Effects of lactate-based therapies on intracranial pressure and brain metabolism of patients with acute brain injury: a systematic review

Abstract

Background

Sodium lactate–based solutions have been proposed as an alternative to conventional osmotic therapies for intracranial pressure (ICP) control in acute brain injury (ABI). Beyond their osmotic properties, lactate may also act as a cerebral metabolic substrate, although its effects appear context-dependent. The aim of this systematic review was to synthesize available data on lactate-based therapies in ABI, focusing on their effects on intracranial dynamics, cerebral metabolism and neurological outcomes to guide future clinical translation.

Methods

We performed a systematic review of preclinical and clinical studies evaluating exogenous sodium lactate administration in ABI, including traumatic brain injury, ischemic stroke, and cardiac arrest. Outcomes of interest included intracranial pressure control, cerebral metabolism, cerebral perfusion and oxygenation, systemic hemodynamics, safety, and functional recovery.

Results

Twelve preclinical and twelve clinical studies were included. Across most models, sodium lactate was effective in reducing ICP and at least as effective and safe as mannitol or hypertonic saline in clinical settings. Several studies reported improved systemic hemodynamic tolerance compared with conventional osmotherapy. Preclinical and clinical metabolic data demonstrated that lactate can be taken up and oxidized by the injured brain; however, metabolic benefits were inconsistent and appeared dependent on preserved oxidative metabolism, baseline metabolic status, timing, and dose. Functional outcome data were limited but suggested potential cognitive and neurological benefits in both experimental and selected clinical settings.

Conclusions

Sodium lactate is an effective therapy for intracranial hypertension and may offer additional metabolic and systemic advantages in ABI patients under specific conditions. Its metabolic effects appear critically dependent on preserved oxidative capacity, highlighting the need for improved patient selection and the potential role of metabolic monitoring to guide therapy. The impact of lactate-based treatments on meaningful functional outcomes remains uncertain and warrants further investigation in targeted clinical trials.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s13054-026-05973-3.

Introduction

One of the cornerstones in the management of acute brain injury (ABI), including traumatic brain injury (TBI), intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), ischemic stroke (IS), and post-cardiac arrest hypoxic encephalopathy (PCA), is the prevention of secondary injury [1, 2]. ABI is commonly associated with elevated intracranial pressure (ICP), which compromises cerebral perfusion and reduces oxygen and glucose delivery to the brain, resulting in ischemia [3]. In parallel, injured neural tissue exhibits increased metabolic activity and energy demand as part of the cellular stress response [4–6]. The combination of reduced substrate availability and excessive energy requirements leads to a state of metabolic disequilibrium, which might translate into poor neurological outcome [7, 8]. Impaired mitochondrial oxidative function, altered glucose utilization, and secondary energy failure constitute key components of this pathophysiological cascade [9, 10]. These mechanisms underscore the rationale for therapeutic strategies that target both osmotic control of ICP and support of cerebral metabolism, which may have broad applicability across different ABI subtypes.

Mannitol and hypertonic saline are currently recommended as first-line osmotic agents for the management of elevated ICP, and comparative studies have not demonstrated consistent superiority of one over the other in terms of intracranial dynamics or clinical outcomes [11–13]. However, neither of them is devoid of adverse effects. Mannitol may induce excessive osmotic diuresis, hypotension, electrolyte disturbances, and acute kidney injury, particularly with repeated administration [14, 15]. Hypertonic saline, when used chronically or at high concentrations, can result in severe hypernatremia, hyperchloremic metabolic acidosis, fluid overload, renal dysfunction, and hematological complications [14, 16]. These limitations emphasize the need for alternative osmotic strategies that not only achieve ICP control but also provide additional neuroprotective or metabolic benefits.

Lactate has traditionally been regarded as a metabolic byproduct of anaerobic glycolysis and, accordingly, its cerebral accumulation has been interpreted as a marker of impaired oxidative metabolism [17, 18]. The lactate/pyruvate ratio (LPR) derived from cerebral microdialysis is used in neurocritical care as an indicator of the cellular energy balance [19]. However, there is increasing evidence on the key role of exogenous lactate to support oxidative metabolism when oxygen or glucose delivery is compromised in the injured brain [20, 21]. Hypertonic lactate-based solutions, in particular, combine the osmotic properties required to reduce cerebral edema with the potential metabolic advantage of providing a preferential fuel during energy crisis [22]. Despite these promising experimental and early clinical findings, the evidence supporting lactate-based therapies in ABI remains limited and heterogeneous.

This systematic review aimed to synthesize and critically appraise the available data on hypertonic and lactate-supplementation therapies, focusing on their effects on intracranial dynamics, cerebral metabolism, and functional outcomes, to guide future clinical translation.

Methods

Search strategy and data extraction

This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and registered in PROSPERO (CRD420251179647). A comprehensive literature search was performed across PubMed/MEDLINE, Embase, Scopus, and Web of Science from inception to October 2025. Search terms combined controlled vocabulary (MeSH or Emtree) and free-text words related to hypertonic sodium lactate, lactate therapy, and acute brain injury (Table S1 in the Supplement). Abstract and full-text screening were performed by two independent reviewer groups. Any disagreements were discussed and resolved by a third reviewer. References were first retrieved into a spreadsheet and, after screening, summarized in a pre-defined Data Collection Form (DCF).

