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Clinical rational application of lactic acid monitoring
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Clinical rational application of lactic acid monitoring. Elevated serum lactic acid is an indicator of metabolic disorders caused by a variety of clinical causes.
Blood lactic acid monitoring has been in clinical use for a long time, and is often used to assess the severity of the disease in critically ill patients and their response to therapeutic interventions. In 1780, Swedish pharmacist Carl Wilhelm Scheele first discovered lactic acid in yogurt; in 1843, German physician Johann Joseph Scherer discovered lactic acid in the blood of shock patients.
In an early study, Schuster explained the value of lactate assessment for critically ill patients. A meta-analysis involving more than 150 studies believes that lactic acid is very important for the risk stratification of critically ill patients and is a potential endpoint of resuscitation.
The blood lactic acid level is positively correlated with the short-term and long-term disability rate and mortality of patients. In 2016, the rescue of sepsis movement 1h cluster treatment included lactic acid monitoring as the primary core, and it is recommended that patients be fluid resuscitation to restore the lactic acid concentration to normal.
In addition to sepsis, elevated lactate occurs in many pathophysiological conditions. Lactic acid is a product of anaerobic metabolism, but hyperlactic acid can also occur when there is no hypoxia. It is very important to understand the production mechanism of lactic acid and the physiological factors of elevated serum lactic acid, otherwise it will cause abuse of lactic acid monitoring and interpretation.
In April 2021, Anesthesiology published an article on clinical focus, discussing the clinical rational application of lactate monitoring. The full text of this article is freely available, and Ma Haixinzhi compiles the content.
As a platform for advocating the academic public welfare of anesthesia, Ma Hai Xinzhi has been committed to disseminating current new knowledge in the field of anesthesia and perioperative medicine. Fear life and pay attention to anesthesia.
Anesthesia is related to everyone’s life and health. Anesthesiologists are the vanguard and main force in emergency and critical care. This article is also one of the academic popular science articles of 2021 Chinese Anesthesia Week (March 29-April 4).
Lactic acid production and metabolism
During normal oxygenation, mitochondria produce adenosine triphosphate (ATP) for aerobic metabolism. At this time, glucose is converted into pyruvate through glycolysis, with acetyl-CoA as an intermediate product, entering the Krebs (citric acid) cycle, and most of ATP is produced in the process of oxidative phosphorylation. If there is insufficient oxygen, these pyruvate will be catalyzed by lactate dehydrogenase to produce lactic acid.
All cells produce lactic acid to varying degrees: muscle (25%), skin (25%), brain (20%), intestine (10%) and red blood cells (20%). Mature red blood cells lacking mitochondria produce lactic acid through the process of glycolytic enzyme synthesis of ATP.
When PaO2 is low, the conformational change of hemoglobin-deoxyhemoglobin makes the glycolytic complex break away, activates phosphofructokinase, and accelerates the production of ATP. ATP stimulates blood vessels through purinergic receptors and increases tissue blood flow.
As a brain signal molecule, lactic acid is related to neuronal activity, metabolism, substrate utilization and blood flow, and may also be related to short-term memory and panic disorder.
Most of the lactic acid in the body is produced by skeletal muscle. Lactic acid enters the circulation from the tissues and is converted back to glucose through gluconeogenesis in the liver (60%) and kidneys (30%), and is again used for glycolysis in various organs (Figure 1). Most of the lactic acid filtered by the kidneys is reabsorbed, and only a small part is lost in the urine. This process is called the Cori cycle.
Figure 1 The elements of the Cori cycle. In skeletal muscle, lactic acid is generated from pyruvate through glycolysis, which is then converted to glucose in an ATP-dependent manner in the liver. 25%~30% of lactic acid is metabolized by the kidneys, and a small part of lactic acid is metabolized by other organs or lost in urine
Lactate and Lactic Acid
Due to the lack of understanding of clinical biochemical basis, the concepts of Lactate and Lactic Acid are often mixed. Lactate often refers to [lactate]-(lactate), which is a weak base converted into pyruvate, which can bind to the protons produced when ATP is hydrolyzed into ADP.
When needed, the reaction speed of glycolysis is orders of magnitude faster than the Krebs cycle and oxidative phosphorylation. When excess hydrogen ions cannot be used by aerobic metabolism or are neutralized by bicarbonate, lactate and other buffer systems, acidosis will form. Therefore, hyperlactic acidosis is mainly the result of cell acidosis, rather than the direct cause of acidosis.
When the arterial blood pH is lower than the normal range and is accompanied by hyperlactic acidosis, it is usually called lactic acidosis. It is more appropriate to use terms such as sepsis-related or drug-related lactic acidosis.
