Carbon Dioxide: Diagnostic Significance and Clinical Insights

Authors: Payal Bhandari, M.D., Abraham Tejeda-Martinez 

Contributors: Nigella Umali Ruguian   

 

 

Carbon Dioxide (CO2) 

 

Carbon dioxide is a waste product created by the body, transported via blood to the lungs, and exhaled. CO2 is measured as part of an electrolyte panel, since electrolytes help balance the levels of acids and bases in the body. Abnormally low CO2 levels reflect too many acids in the blood, called acidosis, while abnormally high CO2 levels reflect too many bases in the blood, called alkalosis. This can indicate kidney, lungs, or adrenal glands dysfunction (e.g., Addison’s disease), or ketoacidosis (a complication of diabetes). 



Typical Adult Range

 

Ranges and thresholds can vary due to: 

(1) Lab-specific equipment, techniques, and chemicals, and 

(2) Patient demographics, including age, sex, and ethnicity.

 



Key Insights 

Carbon dioxide is a critical biomarker in the body, playing a fundamental role in the respiratory and metabolic systems. CO₂ is a waste product produced during cellular respiration after cells in organs and skeletal muscles have used oxygen to harvest energy. The measurement of CO₂ in the blood offers important insights into respiratory function, acid-base balance, and overall metabolic status.

 

CO₂ exists in the blood in three main forms: dissolved CO₂, bicarbonate (HCO₃⁻), and carbonic acid (H₂CO₃). Bicarbonate makes up the majority of CO₂ in the bloodstream and is vital for maintaining the blood acidity level (pH). Produced during cellular respiration by peripheral tissues, CO₂ is transported via the bloodstream and released by the lungs during exhalation. Red blood cells (RBCs) facilitate the transport by its enzyme carbonic anhydrase, catalyzing the conversion between CO₂ and HCO₃⁻.

 

CO₂ levels are typically assessed through blood gas analysis, which measures arterial CO₂ partial pressure (PaCO₂) and HCO₃⁻ concentration. Deviations from the normal PaCO₂ range can signal respiratory or metabolic issues. Low PaCO₂ levels may indicate fasting breathing (hyperventilation) or metabolic alkalosis, while high PaCO₂ levels are often associated with slow breathing (hypoventilation) or respiratory acidosis. In both scenarios, hemoglobin is unable to adequately bind to oxygen. By reducing RBC’s oxygen-carrying capacity, peripheral tissues cannot harvest energy and maintain vital functions efficiently.  

 

What is Carbon Dioxide?

 

Carbon Dioxide is a natural greenhouse gas that makes up about 0.04% of the Earth’s atmosphere. It plays a key role in processes like photosynthesis, where plants use sunlight to create energy, and cellular respiration, which helps living organisms produce energy. CO2’s structure and stability make it easy to move through cell membranes during cellular respiration. It also reacts with water to form carbonic acid (H₂CO₃), helping regulate blood pH between 7.35 and 7.45. CO2 is essential for body functions and is a useful biomarker for measuring metabolic activity.[6][5][4]

Formation and Regulation of Carbon Dioxide (CO₂) in the Body

Cellular respiration shows how the body meets its energy needs and how well cells use oxygen (O₂). This process turns glucose into energy and produces carbon dioxide, which is expelled by the lungs. Hemoglobin (Hb) and red blood cells (RBCs) are essential for delivering O₂ to tissues, removing CO₂, and maintaining blood pH balance. Brain cell receptors and arteries control breathing rate and depth, influencing gas exchange and CO₂ levels in the blood.[7][8].

Glucose is broken down in the cytoplasm into two pyruvate molecules, producing 2 ATP. Pyruvate enters the mitochondria and is further processed in the Krebs cycle, releasing CO₂ and generating electron carriers (NADH, FADH₂) and 1 ATP. The electron transport chain (ETC) in the inner mitochondrial membrane uses NADH and FADH₂ to create a high-energy gradient, producing large amounts of ATP. Oxygen (O₂) acts as the final electron acceptor, forming water. [9]

CO₂, a waste product, leaves the cell and enters the bloodstream in three forms:

  • 2.5% dissolves directly into blood, freely diffusing between tissues and plasma.

  • 80–90% converts to bicarbonate (HCO₃⁻) through a reaction catalyzed by the enzyme carbonic anhydrase in red blood cells. CO₂ combines with water to form carbonic acid, which quickly breaks into HCO₃⁻ and H⁺ for efficient removal and lung excretion.