Eligibility criteria

Studies were considered eligible if they included experimental or clinical models of ABI, encompassing TBI, SAH, ICH, IS or PCA. Eligible interventions involved the administration of hypertonic sodium lactate or lactate-enriched solutions delivered as boluses or continuous infusions, either alone or in combination with other agents. Comparator groups could include isotonic or hypertonic saline, mannitol, other osmotic therapies or no intervention. Studies were required to report at least one relevant outcome related to intracranial pressure (ICP), cerebral perfusion or metabolism, systemic hemodynamics, neurological or functional outcomes, or safety parameters. Eligible designs comprised in vivo animal studies, randomized or non-randomized clinical trials, and prospective or retrospective observational studies. Exclusion criteria included in vitro experiments, studies assessing lactate solely as a diagnostic or metabolic marker, review articles, editorials, and case reports. Investigations involving healthy participants or populations without acute brain injury were also excluded.

Data synthesis and quality assessment

Data were extracted independently by a two-reviewer team using a standardized form, and any discrepancies were resolved by consensus. The extracted information included study characteristics (year, country, design, sample size, and setting); population details (species for animal studies, injury model or etiology, and baseline severity); intervention parameters (sodium lactate concentration, volume, route, duration, and comparator); outcomes (intracranial pressure, cerebral hemodynamics, metabolic markers such as lactate, pyruvate, and lactate/pyruvate ratio, functional or neurological endpoints, systemic hemodynamics, and complications); and the main findings, including the direction and magnitude of effects relative to controls. When required, corresponding authors were contacted for clarification, and all extracted data were cross-checked for accuracy before analysis.

Methodological quality was appraised using validated tools according to study design. Randomized clinical trials were assessed using the Cochrane Risk of Bias 2.0 tool, while non-randomized studies were evaluated using the ROBINS-I tool. Detailed assessments are presented in Supplementary Tables S3 and S4. Each domain was rated as low, unclear, or high risk of bias. Two reviewers conducted these assessments independently, resolving disagreements through discussion. Given the heterogeneity in study designs, injury models, sodium lactate concentrations, and outcome measures, a quantitative meta-analysis was not feasible. Consistency of findings across studies was qualitatively assessed to identify overall trends and knowledge gaps.

Results

Search results

From 1,307 records identified through database screening and reference lists, the above-mentioned inclusion and exclusion criteria were applied to identify 12 animal studies and 12 clinical studies directly addressing the research question (Fig. 1). Main reasons for exclusion in the abstract screening were non-animal/non-human studies or review articles.

Fig. 1.

PRISMA Flowchart diagram for identification and inclusion of studies

Preclinical studies

A total of 12 preclinical studies investigated the effects of exogenous sodium lactate administration in models of ABI by fluid percussion or controlled cortical impact, IS by transient middle cerebral artery occlusion, and cardiac arrest through ventricular fibrillation and later resuscitation. Most studies were performed in rodent models, while others used rabbit or swine models. Sample sizes ranged from 20 to 80 animals (Table 1).

Table 1.

