An interventional study of Genetic analysis of polymorphism of membrane receptors involved in lactate transport in Surgical Procedure, Unspecified, Postoperative Complications and Hyperlactatemia, sponsored by Fondazione Policlinico Universitario Agostino Gemelli IRCCS. Not yet recruiting at 1 site in Italy. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-01-24.
Sponsored by Fondazione Policlinico Universitario Agostino Gemelli IRCCS · Not applicable, Interventional, and Screening
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:
Participants will undergo pre-operative genomic assay testing.
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.
1,332 studies on the registry are indexed under Postoperative Complications; 311 are open to participants now.
This study's planned enrollment of 109 is close to the median of 114 across 766 interventional studies indexed under Postoperative Complications.
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Exclusion Criteria:
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You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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).
Genetic: 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).
Lactate levels
Lactate levels (mmol/L) in the patients carrying the T allele versus the A allele for MCT1 gene.
Time frame: 3 hours after the end of surgery
Polymorphisms of lactate receptors (presence of MCT4 and GPR8)
Prevalence of the lactate receptors MCT4 and GPR8 polymorphisms throughout the genetic analysis of a blood sample.
Time frame: Minutes and an average of 30 minutes before the start of surgery
Lactate clearance
Evaluation of the association between lactate clearance (lactate levels at the end of surgery - lactate levels at 3 hours after the end of surgery)x100/lactate levels at the end of surgery and the presence of lactate receptor polymorphisms (MCT4 and GPR8).
Time frame: 3 hours after the end of surgery
Lactate clearance
Evaluation of the association between lactate clearance (lactate levels at the end of surgery - lactate levels at 24 hours after the end of surgery)x100/lactate levels at the end of surgery and the presence of lactate receptor polymorphisms (MCT4 and GPR8).
Time frame: 24 hours after the end of surgery
Postoperative recovery
Length of stay in recovery room (RR) or in intensive care (ICU)
Time frame: Hours (RR) or days (ICU) and average of three hours for RR and one day in ICU
In-hospital stay
Hospital stay duration
Time frame: Days until discharge, an average of 7 day
Hyperlactacidemia
Analysis of potential risk factors for hyperlactacidemia (lactate levels \>2.2 mmol/L) as well as the presence of lactate receptor polymorphisms including age (years), comorbidities, American Society of Anesthesiologists (ASA) physical status classification system, Body Mass Index (kg/m2), type and duration of surgery (hours), surgical approach (open, laparoscopic, robotic), total of liquids administered (ml), total diuresis (ml), blood losses (ml), intraoperative blood components transfusions (units), blood gas analyses parameters, number of hypotensive episodes during surgery (MAP\<65 mmHg) requiring the administration of norepinephrine or its dosage increase.
Time frame: 3 hours after the end of surgery
This study is not yet recruiting, as verified in Dec 2023. You cannot join it, but the record below documents what was studied.
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