Clinical causes of elevated lactate
Adults produce 15-25mEq/kg of lactic acid per day on average, and the serum concentration is 0.5-1.5mmol/L. It is generally considered that lactic acid <2mmol/L in critically ill patients is normal.
When the lactic acid value is normal, the measured values of the central venous and arterial blood samples are similar, and the peripheral venous blood can also be used; but in the case of hyperlactic acid, the correlation between the former two is not good. Increased production, decreased utilization, or both will cause lactic acid to accumulate.
Therefore, many conditions that do not involve tissue hypoxia can also lead to elevated lactic acid. The use of lactated Ringer’s solution containing 28mmol/L lactic acid will not lead to an increase in serum lactic acid. A double-blind study showed that there was no significant difference in serum lactic acid levels after infusion of 30ml/kg lactated Ringer’s solution or normal saline.
Lactic acidosis is divided into two types, type A is caused by tissue hypoxia or systemic insufficiency of perfusion, type B is caused by other factors, and contains some types. Among them, type B1 is secondary to underlying diseases, type B2 is related to poisons or drugs, and type B3 is related to congenital metabolic defects. Type A and type B lactic acidosis may also overlap.
Type A lactic acidosis
Anaerobic glycolysis is usually seen in critical illness. Any state of systemic circulatory shock (hypovolemia, cardiogenic, distributed, obstructive) will lead to reduced tissue perfusion, resulting in tissue hypoxia and type A lactic acidosis.
Local hypoperfusion is also a common cause of lactic acidosis, such as secondary to arterial or venous thrombosis, compartment syndrome, trauma, burns, necrotizing soft tissue infection, rhabdomyolysis, or iatrogenic surgical block leading to limb or single organ deficiency Blood etc. Even if the perfusion is normal, blood oxygen levels may decrease, leading to type A lactic acidosis.
Common causes include hypoxemia secondary to respiratory failure, severe anemia, or carbon monoxide poisoning. But only when hypoxemia is quite severe (PaO2<35mmHg) lactic acid will increase.
When the lactic acid production rate is greater than the liver lactic acid clearance rate and exceeds the renal excretion rate (5-6mmol/L), all the above-mentioned pathophysiological conditions will lead to hyperlactic acidemia.
Skeletal muscle has the strongest ability to produce lactic acid. In order to supply energy during strenuous activity, the lactic acid under physiological conditions can be increased to 15-20mmol/L. But this process is relatively short, and lactic acid can also be quickly removed.
In general tonic-clonic seizures, the skeletal muscles continue to contract and the lactic acid is extremely elevated, but it usually clears within 1 to 2 hours after the seizure stops. Any acute muscle stiffness disorder, including serotonin syndrome, nerve blocker malignant syndrome and malignant hyperthermia, will increase lactic acid. Increased work of respiratory muscles will also increase lactate.
Hyperlactic acid can also occur in patients with severe chills due to hypothermia or due to agitation against physical restraints. Convulsions caused by energy-conducting weapons (such as stun guns, etc.) that cause a temporary increase in lactic acid are not within the scope of clinical consideration.
Type B lactic acidosis
Type B has no evidence that lactic acidosis occurs when tissue oxygen is insufficient. Although type B lactic acidosis is less common than type A, the differential diagnosis is widespread (Figure 2). In liver and kidney dysfunction, the decrease in clearance rate can lead to the increase of lactic acid; and the liver is the main gluconeogenesis organ, and the increase of lactic acid is particularly obvious when cirrhosis or end-stage liver disease occurs. Many inborn disorders of carbohydrate metabolism, glycogen storage, or mitochondrial dysfunction can cause lactic acid to increase due to the accumulation of pyruvate. These rare congenital diseases are generally only seen in the pediatric population.
Figure 2 Type A lactic acidosis is caused by decreased oxygenation of the upper tissue, manifested by intestinal ischemia and ultrasound showing myocardial dysfunction. Type B lactic acidosis is due to organ dysfunction, metabolic factors, and drug influences that increase the production of lactic acid in oxygenated tissues. In both types of lactic acidosis and cirrhosis, the accumulation of lactic acid exceeds the liver’s ability to metabolize it to glucose.
Other pathological conditions that interfere with the metabolic cascade of cells can also cause lactic acidosis. When alcohol, methanol, and propylene glycol are poisoned, alcohol dehydrogenase produces nicotinamide adenine dinucleotide, which promotes the conversion of pyruvate to lactic acid.
Vitamin B1 is an essential cofactor for a variety of metabolic enzymes involved in the utilization of pyruvate (including pyruvate dehydrogenase), and can promote anaerobic metabolism when lacking. Cyanide poisoning will uncouple the electron transport chain during oxidative phosphorylation, leading to an increase in serum lactic acid.