In vivo experimental studies assessing the effects of sodium lactate therapy

Author	Experimental design	Population	Intervention	Control	Outcomes measured	Main findings
Rice et al. (2002) [34]	Prospective experimental study	Rats (TBI Fluid percussion model) (n = 33)	Continuous IV infusion of sodium lactate (3.5 mEq/kg) 30 min after TBI and continued 3 h	Sham and injured rats with isotonic saline solution (0.9%)	Cell numbers in hypocampus and cognitive function (Morris water maze).	Sodium lactate administration demonstrated a significant improvement in cognitive ability.
Holloway et al. (2007) [23]	Prospective experimental study	Rats (TBI Fluid percussion model) (n = 80)	Continuous IV infusion of hypertonic sodium lactate (10mM, 28mM, 100mM, 280mM) for 3 h post-injury	Sham and TBI rats with continuous IV infusion of isotonic saline	Righting reflex time, cognitive deficits (determined with the Morris water maze), cerebral ATP quantification.	IV infusion of 100mM L-lactate provided the optimal concentration for cognitive recovery, probably via the regeneration of ATP
Berthet et al. (2009) [30]	Randomized controlled experimental study	Rats (IS Transient middle cerebral artery occlusion (MCAO) – ischemia–reperfusion model) (n = 39)	100 mmol/L L-lactate solution injected intracerebroventricularly directly after reperfusion	Phosphate-buffered saline solution (vehicle) injected intracerebroventricularly	Infarct volume, neurological deficit (measured by severity test, beam walking test and Rotarod treadmill).	Administererd inmediately after reperfusion, it showed an improvement in neurological outcome and a significant decrease in lesion size, which was not seen in a later injection 1 h
Prieto et al. (2011) [24]	Randomized controlled experimental study	Rats (TBI Impact-acceleration model, severe diffuse TBI) (n = 80; 10 per group)	Sodium lactate infusion (100 mM − 2000 mM) and one group with 500 mM sodium lactate and magnesium sulfate	Sham and TBI rats with either normal saline (0.9%, 154 mM NaCl) or hypertonic saline solution (7.5%, 1280 mM NaCl)	Brain energy metabolites: (ATP, NAA, NAD⁺, lactate, GSH, MDA)	Sodium lactate did not prevent energy depletion post-TBI; NAD⁺ reduction limits lactate use.
Alessandri et al. (2012) [31]	Prospective experimental study	Rats (TBI Controlled cortical impact model)	Lactate (100 mM), intravenous (30 min injury after the insult), for 3 h	Isotonic saline solution	Lesion volume, glutamate release, and cerebral blood flow (CBF).	Lactate infusion showed a reduction of contusion volume cortical impact and an increase in CBF
Berthet et al. (2012) [32]	Prospective experimental study	Rats (IS Transient middle cerebral artery occlusion– ischemia–reperfusion model)	Two sets of experiments with either sodium lactate administered intracerebroventricularly or intravenously at reperfusion.	Phosphate-buffered saline solution (vehicle) administered intracerebroventricularly	Neurological deficit (measured by beam walking test and Rotarod treadmill), and lesion volume at 48 h, 7 and 14 days after injury.	Lactate protects the mouse brain against ischaemic damage, with behavioural and histological benefits persisting 2 weeks after ischaemia.
Millet et al. (2018) [25]	Randomized controlled experimental study	Rats (TBI Controlled cortical impact model) (n = 20; 10 per group)	Hypertonic sodium lactate solution 11.2% continuous IV infusion (0.5 mL/kg/h for 3 h), starting 30 min after TBI induction.	Isotonic saline (0.9% NaCl) continuous IV infusion (0.5 mL/kg/h for 3 h), starting 30 min after TBI induction.	Brain metabolism parameters, Mitochondrial respiratory control ratio, ICP, cerebral oxygenation, serum electrolytes and osmolality.	HSL reversed post-TBI impairments in brain metabolism and oxygenation, reduced edema, improved mitochondrial function, and restored perfusion
Crespy et al. (2020) [26]	Randomized controlled experimental study	Rats (TBI Impact-acceleration model) (n = 30; 10 per group)	Hypertonic sodium lactate (500 mM) solution IV infusion	Sham and TBI rats with isotonic saline solution (0.9%) or hypertonic saline solution	Serum levels of lactate and osmolality Sensorimotor and cognitive tests.	Improvements in sensorimotor and cognitive test with HSL were likely due to osmotic effects, not lactate administration
Duhaut et al. (2021) [27]	Controlled experimental study	Rats (TBI Impact-acceleration model) (n = 39; 13 per group)	Hypertonic sodium lactate (500 mM) solution IV infusion (1.5mL/kg)	Isotonic saline solution or 20% mannitol solution infusion (1.5mL/kg)	ICP, brain water content, cerebral tissue oxygen pressure (PtiO₂), MAP. Aquaporin-4 (AQP4) and potassium-chloride cotransporter 2 (KCC2).	HSL reduced edema and increased PtiO₂ more effectively and longer than mannitol; effects linked to an upregulation of AQP4 and KCC2 channels
Annoni et al. (2023) [28]	Randomized controlled experimental study	Swine (Cardiac arrest thorugh ventricullar fibrillation and resuscitation) (n = 35)	Continuous hypertonic sodium lactate IV infusion (bolus of 10 mmol diluted in 20mL, followed by 30 mcg/kg/min for 12 h)	Bolus of NaCl 0.9% at the beginning of CPR and continuous infusion of balanced crystalloids during the observation period	Hemodynamic and metabolic variables, vasopressor requirements, brain and cardiac biomarkers.	Sodium lactate reduced the need for vasopressors, increased cerebral activity (EEG) and decreased plasma biomarkers of cardiac and cerebral injury.
Stevic et al. (2022) [29]	Randomized blinded experimental study	“New Zealand White” rabbits (Cardiac arrest and resuscitation model) (n = 42)	Continuous IV infusion of molar sodium lactate (5 mL/kg/h) the 120-minute reperfusion period.	Isotonic saline solution	Pupillary reactivity, levels of S100β protein, in vitro brain mitochondrial functions, cardiovascular function, and fluid balance	Molar sodium lactate improved pupillary reaction and brain mitochondrial function, decreased S100-B levels and improved cardiac recovery.
Faucher et al. (2024) [33]	Randomized blinded experimental study	Male “New Zealand White” rabbits (Cardiac arrest and resuscitation model) (n = 24)	Continuous IV infusion of isotonic molar sodium lactate (30mL/kg, 332mOsm/L) 30 min after cardiac arrest.	Isotonic saline/Pure water Pyruvate solution Oxamate (LDH inhibitor) Fluorocitrate (TCA inhibitor)	Cerebral net uptake of lactate, extracellular concentrations of lactate and pyruvate, LPR, neurological dysfunction score	After cardiac arrest, immediate isotonic lactate administration is associated to worse neurological scores. LDH inhibition was neuroprotective.

AQP4: Aquaporin-4; ATP: Adenosine triphosphate; CBF: Cerebral blood flow; CPR: Cardiopulmonary resuscitation; EEG: Electroencephalogram; GSH: Glutathione; HSL: Hypertonic sodium lactate; ICP: Intracranial pressure; IS: Ischemic stroke; IV: Intravenous; KCC2: Potassium-chloride cotransporter 2; LDH: Lactate dehydrogenase; LPR: Lactate-to-pyruvate ratio; MAP: Mean arterial pressure; MCAO: Middle cerebral artery occlusion; MDA: Malondialdehyde; NAA: N-acetylaspartate; NAD⁺: Nicotinamide adenine dinucleotide; NaCl: Sodium chloride; PtiO₂: Brain tissue oxygen pressure; TBI: Traumatic brain injury; TCA: Tricarboxylic acid

Study design

Interventions differed in concentration, route, timing, compound and strategy. Early studies used intravenous L-lactate ranging from 10 to 280 mM [23] or sodium lactate 100–2000 mM with or without magnesium sulfate [24]. Later work adopted hypertonic sodium lactate (HSL) at molar or half-molar (0.5 M) infusions, given either as boluses or continuous infusions [25–28] (Table S2 in the Supplement). In IS models, lactate was administered intravenously or intracerebroventricularly immediately after reperfusion. Control groups mostly received either isotonic or hypertonic saline solutions or mannitol infusion. Some studies assessed cerebral metabolites via microdialysis (n = 6), while others additionally measured neurological or functional outcomes (n = 5). The most recent studies [28, 33] considered as well systemic hemodynamics and brain injury biomarkers.

