What are the causes of mixed respiratory (ventilatory) acidosis and metabolic acidosis?

From the Guidelines

Mixed respiratory (ventilatory) acidosis and metabolic acidosis can occur simultaneously in various clinical scenarios, including severe chronic obstructive pulmonary disease (COPD) exacerbations and diabetic ketoacidosis.

Causes of Mixed Acidosis

• Respiratory acidosis: caused by impaired ventilation, leading to increased CO2 levels, which combine with water to form carbonic acid, resulting in a decrease in blood pH 1.
• Metabolic acidosis: caused by failure to excrete acid, increased production of acid, or loss of bicarbonate, resulting in a low blood bicarbonate level 1.

Clinical Scenarios

• COPD exacerbations: patients with chronic severe but stable COPD may develop acute on chronic respiratory acidosis, which can be complicated by metabolic acidosis due to tissue hypoxia or other factors 1.
• Diabetic ketoacidosis: a condition characterized by increased production of acid, which can lead to metabolic acidosis, and may be accompanied by respiratory acidosis due to respiratory depression or other factors.
• Lactic acidosis: caused by tissue hypoxia, which can result from decreased oxygen delivery or impaired oxygen consumption, and can lead to metabolic acidosis, which may be combined with respiratory acidosis in certain clinical scenarios 1.
• Renal failure: can cause metabolic acidosis due to failure to excrete acid, and may be accompanied by respiratory acidosis due to impaired ventilation or other factors.
• Chronic diarrhea: can cause metabolic acidosis due to loss of bicarbonate, and may be accompanied by respiratory acidosis due to dehydration or other factors.

From the FDA Drug Label

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal impairment — The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Drug interactions —The concomitant use of metformin hydrochloride tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation Age 65 or greater —The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Hypoxic states —Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia) Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia.

The causes of metabolic acidosis (specifically lactic acidosis) include:

• Renal impairment: significant renal impairment can lead to metformin accumulation and increase the risk of lactic acidosis
• Drug interactions: certain drugs that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation
• Age 65 or greater: elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment
• Hypoxic states: acute congestive heart failure, cardiovascular collapse, acute myocardial infarction, sepsis, and other conditions associated with hypoxemia The causes of mixed respiratory (ventilatory) acidosis and metabolic acidosis are not explicitly stated in the provided text, but it can be inferred that conditions associated with hypoxemia may contribute to the development of mixed acidosis. 2 2

From the Research

Causes of Mixed Respiratory (Ventilatory) Acidosis and Metabolic Acidosis

• Mixed respiratory and metabolic acidosis can occur due to various factors, including hepatic impairment, severe left ventricular dysfunction, and impaired renal function 3
• Metformin use is not a significant predictor for the development of acidosis, whereas hepatic, renal, and cardiac dysfunction are more important predictors 3
• Mixed acid-base disorders can occur as a combination of primary respiratory and metabolic acidosis or alkalosis, and can be diagnosed by interpreting perturbations in PCO2, HCO3(-), pH, and serum electrolytes 4
• Severe mixed metabolic acidosis can be caused by a combination of drugs and diseases, such as metformin and diclofenac, especially in the elderly 5
• Respiratory acidosis can be caused by hypercapnic respiratory failure or hypoxemic respiratory failure with coexisting hypercapnia, and alkali therapy may be indicated for severe acidemia caused by mixed acidosis 6
• Metabolic acidosis can occur as a result of the accumulation of endogenous acids or loss of bicarbonate from the gastrointestinal tract or the kidney, and can be caused by various factors such as lactic acidosis, ketoacidosis, renal failure, and intoxication with certain substances 7