Many drugs are also associated with lactic acidosis. The classic example is metformin, which rarely causes lactic acidosis by itself, but not when there are other comorbidities. Metformin can reduce liver gluconeogenesis, thereby reducing the liver’s uptake of lactic acid; damaging mitochondrial complex 1 (maintaining the proton gradient required for ATP production) increases glycolysis, thereby promoting lactic acid production; large doses of metformin can reduce liver lactic acid Ingestion, and increase the production of lactic acid in the intestines and other organs.
A study of 37,000 ICU patients showed that when the lactate value was 5-10mmol/L, the mortality rate of metformin users (35%) was lower than that of non-users (43%). The relationship between diabetes and lactic acidosis is not affected by metformin.
The antibiotic linezolid and many nucleoside reverse transcriptase inhibitors used to treat HIV infection have mitochondrial toxicity. Any drug overdose that causes liver and kidney damage or sympathetic hyperexcitability can cause lactic acidosis. Increased anaerobic metabolism of tumor cells may also lead to lactic acidosis.
β2 receptor agonism can change the plasma lactic acid concentration. The use of epinephrine during septic shock increases the ratio of lactate/pyruvate and reduces visceral blood flow. Injecting epinephrine into healthy volunteers under aerobic conditions can increase lactic acid, which may be the direct effect of epinephrine on carbohydrate metabolism, which is called aerobic glycolysis.
An early study showed that injection of norepinephrine will slightly increase lactic acid within the normal range, while dobutamine does not affect the concentration of lactic acid. In sepsis, an increase in the dose of adrenaline leads to a linear increase in lactic acid, while dobutamine makes it decrease. Inhaled beta receptor agonists for the treatment of asthma can cause hyperlactic acidemia, sometimes even exceeding 4mmol/L.
Anesthesiologists also need to understand the effect of propofol on lactic acid metabolism. A large number of case reports have shown that high-dose or prolonged infusion of propofol can cause propofol infusion syndrome, accompanied by hyperlactic acidemia. However, a study of 8 hours of spinal surgery under different anesthesia methods showed that total intravenous anesthesia with propofol did not increase serum lactic acid, while sevoflurane increased it by 7%.
D-lactic acid is a stereoisomer of L-lactic acid, which is produced by certain intestinal bacteria in cheese or large amounts of undigested carbohydrates through the pyruvaldehyde pathway. D-lactic acidosis is more special and can occur in patients with short bowel syndrome. The research on D-lactic acid as an index of intestinal ischemia is still inconclusive.
The elevated level of D-lactic acid in the urine of diabetic patients, together with microalbuminuria, may be used as an early indicator of kidney disease. Routine lactic acid test will not distinguish D-lactic acid, but patients with short bowel syndrome and unexplained anion gap metabolic acidosis should be differentiated.
Sepsis is associated with both type A and type B lactic acidosis. Due to the imbalance of the host’s response to infection, sepsis and septic shock can cause disturbances in the macrocirculation, microcirculation, and cellular levels. Even after adequate fluid resuscitation, lactic acid will still rise through a variety of mechanisms.
After hemodynamics are normal or corrected, capillary endothelial damage may also affect the release of oxygen from red blood cells. Animal studies have shown that when PaO2 is low, lactic acid affects the production and release of ATP from red blood cells.
Sepsis and hypotension are often caused by cardiac dysfunction. Sports research can provide inspiration for understanding myocardial metabolism in sepsis. During exercise, the oxidation of glucose and lactic acid by the myocardium increases; glucose uptake increases during light/moderate exercise, and decreases during high-intensity exercise. These findings suggest that substrates such as lactic acid may also contribute to cardiac energy metabolism.
In sepsis and critical illness, endogenous catecholamine release and exogenous infusion will make the patient in an adrenergic state, and glycolysis will increase accordingly.
In experimental endotoxin shock, β2 activation can increase lactic acid production, and is related to the increase of endogenous adrenaline, which indicates that hyperlactic acid may be an adaptive mechanism.
In sepsis, due to enzymes (including pyruvate dehydrogenase) and mitochondrial dysfunction, even if the cell’s oxygen supply is sufficient, it cannot be used. In severe acidemia, not only the renal and liver perfusion is limited, but the gluconeogenesis ability is also greatly reduced.
When lactic acid is infused into patients with stable sepsis, patients with hyperlactic acidemia have lower lactic acid clearance rates than those who do not, which means that the increase in lactic acid is secondary to utilization defects.
When the patient first develops an increase in lactate, it should be diagnosed carefully and treated for the cause. The determination of lactate has three purposes: diagnosis of severe sepsis, initiation of goal-oriented treatment, and establishment of a reference baseline to assess efficacy.
For type A lactic acidosis, attention should be paid to the restoration of local or systemic tissue perfusion. The first principle is volume resuscitation, the use of vasoactive drugs for circulatory support, and the control of primary factors. If the diagnosis is not clear, hypoperfusion can be assumed until other evidence is found.
For type B lactic acidosis, it is usually necessary to stop the inducing drugs or correct the primary metabolic disorder, but it is often difficult to determine the source.
Traditional research believes that elevated lactate indicates an increase in adverse outcomes and mortality. The current application of lactic acid focuses on the early recognition and treatment of sepsis. The main points of the 2016 rescue sepsis movement 1h cluster treatment include the initial lactic acid monitoring, if ＞2mmol/L, retest within 2~4h, if hypotension or lactic acid ≥4mmol/L, rapid infusion of 30ml crystalloid solution /kg (The 2018 version continues this recommendation). Multiple randomized controlled trials have shown that early lactic acid targeted therapy can significantly reduce mortality.
After the initial fluid resuscitation, the patient’s volume status should be carefully evaluated to avoid overload. After 5L fluid resuscitation, the mortality rate increased by 2.3% for every additional 1L infusion. If the removal fails, we should broaden our horizons and perform a differential diagnosis again to find the hidden cause of the increase in lactate.
Use lactic acid to guide treatment
Tissue perfusion will achieve a balance between oxygen supply and oxygen consumption. In the past, it was thought that mixed venous oxygen saturation (pulmonary artery blood) had an inverse relationship with the lactic acid value. Proponents of the original goal-directed treatment focused on the mixed venous oxygen saturation of the central venous blood and regarded this as the end point for resuscitation from sepsis.
However, studies have shown that when the patient is in septic shock and the central venous oxygen saturation is ≤65%, but the liver and kidney functions are normal, the correlation between central venous blood lactic acid and mixed venous oxygen saturation is not good.
Studies have also found that in 79% of patients during the first 6 hours of resuscitation, when the central venous mixed venous blood oxygen saturation is ≥70%, the oxygen saturation is not related to the lactate clearance rate. There is no difference in mortality using peripheral perfusion targeted resuscitation compared with lactate targeted resuscitation.
In cardiogenic shock, the ratio of lactic acid/pyruvic acid is higher; but when the condition is stable, the ratio of lactic acid/pyruvate only slightly increases, which indicates that the ratio is not superior to the lactic acid level. In patients with septic shock treated with catecholamines, hyperlactemia with an elevated lactate/pyruvate ratio is more related to the prognosis of multiple system organ failure and death.
Lactic acid clearance rate is an important indicator for predicting mortality in a multi-center study. After lactic acid-targeted fluid resuscitation, the mortality rate of sepsis patients who reached the goal of lactic acid removal was 19%, while the mortality rate was 60% for those who did not. In another study, the goal of the experimental group was to reduce lactic acid by 20% or more after 2 hours of treatment, and the control group was blinded to the lactic acid value after admission; the results showed that the mortality of the lactic acid group was lower, despite the amount of fluid infusion and vasodilation in this group More volume (but no significant difference).
Elevated lactate in critical illness does not necessarily reflect hypoxia. Even if the oxygen supply is sufficient, the mitochondria cannot process all pyruvate, so the effect of oxygen supply at an abnormal ratio may not be good. In order to achieve homeostasis, many people take bicarbonate solution to neutralize lactic acidosis.
This may benefit people with renal failure or right heart dysfunction, but its effectiveness for other people has not been proven, and it may even be harmful.
Vitamin C, corticosteroids and vitamin B1 are also recommended for the treatment of sepsis. Vitamin B1 is an important cofactor for aerobic metabolism in a variety of enzymatic reactions, including pyruvate dehydrogenase in the Krebs cycle and the pentose-phosphate pathway for regeneration of nicotinamide adenine diphosphate.
Increased mitochondrial stress in sepsis will lead to a deficiency of vitamin B1, and supplementation at this time may reduce hyperlactic acidemia. Studies have shown that the use of vitamin B1 within 24 hours after admission of patients with septic shock can increase the lactic acid clearance rate and reduce the 28-day mortality rate. However, a recent trial did not find any benefit: a randomized controlled trial compared 28-day mortality, but the patient’s initial lactate did not increase significantly (1.6-3.2mmol/L); another multicenter study found that vitamin B1 did not Reduce 7d mortality or vasoconstrictor dosage. Neither trial monitored initial vitamin B1 levels.
Elevated serum lactic acid is an indicator of metabolic disorders caused by a variety of clinical causes. For patients with an initial increase in lactate, the source should be determined as soon as possible for targeted treatment.
Restoring tissue perfusion is essential. Lactic acid level can predict the patient’s prognosis very well, but it is not so closely related to fluid resuscitation.
A large number of infusions is not advisable, and persistent hyperlactic acid needs to be reassessed, the source is controlled, and alternative treatment interventions should be considered.
Clinical rational application of lactic acid monitoring
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