Brain metabolism and structural changes

Several studies demonstrated that exogenous lactate supplementation can restore or preserve cerebral energy metabolism following brain injury (n = 6). Holloway et al. [23] showed that lactate infusion improved cortical ATP levels and reduced metabolic crisis after fluid-percussion injury, with the 100 mM dose yielding optimal neurochemical and behavioral recovery. Similarly, Millet et al. [25] showed that hypertonic sodium lactate corrected post-traumatic alterations in oxygen metabolism and mitochondrial function, increasing lactate and glucose availability and reducing lactate/creatinine ratios; Stevic et al. [29] found a parallel improvement in mitcochondrial function after treatment. In contrast, Prieto et al. [24] examined brain energy metabolites and lactate in diffuse TBI, and found that sodium lactate failed to restore energy metabolism at any concentration.

Histological analyses (n = 6 studies) reinforced the metabolic data. Berthet et al. [30, 32] observed significant reductions in infarct volume and neuronal death when lactate was administered shortly after reperfusion of IS, while Alessandri et al. [31] reported structural protection after cortical impact independent of glutamate uptake. Millet et al. [25] and Duhaut et al. [27] documented attenuated brain edema and reduced markers of oxidative stress after HSL infusion. However, in the global ischemia rabbit model, Faucher et al. [33], reported greater histological injury associated with cerebral lactate uptake; notably, this occurred with a lower cumulative lactate dose and shorter exposure compared with other experimental studies.

Cerebral perfusion, oxygenation, and hemodynamics

Several studies have focused on the effects of lactate on cerebral perfusion, oxygenation, and systemic hemodynamics (n = 4), highlighting both protective and context-dependent responses. In TBI and IS models, HSL was effective in reducing intracranial pressure and cerebral edema. Furthermore, HSL also improved brain tissue oxygenation [25, 27]. Annoni et al. [28] reported that HSL infusion after return of spontaneous circulation (ROSC) improved hemodynamic stability and reduced biomarkers of cerebral and cardiac injury, indicating neuro- and cardioprotective effects; similarly, Stevic et al. [29] found less brain and cardiac damage after lactate treatment.

Neurological outcomes

Some studies emphasized on neurological outcomes (n = 4); two of them [23, 34] demonstrated improved cognitive and sensorimotor performance following lactate infusion. Crespy et al. [26] also observed improved sensorimotor and cognitive performance in rats, likely mediated by osmotic rather than metabolic effects. Conversely, Faucher et al. [33] reported that, after cardiac arrest, immediate isotonic lactate administration is associated to worse neurological scores.

Clinical studies

Across the 12 clinical studies included in the review, most works (n = 8) focused on severe TBI patients admitted to neurocritical care units; other studies (n = 2) investigated mild to moderate TBI [38, 41] and two studies enrolled patients with ABI of mixed etiology [22, 43]. Only Ahmad et al. represented a strictly peri-operative setting after TBI, while all others were conducted in the intensive care environment. Study design varied from randomized controlled studies (n = 4) to prospective pilot studies (n = 6). One study included a retrospective cohort study with sequential therapy [22] and other compared a high dose lactate infusion versus a low dose one [45] (Table 2).

Table 2.

