Hyperlactacidemia in Major Abdominal Surgery and Monocarboxylate Receptors

NCT ID: NCT06222021

Last Updated: 2024-01-24

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 109 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-02-29
• Study Completion Date: 2025-10-31

Brief Summary

The goal of this clinical trial is to identify those situations in which the increase of lactate levels is not clinically relevant since it is associated with altered genetic polymorphism of the genes involved in the membrane proteins acting as carriers for lactate (mainly monocarboxylate transporters, MCTs) patients undergoing major abdominal surgery.

The main questions it aims to answer are:

1. Is there a relationship between the lactate levels in the immediate post-operative period and the presence of some lactate receptor polymorphisms?

2. Can hyperlactacidemia related to lactate receptor polymorphisms affect length of stay in the recovery room and/or in intensive care unit, postoperative hospital stay, postoperative complications? - Which are the risk factors for hyperlactacidemia in the immediate post-operative period in addition to the presence of lactate receptors polymorphisms?

Participants will undergo pre-operative genomic assay testing.

Detailed Description

Lactic acidosis is traditionally attributed to cellular hypoxia, to an imbalance between the body's demand for oxygen and its availability. Lactate is produced by the muscles, skin, brain, red blood cells and intestine and eliminated by the liver and kidneys. Lactate is produced by the following biochemical reaction: Pyruvate + reduced nicotinamide adenine dinucleotide (NADH) + H+ ↔ Lactate + nicotinamide-adenine dinucleotide (NAD+). Under normal conditions, this reaction produces lactate from pyruvate in a ratio of 10 to 1. Pyruvate comes from glycolysis and is used by mitochondria. When glycolysis is increased or mitochondrial oxidative phosphorylation is blocked, pyruvate accumulates and is converted into lactate generating hyperlactacidemia and acidosis. Normal lactate levels are 0-2 mmol/L. Hyperlactacidemia, usually defined as values above 2.2 mmol/L, is divided into two types: A (associated with hypoxia) and B (related to increased stress-induced aerobic metabolism, mitochondrial diseases and the use of drugs such as metformin and beta2 agonists). The lactate/pyruvate ratio allows us to distinguish the two types of hyperlactacidemia. In hyperlactacidemia type A, this ratio is >10 while in type B it remains constant (L/P=10). In case of liver dysfunction, hyperlactacidemia may be associated with a variable L/P ratio based on the determining cause reduction in lactate clearance. In fact, lactate extraction may depend on the hepatic blood flow, the polymorphism of some genes involved in the lactate transport (mainly MCT1) and the potential of hydrogen (pH) which inhibits gluconeogenesis when lower than 7.10. Since lactic acid is an hydrophilic weak acid, its transport across membranes requires transporters that belong to the transporter family monocarboxylates (MCTs) encoded by the solute carrier family 16 (SLC16) gene family. It has been demonstrated that the MCT1 (rs1049434) T1470A polymorphism is associated with a deficit in the transmembrane transport of lactate: in fact, the T allele is correlated with an approximately 50% reduction in the lactate transport rate compared to the A6 allele. MCT4, which has a very low affinity for pyruvate and a greater affinity for lactate, ensures that pyruvate is converted into lactate before transmembrane transport. Polymorphisms affecting these receptors can influence the different speed of transmembrane lactate flow and therefore correlate with lesser or greater accumulation of serum lactate. Another membrane receptor involved in lactate transport has recently been described: G-coupled protein receptor 81 (GPR81), present in adipocytes. Polymorphisms affecting the gene encoding this receptor could correlate with a different accumulation of lactate. An increase in the level of lactates is often correlated with increased morbidity and mortality in critical situations critical such as sepsis, trauma, major cardiac and abdominal surgery. Measurement of perioperative biomarkers such as lactate is often used in clinical practice as an outcome predictor. However, there are no studies aimed to identify those situations in which the increase of lactates is not clinically relevant since it is associated with altered genetic polymorphism.

The investigators hypothesized that lactate levels at 3 hours after the end of major abdominal surgery will be higher in the patients carrying the T allele versus the A allele for MCT1 gene.

Conditions

Surgical Procedure, Unspecified; Postoperative Complications; Hyperlactatemia; Abdomen Disease

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: SCREENING
• Blinding Strategy: NONE

Study Groups

Genetic analysis of polymorphisms of membrane receptors involved in lactate transport

Before the start of surgery, after arterial line cannulation, a blood sample will be collected in an ethylenediaminetetraacetic acid (EDTA) test tube for genetic analysis of polymorphisms of membrane receptors involved in lactate transport including transporter family monocarboxylates 1 (MTC1), transporter family monocarboxylates 4 (MTC4) and Gi-coupled protein receptor 81 (GPR81).

Group Type: OTHER

Genetic analysis of polymorphism of membrane receptors involved in lactate transport

Intervention Type: GENETIC

The DNA extracted from the blood samples (through extractor MagCore) will then undergo gene sequencing by Sanger sequencing and/or Custom NGS (Next Generation Sequencing) panels and will be used to identify nucleotide variants within genes involved in lactate transport (MCT-1/4, GPR81).

Interventions

Genetic analysis of polymorphism of membrane receptors involved in lactate transport

The DNA extracted from the blood samples (through extractor MagCore) will then undergo gene sequencing by Sanger sequencing and/or Custom NGS (Next Generation Sequencing) panels and will be used to identify nucleotide variants within genes involved in lactate transport (MCT-1/4, GPR81).

Intervention Type: GENETIC

Eligibility Criteria

Inclusion Criteria

• Age ≥ 18 years
• Indication for elective major abdominal surgery

Exclusion Criteria

• Age <18 years
• Liver cirrhosis
• Liver surgery
• Intraoperative chemotherapy
• Previous gastric bypass surgery (thiamine deficiency)
• Severe cardiovascular/respiratory impairment
• Mitochondrial diseases
• Pheochromocytoma
• Chronic renal failure ≥ stage III
• Refusal to sign the informed consent

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

UOC Anestesia delle Chirurgie Generali e dei Trapianti, Fondazione Policlinico Universitario A. Gemelli IRCCS

Rome, Italy/Lazio, Italy

Countries

Italy

Central Contacts

Paola Aceto, MD

Role: CONTACT

paola.aceto@policlinicogemelli.it

00390630154507

Chiara Cambise, MD

Role: CONTACT

chiara.cambise@policlinicogemelli.it

00390630154507

Other Identifiers

5675

Identifier Type: -

Identifier Source: org_study_id