  • 5–10% binds to hemoglobin (Hb) and plasma proteins, forming carbaminohemoglobin and other compounds, transporting CO₂ to the lungs for exhalation.[1]

                             

Figure 1: Carbon dioxide is a byproduct released during cellular respiration, a set of metabolic reactions that convert electrons from chlorophyll-rich plants and microorganisms that do direct photosynthesis into high-energy, electron-carrying molecules. The electron transport chain in the mitochondria generates the greatest amount of energy: 34 adenosine triphosphate (ATP) compared to 2 ATP, each derived from breaking down glucose in food in the cytoplasm of cells. 

 

Figure 2: Oxygen (O2) is the final electron acceptor in the electron transport chain, generating copious amounts of energy. O2 is vital in pulling down electrons in the mitochondria, creating a proton gradient that harvests energy. The proton gradient comprises protons and hydrogen ions (H+) that break off from other enzymes and require adenosine triphosphate (ATP) to be transported. Electrons move downhill from electron carrier to carrier, losing their charge until, in the end, in the presence of O2, ATP is harvested.



Clinical Significance of High Carbon Dioxide Blood Levels (Hypercapnia)

High levels of carbon dioxide in the blood, called hypercapnia, make the blood too acidic and slow breathing (hypoventilation), which reduces CO₂ removal and oxygen delivery to tissues (hypoxia). This affects the lungs’ ability to support other organs’ functions. CO₂ also helps regulate brain blood flow and spinal fluid pH by relaxing or contracting smooth muscles. Hypercapnia causes brain blood vessels to widen, increasing blood flow and pressure in the skull. The resulting respiratory acidosis triggers nerve cells in the brain, especially in the hypothalamus and pituitary gland, to release hormones that adjust organ functions.[10]

  1. To restore blood pH balance, the kidneys retain bicarbonate and excrete hydrogen ions, which can lead to temporary metabolic alkalosis. They also boost production of erythropoietin (EPO), a hormone that converts immature red blood cells (RBCs) into mature ones in the bone marrow.

  2. The hypothalamus increases thyrotropin-releasing hormone (TRH), prompting the pituitary to release thyroid-stimulating hormone (TSH), which triggers the thyroid gland to produce thyroid hormones (TH). TH works with EPO to raise RBC levels, improving oxygen delivery to tissues, boosting energy production, and increasing heat and reactive oxygen species (ROS) generation.

Hypercapnia (high CO₂ levels) can cause premature cell damage, gene mutations, and disrupted metabolism, leading to inflammation and impaired cell and microbiota function. Acute hypercapnia weakens lung muscles, causing confusion, headaches, drowsiness, fatigue, shortness of breath, and potentially severe conditions like myasthenia gravis, Guillain-Barré syndrome, COPD, or asthma.

Persistent hypercapnia increases non-functional lung spaces, where ventilation occurs without gas exchange, and damages capillaries in the lungs and tissues. This activates megakaryocytes (platelet precursors), causing blood clotting, scar tissue formation (fibrosis), and new blood vessel growth (angiogenesis). These changes shorten red blood cell (RBC) lifespans, misdirect platelet activity, and overactivate white blood cells (WBCs), which produce antibodies against the body, reactivate dormant gut pathogens, and promote the growth of mutated or cancerous cells.

Chronic respiratory acidosis and metabolic alkalosis increase the risk of vascular diseases like atherosclerosis, autoimmune disorders, infections, cancer, and multiorgan damage, potentially leading to organ failure.



Clinical Significance of Low Carbon Dioxide Blood Levels (Hypocapnia)

Low blood carbon dioxide, called hypocapnia, makes the blood too alkaline, causing faster breathing (hyperventilation) and increased CO₂ loss. This reduces hemoglobin’s ability to deliver oxygen to tissues (hypoxia), lowering energy production and disrupting vital body functions.

Respiratory alkalosis decreases hydrogen ions, upsetting the blood and spinal fluid pH balance. Brain blood vessels constrict, lowering intracranial pressure and altering nerve signals to organs, which shifts their normal physiological activity.[4]

The kidneys excrete bicarbonate and retain hydrogen ions to rebalance the pH, resulting in rebound metabolic acidosis. 