Clinical studies assessing the effects of sodium lactate therapy

Author	Study design	Population	Intervention	Control	Outcomes measured	Main findings
Ichai et al. (2009) [35]	Prospective, open-label randomized study	Severe TBI patients with intracranial hypertension (n = 34)	Half molar sodium lactate 0.5 M (1.5 ml/kg bolus over 15 min)	20% mannitol (1.5 ml/kg bolus over 15 min)	ICP reduction at 4 h, percentage of successfully treated intracranial hypertension episodes, systemic and metabolic variables and one-year neurological outcomes (GOS)	HSL produced a larger and longer ICP decrease than mannitol and a higher success rate treating ICP episodes; better GOS in lactate arm in this cohort.
Gallagher et al. (2009) [36]	Prospective experimental study	Severe TBI patients (n = 14)	Continuous intravenous infusion of [3-¹³C] sodium L-lactate	Patients served as their own control	(13)C-labelled cerebral microdialysis metabolites (lactate, alanine, glutamine, glutamate) and high-resolution (13)C nuclear magnetic resonance	Exogenous lactate crosses the blood–brain barrier and is oxidatively metabolized via the tricarboxylic acid (TCA) cycle, indicating lactate as an alternative cerebral energy substrate after TBI.
Ichai et al. (2013) [37]	Prospective, double-blind randomized controlled study	Severe TBI patients requiring ICP monitoring (n = 60)	Half-molar sodium lactate infusion (0.5 mL/kg/h over 48 h)	Isotonic saline solution infusion (0.5 mL/kg/h over 48 h)	Prevention of ICP surge (number of raised ICP episodes ≥ 20 mmHg), fluid, chloride and sodium balance, serum osmolality, pH, bicarbonate, lactate; and 6-month neurological outcome (GCS)	HSL reduced frequency of raised ICP episodes and improved fluid and chloride balance vs. saline. Fluid and chloride balance were lower in HSL group.
Ahmad et al. (2014) [38]	Prospective randomized controlled study	Moderate TBI patients requiring craniectomy (n = 42)	Hypertonic sodium lactate 0.5 M solution (2.5 mL/kg bolus over 15 min)	20% mannitol solution (2.5 mL/kg bolus over 15 min)	Intraoperative brain relaxation (surgeon score), hemodynamic variables (MAP, CVP, urine output) and blood glucose up to 60 min	Half-molar HSL was as effective as 20% mannitol for brain relaxation, with better hemodynamic stability (higher MAP) but increased blood glucose levels significantly.
Bouzat et al. (2014) [39]	Prospective, single-center, phase II clinical trial	Severe TBI patients (n = 15)	Hypertonic lactate infusion 0.5 M (1–2 ml/kg) bolus, followed by continuous infusion over 3 h	Patients served as their own control (pre/post infusion comparison)	Cerebral microdialysis metabolites (glucose, lactate, pyruvate, LPR), ICP, PbtO₂, systemic glucose and lactate	Sodium lactate increased cerebral lactate and glucose availability and improved cerebral energy metabolism. LPR was unchanged.
Quintard et al. (2015) [40]	Prospective, single-center pilot study	Severe TBI patients (n = 15)	Hypertonic sodium lactate infusion 0.5 M, bolus + 30–40 µmol/kg/min infusion for 3 h	Patients served as their own control (pre/post infusion comparison)	Cerebral microdialysis: lactate, pyruvate, lactate/pyruvate ratio (LPR), glucose; ICP; PbtO₂; systemic lactate and glucose levels	HSL improved cerebral energy metabolism primarily in patients with elevated baseline LPR; no adverse effects reported.
Bisri et al. (2016) [41]	Prospective, single-blind, randomized controlled study	Mild TBI patients requiring emergency neurosurgery (n = 60)	Hypertonic sodium lactate (1.5 mL/kg bolus over 15 min before surgery)	Hyperosmolar sodium chloride (3%) (1.5 mL/kg bolus over 15 min before surgery)	Cognitive function (MMSE) at baseline, 24 h, 30 d and 90 d; Hemodynamic variables; blood sodium and plasma osmolality; and adverse events 24 h postsurgery	HSL infusion significantly improved cognitive recovery in mild TBI. No adverse events were recorded.
Wolahan et al. (2017) [42]	Prospective, single-center pilot study	Moderate to severe TBI patients (n = 11)	Sodium L- lactate infusion (3.4 mg/kg/min bolus over 5 min and then 1.1 mg/kg/min for 3 h	Patients served as their own control (pre/post infusion comparison)	Cerebral uptake of glucose and lactate, systemic metabolites, safety	Infusion increased cerebral lactate uptake and increased concentrations of systemic metabolites. Sodium lactate did not prevent energy depletion post-TBI.
Carteron et al. (2018) [43]	Prospective clinical study	Acute brain-injured patients (13 TBI, 10 SAH) (n = 23)	Hypertonic sodium lactate solution 1 M (30 µmol/kg/min) over 3 h	Patients served as their own control (pre/post infusion comparison)	Cerebral microdialysis (lactate, glucose), transcranial Doppler (flow velocities), pulsatility index, systemic vitals.	HSL increased cerebral blood flow and brain glucose availability after acute brain injury
Bernini et al. (2022) [22]	Retrospective cohort study with sequential therapy	Severe acute brain injury patients (13 TBI, 4 non-TBI) (n = 17)	Hypertonic sodium lactate bolus (1.5 mL/kg, 2400 mOsmol/L) administered during episodes of ICP > 20 mmHg	Hypertonic saline bolus (1.5 mL/kg) used as a first-line treatment to reduce ICP in the same patients for comparison	ICP, Brain tissue oxygen pressure (PbtO2), microdialysis biomarkers, and blood variables (sodium, chloride, lactate, pH)	HL and HS both reduced ICP, while HL could potentially avoid hyperchoremic acidosis. No significant differences in cerebral oxygenation or energy metabolism
Plourde et al. (2024) [44]	Prospective, single-center pilot study	Severe TBI patients (n = 23)	Half‑molar sodium lactate bolus in intracranial hypertension crisis	Mannitol bolus in intracranial hypertension crisis	Arteriovenous lactate difference (AVDₗₐc) (net brain lactate uptake or export); intracranial hypertension episodes	HSL group showed positive AVDₗₐc (i.e. net brain lactate uptake), mannitol group showed negative AVDₗₐc (i.e. net lactate export), confirming integration of lactate into brain metabolism.
Vespa et al. (2025) [45]	Single-center cohort + literature analysis	Severe TBI patients (n = 5) (n = 178 in prior studies)	High-dose lactate infusion (targeting 4–6 mM arterial lactate) over 3 h	Low dose lactate infusion (targeting 2-4mM arterial lactate) over 3 h	ICP, brain metabolism (microdialysis), arterial lactate concentrations, physiologic responses	Across cohorts, high-dose protocol showed consistent metabolic improvement and ICP reduction compared with low dose.

