a catastrophic influx of calcium ions into surrounding neurons, creating an enormous and Furthermore, immediate demand for cellular energy (ATP) to power the ion pumps that frantically attempt to restore ionic acidosis worsens cerebral edema, which in turn Concurrently, this intracellular calcium increases intracranial pressure (ICP), reduces cerebral overload, along with the associated oxidative stress blood flow .
eading to ischemi.
, and drives even more anaerobic glycolysis and lactate production.
This mitochondrial dysfunction, powerfully depicted by a devastating vicious cycle, illustrated in the schematic, low-battery icon.
This cripples the cellAos primary accelerates the brain's descent into irreversible injury.
energy-generating machinery, impairing the process of Stage 5: Final Clinical Consequences The final, oxidative phosphorylation and preventing the efficient inexorable outcome of this irreversible energy failure conversion of pyruvate to ATP.
Finally, the brain and toxic intracellular environment is widespread mounts an intense neuroinflammatory response, neuronal cell death, powerfully visualized by a self-amplifying.
schematic of a decaying neuron within the brain.
This 20 A failure to clear lactate within the first 24- extensive loss of functional brain tissue is the ultimate 48 hours may signify a failure of initial resuscitation, biological substrate for the poor clinical outcomes inadequate control of ICP, or a relentlessly progressing observed in the study.
It manifests clinically as an secondary injury cascade, all of which portend an extremely poor prognosis.
Although a formal analysis Glasgow Outcome Scale score of 1 to 3Aiand a of lactate clearance was beyond the primary scope of significantly increased risk of mortality, thereby this paper, our findings underscore the need for serial closing the loop from the initial macroscopic injury to Future research should focus on the systemic biomarker and, finally, to the patientAos lactate kinetics as a dynamic biomarker to guide clinical fate.
outcomeAiclassified The findings of this study have significant and identifying patients who require an escalation of care.
practical implications for the clinical management of This study has several important limitations that TBI patients.
Serum lactate measurement is a rapid, must be acknowledged when interpreting its findings.
inexpensive, and universally available test, making it First, the single-center design and small sample size an ideal biomarker for broad application.
19 Our results (N=.
limit the statistical power and the external strongly advocate for its integration into the standard validity of our findings.
The results require validation initial assessment of all TBI patients.
An elevated in larger, multi-center cohorts to ensure they are generalizable across different patient populations and multivariate analysis, should serve as a critical "red healthcare systems.
Second, the primary outcome of flag" for clinicians.
For example, a patient with a GOS at discharge is a significant limitation due to moderate GCS score but a markedly high lactate level temporal bias.
It reflects in-hospital outcome, which is may be harboring a more severe underlying metabolic influenced by length of stay and local discharge injury than is clinically apparent and should be practices, rather than true long-term neurological recovery, which continues to evolve for months.
Future aggressive management.
This allows for a more studies must incorporate standardized, fixed-time nuanced risk stratification that moves beyond sole point follow-up .
t 6 or 12 month.
to assess long-term reliance on the GCS and structural imaging.
Third, while we controlled for major confounders, other unmeasured variables, such as envisioned where a lactate level above a certain pre-hospital hypoxia or hypotension and the specifics threshold (>2.
5 mmol/L) in a moderate TBI patient of resuscitation fluids, could have influenced the neuro-intensivist Finally, our study used venous lactate, and consult, an earlier repeat CT scan, or consideration for while strongly correlated with arterial lactate in many invasive ICP monitoring.
In resource-limited settings, settings, arterial samples are considered the gold where advanced neuromonitoring may be unavailable, standard for assessing global metabolic state.
These lactate can serve as an invaluable tool for guiding limitations highlight the need for further, more resource allocation and providing objective prognostic comprehensive research to build upon our findings.
"lactate information to families.
While our primary analysis focused on the prognostic power of the admission Conclusion lactate value, the collection of serial data highlights This prospective, single-center study demonstrates the importance of lactate kinetics.
A single lactate that an elevated admission serum lactate level is a value is a static snapshot, whereas the trend over time, strong and independent predictor of unfavorable in- or lactate clearance, reflects the patient's response to hospital functional outcome and mortality in patients resuscitation and the evolution of the secondary with traumatic brain injury, even after adjusting for initial injury severity and age.
While the study's Zhang K-Y.
Li P-L.
Yan P.
Qin C-J.
He H.
Liao conclusions regarding long-term prognosis are limited C-P.
The significance of admission blood by the use of a discharge-based endpoint, the findings lactate and fibrinogen in pediatric traumatic powerfully reinforce the interpretation of lactate as a brain injury: a single-center clinical study.
critical and accessible biomarker that reflects the Childs Nerv Syst.
: 1207Ae12.
severity of the underlying neurometabolic cascade Plourde G.
Ichai C.
Quintard H.
Cerebral involving mitochondrial failure, excitotoxicity, and lactate uptake after half-molar sodium lactate Given its universal availability therapy in traumatic brain injury: a brief and low cost, serum lactate measurement should be J Neurotrauma.
Ae.
integrated as a standard component in the early e1807Ae11.
assessment and risk stratification of TBI patients.
Martin-Rodriguez F.
Sanz-Garcia A.
Lopez- where it can provide invaluable prognostic information Izquierdo R.
Delgado Benito JF.
Martynez to enhance clinical decision-making and aid in the Fernyndez FT.
Otero de la Torre S, et al.
Prehospital lactate levels obtained in the consequences of secondary brain injury.
ambulance and prediction of 2-day in-hospital mortality in patients with traumatic brain
References