Lactate Therapy After Traumatic Brain Injury (LS_TCC)

Neuroprotective Role of Lactate Therapy in Humans With Traumatic Brain Injury

Background: Although glucose is essential to cerebral function, abundant experimental and clinical evidence demonstrates that endogenously released lactate, rather than glucose, is the preferential energy substrate for the brain in conditions of stress and acute injury. In patients with severe Traumatic Brain Injury (TBI) and aneurysmal subarachnoid hemorrhage (SAH) monitored with cerebral microdialysis and brain tissue oxygen (PbtO2), our preliminary data show that increased brain extracellular lactate is frequently observed. Our findings indicate that elevated brain lactate more often occurs in the absence of brain hypoxia/ischemia and is mainly the consequence of increased cerebral glycolysis, i.e. it occurs in association with high extracellular pyruvate. These data suggest that the primary source of elevated lactate is activated glycolysis and strongly support the concept that endogenously released lactate can be utilized by the injured human brain as energy substrate. They prompt further investigation to examine whether exogenous lactate supplementation can be a valuable neuroprotective strategy after TBI or SAH. Indeed, in animal models of brain injury, administration of exogenous lactate improves neuronal and cognitive recovery.

Hypothesis: The investigators test the hypothesis that lactate therapy, administered during the acute phase of TBI or SAH, might exercise neuroprotective actions by restoring brain energetics and improving brain tissue PO2 and cerebral blood flow (CBF).

Aim of the study: The aim of this single-center study is to examine the effect of sodium lactate infusion on cerebral extracellular metabolites, brain tissue PO2 and cerebral blood flow, measured with CT perfusion and transcranial doppler (TCD).

Design: Prospective phase II interventional study examining the effect of a continuous 3-6 hours infusion of sodium lactate (20-40 µmol/kg/min), administered within 48 hours from TBI or SAH, on cerebral extracellular glucose, pyruvate, glutamate, glycerol, PbtO2 and CBF.

Study Overview

• Status: Completed
• Conditions: Traumatic Brain Injury; Subarachnoid Hemorrhage
• Intervention / Treatment: Other: sodium lactate infusion

Detailed Description

Study: Prospective, single-centre phase II interventional study. The study will take place at the Department of Intensive Care Medicine, Lausanne University Medical Center (Centre Hospitalier Universitaire Vaudois, CHUV), Lausanne, Switzerland.

Patient population:

Patients will be monitored with an intra-parenchymal monitoring system, consisting of ICP (Codman®, Integra Neurosciences), PbtO2 (Licox®, Integra Neurosciences) and cerebral microdialysis (CMA Microdialysis®) catheters, based on the protocol for management of TBI presently in use at our center.

Each patient will receive a continuous infusion of sodium lactate (composition: lactate 1'000 mmol/L, Na 1'000 mmol/L: concentration 20-40 µmol/kg/min) for 3-6 hours. Sodium lactate will be prepared locally by the Pharmacie Centrale, CHUV, Lausanne.

Each patient will serve as his/her internal control, and the effect of sodium lactate on all brain physiological variables measured will be anayzed before, during and at the end of sodium lactate infusion.

The main parameters of efficacy are increases of MD glucose, MD pyruvate, PbtO2, and CBF, during sodium lactate perfusion.

For both MD glucose and MD pyruvate, we fixed as the minimal detectable effect of sodium lactate infusion a 30% increase of glucose and pyruvate at the end of the study. To obtain a power of 0.8 with an alpha of 0.05, the number of patients required to complete the study is 33. We therefore plan to include 35 patients.

Statistical analysis: At each time-point (baseline, during perfusion, end of sodium lactate infusion), differences of mean MD glucose, lactate, pyruvate, PbtO2, CBF, Mean transit time, ICP, CPP will be analyzed. We will also examine the percentage time spent with abnormal values (MD glucose < 1 mmol/L, PbtO2 < 20 mm Hg, ICP > 20 mm Hg). Differences will be compared using ANOVA for repeated measures.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • Lausanne, Switzerland, 1011
    • CHUV, Lausanne University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients admitted to our intensive care unit (ICU) after severe TBI or poor-grade aneurysmal subarachnoid hemorrhage (SAH), defined by a post-resuscitation Glasgow Coma Scale (GCS) < 9
• Age 18-75 years
• Abnormal head CT-scan (Marshall grade ≥ 2 or Fisher >2)
• Intracranial pressure (ICP), PbtO2 and cerebral MD monitoring as part of standard care

Exclusion Criteria:

• Penetrating TBI
• non aneurysmal SAH
• Age < 18 or > 75 years,
• More than 1 extra-cranial injury with sustained hemodynamic instability and sustained blood lactate elevation > 4 mmol/L
• Cognitive handicap due to previous neurological or neurosurgical history
• Non-survivable injury, brain death or expected death within 48 hours
• Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: sodium lactate infusion; Continuous i.v. infusion of Sodium Lactate (2'400 mOsmol/L) over 3 hours	Other: sodium lactate infusion; 3-6 hours continuous infusion of sodium lactate (20-40 mcg/kg/min)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Increase from baseline in brain extracellular lactate, pyruvate and glucose	Increase from baseline in brain extracellular lactate, pyruvate and glucose measured with intra-parenchymal cerebral microdialysis catheter	6 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Increase from baseline in brain tissue PO2	Brain tissue PO2 will be measured with intra-parenchymal probes	6 hours
Increase from baseline in cerebral perfusion pressure		6 hours
Decrease from baseline in intracranial pressure		6 hours
plasma sodium		6 hours
plasma osmolality		6 hours
mean CBF, measured by transcranial doppler		6 hours

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire Vaudois
• Collaborators: Swiss National Science Foundation; European Society of Intensive Care Medicine

Publications and helpful links

General Publications

• Carteron L, Solari D, Patet C, Quintard H, Miroz JP, Bloch J, Daniel RT, Hirt L, Eckert P, Magistretti PJ, Oddo M. Hypertonic Lactate to Improve Cerebral Perfusion and Glucose Availability After Acute Brain Injury. Crit Care Med. 2018 Oct;46(10):1649-1655. doi: 10.1097/CCM.0000000000003274.
• Bouzat P, Sala N, Suys T, Zerlauth JB, Marques-Vidal P, Feihl F, Bloch J, Messerer M, Levivier M, Meuli R, Magistretti PJ, Oddo M. Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain. Intensive Care Med. 2014 Mar;40(3):412-21. doi: 10.1007/s00134-013-3203-6. Epub 2014 Jan 30.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2012
• Primary Completion (Actual): December 18, 2017
• Study Completion (Actual): December 18, 2017

Study Registration Dates

• First Submitted: April 1, 2012
• First Submitted That Met QC Criteria: April 6, 2012
• First Posted (Estimate): April 9, 2012

Study Record Updates

• Last Update Posted (Actual): September 9, 2021
• Last Update Submitted That Met QC Criteria: September 8, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: subarachnoid hemorrhage; traumatic brain injury; lactate; transcranial doppler; brain metabolism; cerebral microdialysis
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Intracranial Hemorrhages; Brain Injuries; Wounds and Injuries; Hemorrhage; Brain Injuries, Traumatic; Subarachnoid Hemorrhage
• Other Study ID Numbers: 237/10

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No