AVDO₂: Arteriovenous oxygen difference; CPP: Cerebral perfusion pressure; CVP: Central venous pressure; GCS: Glasgow Coma Scale; GOS: Glasgow Outcome Scale; HL: Hypertonic lactate; HS: Hypertonic saline; HSL: Hypertonic sodium lactate; ICP: Intracranial pressure; LPR: Lactate/pyruvate ratio; MAP: Mean arterial pressure; NaCl: Sodium chloride; PbtO₂: Brain tissue oxygen partial pressure; SAH: Subarachnoid hemorrhage; TBI: Traumatic brain injury; TCA: Tricarboxylic acid

Brain metabolism and neuroenergetics

Among studies which evaluated brain metabolism (n = 5), Bouzat et al. [39] reported increased cerebral lactate, pyruvate and glucose levels, as well as reductions in the glutamate in cerebral microdyalisis (CMD), by using short-term infusion protocols of lactate; Wolahan et al. found an increase in lactate but not in pyruvate [42]. Gallagher et al. demonstrated cerebral lactate oxidation by showing incorporation of intravenously administered ¹³C-labelled lactate into TCA-cycle–derived metabolites using CMD and ¹³C magnetic resonance (MR) spectroscopy [36]. In a pre–post comparison study of TBI patients receiving a short-term bolus followed by continuous infusion of 0.5 M HSL, Quintard et al. [40] further highlighted that these metabolic effects were dependent on baseline LPR, with patients exhibiting elevated LPR at baseline experiencing the most pronounced improvements after lactate treatment. In contrast, in a similar model, Bouzat et al. observed increased cerebral lactate and glucose availability without significant changes in LPR [39].

Cerebral perfusion, oxygenation and hemodynamics

Among studies focusing on ICP and osmotic effects (n = 7), Ichai et al. observed significant reductions in ICP episodes compared with saline or mannitol controls [35], while, Ahmad et al. [38] demonstrated that 0.5 M sodium lactate produced brain relaxation comparable to 20% mannitol, but with improved hemodynamic stability. Additional physiological data from Vespa et al. [45] revealed a dose-dependent ICP reduction and improved cerebral metabolic profiles at higher lactate infusion targets (plasmatic lactate 4–6 mM). Regarding cerebral oxygenation, Bouzat et al. reported a decrease in PbtO₂ after lactate treatment [39], while Bernini et al. found no changes in PbtO₂ [22].

Better hemodynamic stability and reduced vasopressor requirements were demonstrated in lactate-treated patients compared with mannitol [35, 38]. Two studies found a more favorable electrolyte and acid–base balance, with sodium lactate avoiding hyperchloremic acidosis and excessive serum sodium increases [38, 39]. No significant renal or metabolic complications were reported in any study.

Neurological outcomes

Regarding neurological outcomes (n = 2), Bisri et al. [41] reported improved Mini-Mental State Examination scores in mild TBI patients receiving sodium lactate, whereas Vespa et al. [45] reported that higher-dose lactate infusions trends toward enhanced neurological recovery and cognitive performance, although these findings remain preliminary (Fig. 2).

Fig. 2.

Graphical summary of lactate-based therapy in acute brain injuries. Studies on the effects of lactate-based therapies are divided according to the main effects studied, mainly on intracranial pressure and hemodynamics and on brain metabolism, where astrocyte-neuron lactate shuttle (ANLS) plays a key role. Animal studies are shown in green; clinical studies are shown in orange. ICP: intracranial pressure, HL: hypertonic lactate, HSL: hypertonic sodium lactate, TBI: traumatic brain injury. Created in BioRender. Romero, N. (2026) https://BioRender.com/yhh6vjt

Discussion

This updated systematic review incorporates recent preclinical and clinical studies supporting a dual role for lactate-based therapies in acute brain injury, both as an osmotic therapy for intracranial hypertension and as a potential metabolic substrate for the injured brain. Clinically, interest in lactate-based osmotherapy has increased due to the limitations associated with conventional agents such as mannitol, particularly regarding hemodynamic tolerance and electrolyte disturbances [13, 14]. In parallel, advances in neurocritical care have highlighted that secondary brain injury is frequently driven by cerebral metabolic dysfunction that may persist despite adequate intracranial pressure control, emphasizing the need for therapies addressing both mechanical and metabolic components of injury [20].

Brain metabolism and neuroenergetics

Cerebral metabolic crisis is commonly defined by an elevated LPR (> 25), reflecting impaired oxidative metabolism [46]. This impairment can be due to ischemia, accompanied by low pyruvate and low oxygen, or other causes unrelated to tissue hypoxia [47], such as mitochondrial dysfunction (normal or high pyruvate and normal oxygen) or hyperglycolysis. Recent clinical studies demonstrate that metabolic crisis (LPR > 40 and brain glucose < 0.2mmol/L in CMD) is frequent in ABI, including TBI and SAH, even when intracranial pressure and cerebral oxygenation appear acceptable [4].