  1. Metabolic acidosis lowers the kidneys’ production of erythropoietin (EPO), a hormone needed to turn immature red blood cells (RBCs) into mature oxygen-carrying cells. Fewer RBCs (anemia) reduce oxygen delivery, slowing lung muscle contractions and breathing. This worsens CO₂ imbalance and reduces energy production in tissues.

  2. To compensate, the brain (hypothalamus and pituitary) and adrenal glands boost thyroid hormone (TH) levels to increase RBC production. While TH helps meet oxygen needs, it also produces reactive oxygen species (ROS), leading to heat and cellular stress. Prolonged TH activation causes more ROS than energy, resulting in cell damage, gene mutations, disrupted metabolism, and slower cell and microbiota growth.

Acute hypocapnia, often caused by anxiety, fever, or pain, can lead to alkalosis symptoms such as dizziness, tingling in the limbs, muscle cramps, rapid heart rate, sweating, confusion, fainting, or seizures. The kidneys may not respond quickly enough to rebalance pH.

Chronic hypocapnia causes tissue damage that reduces arterial blood flow, increases blood pressure and thickness, and alters blood circulation. This leads to organ damage and loss of function. Inflammation increases, shifting metabolism and causing fat (cholesterol) to deposit in blood vessels and organs (like the liver, pancreas, and thyroid) to prevent bleeding. Overactive white blood cells (WBCs), platelets, and smooth muscle cells can cause excessive clotting, scar formation, and autoimmunity, as WBCs release harmful proteins and reactive oxygen species (ROS) that attack healthy tissues. Dormant gut pathogens may activate, and abnormal cell growth (cancer) can accelerate.

Persistent hypocapnia raises the risk of atherosclerosis, autoimmune diseases, infections, cancer, and multiorgan damage or failure.



Conclusion

Carbon dioxide is a vital biomarker that connects respiratory, metabolic, and vascular processes affecting every cell in the body. High CO₂ levels (hypercapnia) can cause hyperventilation, respiratory acidosis (low pH), reduced oxygen delivery (hypoxia), and decreased energy production. Low CO₂ levels (hypocapnia) trigger hypoventilation, raising blood pH (respiratory alkalosis). Both conditions restrict blood flow, increase blood pressure and thickness, and cause tissue damage, inflammation, and organ dysfunction.

Managing abnormal CO₂ levels requires lifestyle changes, stress reduction, proper hydration, and addressing medication side effects. Restoring CO₂ balance helps prevent severe conditions like vascular damage, autoimmune disorders, infections, cancer, and multiorgan failure.

 

Source References and Supplemental Research:

 

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  2. Erslev AJ. Erythropoietin. N Engl J Med. 1991;324(19):1339-1344. doi:10.1056/NEJM199105093241907 [NEJM]

  3. Eckardt KU, Kurtz A, Bauer C. Triggering of erythropoietin production by hypoxia is inhibited by respiratory and metabolic acidosis. Am J Physiol Regul Integr Comp Physiol. 1990;258(3). [APS]

  4. Guais A, Brand G, Jacquot L, et al. Toxicity of Carbon Dioxide: A Review. Chem Res Toxicol. 2011;24(12):2061-2070. doi:10.1021/tx200220r. [ACS]

  5. AMTHOR, J.S. (1991), Respiration in a future, higher-CO2 world. Plant, Cell & Environment, 14: 13-20. [PC&E]

  6. Sood P, Paul G, Puri S. Interpretation of arterial blood gas. Indian J Crit Care Med. 2010 Apr;14(2):57-64. doi: 10.4103/0972-5229.68215. PMID: 20859488; PMCID: PMC2936733. [PubMed]

  7.  Kraut, J., Madias, N. Metabolic acidosis: pathophysiology, diagnosis and management. Nat Rev Nephrol 6, 274–285 (2010). https://doi.org/10.1038/nrneph.2010.33. [Nature]

  8.  Lim S. Metabolic acidosis. Acta Medica Indonesiana. 2007 Jul-Sep;39(3):145-150. PMID: 17936961. [Europepmc] 

  9.  Doyle J, Cooper JS. Physiology, Carbon Dioxide Transport. [Updated 2023 Jul 4]. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024 Jan

  10.  Drechsler M, Morris J. Carbon Dioxide Narcosis. [Updated 2023 Jan 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan