What is the pathophysiology of lactic acidosis (elevated lactate levels) toxicity in the human body?

From the Guidelines

Lactic acidosis is toxic to the body primarily because it disrupts the body's acid-base balance, creating an excessively acidic environment that impairs normal cellular function. When blood pH drops below the normal range of 7.35-7.45 due to lactic acid accumulation, multiple organ systems begin to malfunction. The excess acidity interferes with enzyme function throughout the body, as most enzymes operate optimally within a narrow pH range. This acidic environment also affects protein structure and function, disrupts cell membrane integrity, and impairs calcium binding to proteins, which can lead to decreased cardiac contractility and vascular tone. Additionally, lactic acidosis can cause potassium to shift out of cells, leading to dangerous hyperkalemia. The brain is particularly sensitive to acidosis, which can result in altered mental status, confusion, and even coma in severe cases. Respiratory compensation occurs as the body attempts to eliminate excess acid through increased breathing, causing the characteristic deep, rapid breathing pattern. If left untreated, severe lactic acidosis can lead to cardiovascular collapse, as the heart becomes less responsive to catecholamines, blood vessels dilate inappropriately, and cardiac output falls, ultimately resulting in shock and potentially death.

Key Points to Consider

• Lactic acidosis can be exacerbated by certain conditions, such as sepsis, hypoxia, and impaired metformin clearance, as noted in a study published in The Lancet Diabetes and Endocrinology 1.
• The use of sodium bicarbonate therapy to improve hemodynamics or reduce vasopressor requirements in patients with hypoperfusion-induced lactic acidemia is not recommended, according to the Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016 1.
• Patients with mitochondrial disease are at risk of developing lactic acidosis, particularly during periods of metabolic stress, such as surgical procedures and perioperative fasting, and may benefit from the use of lactate-free IV fluids, as suggested in a study published in the British Journal of Anaesthesia 1.

Management and Prevention

• Metformin should be avoided in patients at risk for lactic acidosis, such as those with significant renal impairment or liver failure, and discontinued if the estimated glomerular filtration rate (eGFR) is less than 30 mL/min per 1.73 m², as recommended in a study published in The Lancet Diabetes and Endocrinology 1.
• Lactate concentrations should be measured in fragile patients, and metformin should be withdrawn if increased lactate concentrations are apparent.
• In patients with mitochondrial disease, meticulous individual assessment and careful attention to fluid management are essential to prevent lactic acidosis, and the routine use of lactate-free IV fluids is recommended, as suggested in a study published in the British Journal of Anaesthesia 1.

From the FDA Drug Label

Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

Lactic acidosis is toxic to the body because elevated lactate levels can lead to:

• Anion gap acidosis: a condition where the body's blood becomes too acidic
• Hypotension: low blood pressure
• Resistant bradyarrhythmias: abnormal heart rhythms
• Organ failure: if left untreated, lactic acidosis can lead to failure of vital organs such as the kidneys and liver
• Death: in severe cases, lactic acidosis can be fatal 2

From the Research

Lactic Acidosis Toxicity

• Lactic acidosis is a serious condition that can be toxic to the body, with an overall mortality rate of approximately 50% 3.
• The toxicity of lactic acidosis is associated with the accumulation of lactate in the body, which can lead to acid-base imbalance and organ dysfunction 4, 5.
• Severe lactic acidosis can cause hemodynamic instability, requiring vasopressors and prolonged dialysis to correct the acid-base disorders and remove excess lactate 4, 5.

Causes of Lactic Acidosis

• Lactic acidosis can be caused by various factors, including metformin use in patients with type 2 diabetes, acute renal failure, and sepsis 4, 3, 6.
• Metformin-associated lactic acidosis (MALA) is a rare but serious complication of metformin therapy, which can be exacerbated by factors such as renal impairment and gastrointestinal fluid loss 4, 5.
• Diabetes itself is a major risk factor for the development of lactic acidosis, rather than metformin therapy alone 6.

Consequences of Lactic Acidosis

• Lactic acidosis can lead to severe consequences, including cardiovascular collapse, acute renal failure, and death 4, 5, 3.
• Higher lactate levels and lower pH are associated with increased risk of mortality in patients with cardiogenic shock 7.
• Severe lactic acidosis may serve as a risk modifier for shock severity, and definitions of refractory or hemometabolic shock should include high lactate levels and low blood pH 7.