Preclinical data indicate that exogenous lactate can support cerebral energy metabolism following focal traumatic or ischemic injury when mitochondrial oxidative capacity is preserved. In rodent TBI models, lactate administration improved cerebral ATP levels and cognitive recovery [23, 34]. In ischemia–reperfusion models, early lactate delivery reduced infarct volume and improved neurological outcomes [30, 32]. Similarly, controlled cortical impact studies demonstrated restoration of mitochondrial function and normalization of metabolic markers following HSL infusion [25]. In ABI, direct evidence of cerebral lactate utilization was first provided by Gallagher et al., who demonstrated that exogenous lactate crosses the blood–brain barrier and is oxidively metabolized via the TCA cycle in severe TBI patients [36]. Plourde et al. measured arteriovenous difference of lactate, confirming integration of supplementary lactate into brain metabolism [44]. However, subsequent clinical studies showed that increased cerebral lactate availability does not uniformly translate into metabolic improvement. Bouzat et al. reported increased brain lactate and glucose concentrations without significant changes in LPR [39], while Wolahan et al. observed increased cerebral lactate uptake without prevention of energy depletion [42].

Interestingly, several studies suggest limits to lactate utilization, with metabolic responses depending on factors such as baseline cerebral metabolic status, dosing, and timing of administration. In a severe TBI model, lactate failed to restore cerebral energy metabolism at any concentration, which could be due to NAD⁺ depletion limiting lactate oxidation [24]. Quintard et al. demonstrated that improvements in cerebral metabolism following HSL infusion occurred predominantly in patients with elevated baseline LPR, whereas patients without metabolic distress showed minimal benefit [40]. Dose-dependent metabolic improvements were suggested in a recent cohort analysis targeting higher arterial lactate concentrations [45]; however, formal dose–response studies remain lacking. In contrast, preclinical dose-comparison data demonstrated an optimal effect at intermediate concentrations, with Holloway et al. reporting maximal ATP restoration and neurological recovery at a lactate concentration of 100 mM [23]. Duhaut et al. used half-molar sodium lactate and state that a previous dose-response study found no improvement with higher doses, although results were not shown [27]. The time of administration is also a matter of controversy, particularly in ischemia models: while some studies administered lactate immediately after reperfusion with favorable metabolic and neurological effects [23, 32], Faucher et al. showed that early cerebral lactate uptake occurred during a phase of impaired oxidative metabolism and was associated with worse neurological outcomes, with inhibition of lactate metabolism being neuroprotective [33]. Notably, differences in dosing strategy and cumulative exposure may contribute to these discrepant findings. In the Faucher model, lactate was administered at a relatively high rate over a short period (89 µmol/kg/min for 30 min; cumulative dose 2.7 mmol/kg), whereas other experimental studies reporting benefit used lower infusion rates over longer durations, resulting in substantially higher cumulative doses (Annoni et al.: 30 µmol/kg/min for 12 h, 21.6 mmol/kg; Stevic et al.: 80 µmol/kg/min for 2 h, 9.6 mmol/kg). These findings suggest that while lactate supplementation can effectively impact metabolism, its benefits may ultimately dependent on several factors related to the integrity of cerebral oxidative capacity. In addition, some experimental works have described how lactate utilization may indirectly support cerebral metabolism by sparing glucose availability for alternative pathways such as the pentose phosphate pathway, potentially contributing to redox homeostasis and membrane repair [60].

Intracranial pressure and hemodynamics

Across preclinical models, treatment with HSL showed consistent effects on ICP. Direct comparisons with other osmotic agents were limited, with superiority over mannitol reported in a single experimental study showing greater magnitude and longer duration of ICP reduction [27], while most studies used isotonic saline as control [23, 25]. In the work by Duhaut et al., reductions in brain water content were accompanied by modulation of aquaporin-4 and potassium–chloride cotransporter expression, suggesting a combined osmotic and molecular antiedematous mechanism [27]. In another work, functional improvements with HSL were comparable to those with hypertonic saline, supporting a predominantly osmotic mechanism [26]. In moderate TBI in clinical studies, HSL achieved brain relaxation comparable to mannitol while providing superior hemodynamic stability [38], and similar intracranial pressure reductions when compared with hypertonic saline [22]. In severe TBI, direct comparison with mannitol demonstrated a larger and more sustained reduction in intracranial pressure with HSL in one study [35].

Few studies evaluate cerebral oxygenation; Bouzat et al. reported a reduction in PbtO₂ following HSL infusion despite increased cerebral substrate availability, a finding interpreted as reflecting increased oxygen extraction or, alternatively, secondary to lactate-induced alkalemia and increased hemoglobin affinity for oxygen rather than tissue hypoxia, particularly given concomitant evidence of cerebral vasodilation [39]. In contrast, in preclinical TBI models, a greater improvement in PbtO₂ with hypertonic sodium lactate compared with mannitol [27] or isotonic saline [25], whereas no similar effect on cerebral oxygenation was detected when compared with hypertonic saline in a clinical study [22].

Both experimental and clinical observations support the concept that lactate may act as a cerebral vasodilator under normoxic conditions, thereby contributing to coupling between metabolism and perfusion [31, 39, 43]. In line with this interpretation, Oddo et al. have shown that brain lactate is frequently elevated in SAH predominantly due to hyperglycolysis rather than hypoxia, and that a pattern of increased hyperglycolytic lactate was associated with favorable neurological recovery, which may be related to neurovascular tone preservation [48]. Complementary in vitro data have further suggested that lactate may influence astrocyte–vascular signaling, acting as a vasodilator and increasing cerebral blood flow when perfusion is compromised [49].

Hemodynamic effects of lactate administration were favorable across experimental and clinical settings. In preclinical models of cardiac arrest, HSL after ROSC improved hemodynamic stability and reduced vasopressor requirements, alongside reductions in biomarkers of cardiac injury [28, 29]. Similar results were found in clinical studies in TBI [38]. These findings are supported by controlled human studies outside the neurocritical care setting showing direct cardiac effects of sodium lactate: both in healthy volunteers [50] and acute heart failure [51], it has shown to improve indices of left and right systolic function compared with hypertonic saline [50]. Experimental work has shown that L-lactate can simultaneously reduce systemic vascular resistance through arterial relaxation, increase venous return via selective venoconstriction, and enhance myocardial contractility, resulting in increased cardiac output without tachycardia or hypotension [52]. Importantly, these effects appear highly dependent on preserved mitochondrial oxidative capacity, providing a plausible explanation for the heterogeneous hemodynamic responses observed in states of profound circulatory or metabolic failure [53]. Future clinical trials, such as the LATTE trial (NCT05004610), will be key to validate these findings.

Functional recovery

Overall, lactate administration was associated with improved functional recovery across both preclinical and clinical studies, although outcome data remain limited. In experimental models of traumatic brain injury, lactate infusion was associated with improvements in cognitive and sensorimotor performance [23, 26, 27, 34]. In clinical studies, sodium lactate was associated with improved cognitive scores in mild TBI [41], while higher-dose lactate protocols in severe TBI showed preliminary trends toward improved neurological and cognitive recovery [45]. These functional effects likely reflect the combined impact of lactate on cerebral metabolism, intracranial pressure control, and systemic hemodynamics, including improved cardiovascular performance.

Beyond these indirect effects, lactate may also influence functional recovery through direct actions on synaptic function and neuroplasticity, as described by the astrocyte–neuron lactate shuttle (ANLS) pathways. According to this model, astrocytes preferentially perform glycolysis and glycogenolysis in response to synaptic activity, releasing lactate that is taken up by neurons and oxidized to sustain energetic demands during activation [54]. Experimental studies have shown that ANLS is required for long-term memory formation and maintenance of synaptic plasticity, as disruption of astrocytic lactate production or transport impairs long-term potentiation and memory, effects rescued by lactate but not glucose [55]. Additional work demonstrated that lactate transport from astrocytes to neurons is essential for recovery of synaptic function after hypoxia [56], supports activity-dependent neuronal translation required for memory consolidation [57], and modulates synaptic signaling through astrocyte–vascular and gliotransmission pathways [58, 59]. Together, these mechanisms provide a biologically plausible link between lactate availability and functional recovery after acute brain injury, although their clinical relevance remains to be fully established.

Strenghts and limitations

This systematic review is, to our knowledge, the first to comprehensively synthesize both preclinical and clinical evidence on the use of sodium lactate in acute brain injury, enabling a translational interpretation of its osmotic, metabolic, and systemic effects. The inclusion of studies using advanced neuromonitoring techniques strengthens the mechanistic understanding beyond intracranial pressure control alone and highlights the relevance of cerebral metabolic context. However, the available evidence is limited by small sample sizes, heterogeneous study designs, and substantial variability in lactate formulations, dosing strategies, timing of administration, and patient selection. Current clinical evidence is largely TBI-centered and extrapolation to other ABI subtypes (e.g., ischemic stroke, subarachnoid hemorrhage, post–cardiac arrest) should be made with caution. Importantly, metabolic responses to lactate are likely condition-specific, differing substantially across traumatic, hemorrhagic, and anoxic brain injury, which may partly explain the heterogeneity of observed effects and limits extrapolation across disease entities. In addition, the alkalinizing effect of lactate as a conjugate base may confound metabolic and oxygenation responses and represents a potential limiting factor in several experimental and clinical scenarios. Most clinical studies relied on physiological or metabolic surrogate endpoints, while robust long-term functional outcomes were infrequently assessed. Overall, while the existing data are promising, the heterogeneity of results underscores the need to better identify patient subgroups most likely to benefit from lactate-based therapies in neurocritical care and suggests that future clinical trials should carefully define target pathologies (initially TBI, potentially expanding to other ABI subtypes), standardize dosing regimens, and incorporate both mechanistic monitoring and meaningful functional endpoints.

Conclusions

Sodium lactate is an effective treatment of elevated intracranial pressure, with the additional advantage of avoiding hyperchloremia. Potential metabolic benefits have been reported, but these effects seem to be limited to patients with preserved oxidative metabolism, highlighting the importance of appropriate patient selection and the possible role of metabolic monitoring to guide therapy. The impact of lactate-based treatments on meaningful functional outcomes remains to be determined in future targeted clinical trials.

Author contributions

(*) NRG and ARZ are co-first authors. CR and RB are co-last authors. (†) Corresponding Author: Alberto Ruiz Pacheco (albertoruizp96@gmail.com).NRG, ARZ, CR, and RB conceived and designed the study. NRG, ARZ, SUM, JMM, BM, NS, PR, and FA performed the literature search and abstract screening. ARP, NRG, and ARZ conducted full-text screening and data extraction. NRG, ARZ, PB, FST, MO and CR assessed the methodological quality and risk of bias of the included studies. Interpretation of the results was performed by NRG, ARZ, ARP, CR, and RB, with critical input from all authors.NRG and ARZ drafted the initial version of the manuscript. The manuscript was critically revised for important intellectual content by ARP, CR, RB, FST, PB and MO. All authors reviewed and approved the final version of the manuscript.

Funding

This study was conducted without any specific funding.

Data availability

No datasets were generated in this study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.