Carbon Dioxide Transport in Blood

Context

Exhaust to exhale

Carbon dioxide may be considered the exhaust of metabolism. There is a biological imperative to expel this gas which at too high a level will prove detrimental. At rest 200 ml/min of this gas is generated by the tissues and thus needs to be excreted to maintain equilibrium.

The image illustrates carbon dioxide exchange at the tissues.

Fig. 1 via Anatomy and Physiology

Definition

Carbon dioxide migration

At the mitochondrial level the metabolism of carbohydrate, fat or protein leads to the generation of CO2. As CO2 is very soluble (x 25 that of O2) in biological fluids and across cellular membranes, it migrates very readily from the peripheral tissue cytoplasm to the capillaries and thence to the red blood cells (RBCs).

Despite CO2‘s high plasma solubility the majority of this gas is transported as HCO3– and its relationship to dissolved CO2 is provided by the Henderson-Hasselbalch equation:
pH = pKa + log [HCO3–]/[CO2]

As hydrogen ion concentration ([H+]) is inversely related to pH it is thus directly related to the [CO2].

Carbonic anhydrase

Carbon dioxide moves from the peripheral tissue where it is relatively abundant to the RBCs which are replete with oxygen (O2). This gradient is in part generated by the facilitated reaction between CO2 and H2O where the enzyme carbonic anhydrase (CA) plays an important role. The inter conversion between CO2 and HCO3– within RBCs requires only 2ms for 95% completion.

Within the cell the reaction between CO2 and water that produces H2CO3 moves further to the right as the carbonic acid dissociates into bicarbonate (HCO3–) and a proton (H+). Hypercarbia therefore leads to acidosis and, in situations where CO2 cannot be adequately excreted at the lungs, respiratory acidosis ensues. The transport of CO2 as bicarbonate in this fashion is referred to as facilitated CO2 diffusion.

Inhibitors of carbonic anhydrase like the drug Acetazolamide are useful as a diuretic agent as they prevent this reaction occurring in renal tubular cells and thus allow more H2O to be excreted.

Haldane effect

In peripheral tissues, deoxygenated haemoglobin has a higher affinity for carbon dioxide which helps with the removal of CO2 from tissues. This is called the Haldane effect, and it occurs because deoxyHB has a greater affinity for protons which drives the CA-catalysed reaction to the right in the presense of deoxyHb

It may thus be appreciated that the increase in CO2 leads to a rise in H+ since the HCO3– is mobilised to the extracellular spaces in exchange for Chloride (Cl–) by a membrane bound ion exchange mechanism. This trade between intracellular HCO3– and extracellular Cl– is the Chloride Shift or Hamburger Shift which maintains electrical neutrality within the RBC.

The Chloride Shift is rapid and is complete before the cells exit the capillary and the osmotic effect of the extra HCO3– and Cl– in venous RBCs causes them to swell slightly. Consequently, venous hematocrit slightly surpasses the arterial hematocrit.

Carbon Dioxide and the Amino Group

In plasma the protein concentration is about 7%. However, in the RBCs, haemoglobin – the principal erythrocyte protein – constitutes about 30% of the contents, so a greater amount is proportionately transported intracellularly as haemoglobinic acid. The amount of CO2 bound as carbamate to Hb in erythrocytes or to plasma proteins depends on Hb O2 saturation, 2,3-diphosphoglycerate (2,3-DPG) concentration in the case of RBCs, and on [H+] in the case of both RBCs and plasma.

Carbon Dioxide Release

When CO2 in it’s varying guises arrives at the alveolar capillary it is liberated to the alveoli and excreted with the expired air. The mechanism of CO2 release is supported by the pressure gradient of the gas between the capillary 4.5 to 6 kPa and the inspired air <1 kPa. Additionally, because there is a much higher concentration of O2 at the lungs, the oxyHb that forms has a reduced affinity for protons and so the usual rightward direction of the carbonic anhydrase catalysed reaction between CO2 and H2O moves to the left.

The graph illustrates CO2 content variability with PCO2.

Fig. 2

Learning Bites

• CO2 should be considered to be an acid because when dissolved in plasma it reacts with H2O to generate protons
• With greater quantities of CO2, the reaction is driven rightward with more protons being produced
• During heavy exercise, the contribution of dissolved CO2 can increase sevenfold and then makes up almost one-third of the total CO2 exchange.

Proton Buffering

CO2 in tissue

The trimodality of CO2 transport in plasma

CO2 migration in RBC

Hb migration in plasma

O2 in tissue

Potassium proton exchange

Carbon Dioxide and Acid-Base Balance

From the previous discussion it is appreciated that CO2 acts like an acid and therefore its excretion serves a very essential function in maintaining acid-base balance.

The image illustrates proton buffering in the blood.

After blood buffers have acted, the next most immediate means of regaining acid-base stability is through the respiratory system and the manipulation of CO2 levels. Subsequent to the lungs, the kidneys effect change but there is at least a six-hour lag before they can achieve their aims.

Metabolic acidosis

When there is an excess of protons in the blood, they are first mopped up by the proteins, including haemoglobin and the phosphate buffers, the former contributing about 90% of the response within usual physiological limits. However, when these are exhausted the respiratory system is able to excrete H+ through the exhalation of CO2, thus, hyperventilation raises the serum pH by excreting the proxy of protons, namely carbon dioxide.

Hypercarbia

Consequence of hypercarbia

The relationship between PCO2 levels and the state of ventilation is represented by the following equation:
PaCO2 = PACO2 = VCO2 x 0.115/VA

VA = VE – VD

alveolar ventilation (VA); minute ventilation (VE); dead space ventilation (VD)

The constant 0.115 is necessary to equate dissimilar units for VCO2 (ml/min) and VA (L/min) to PACO2 pressure units (kPa).

Question 1: What does the equation show to be the only physiologic reason for raised PaCO2?

Insufficient alveolar ventilation. Since VA is the difference between VE and VD, hypercarbia may occur due to insufficient VE and/or increased VD.

Question 2: Consider a patient with respiratory rate 25 bpm; tidal volume 280ml dead space volume 150 ml, CO2 production 300ml/min. The patient shows some evidence of respiratory distress. What is the PaCO2?

Using the alveolar ventilation equation:
VA = (25 x 280) – (25 x 150) = 25 x (280 – 150) = 25 x 130 = 3250 ml/min or 3.25 L/min.

PaCO2 = (300 x 0.115)/3.25 = 34.5/3.25 = 10.6 kPa

This example illustrates what may be obtained in a patient with COPD who increases his CO2 production, say during exercise or physiologic stress, but is unable to match this with a sufficient increase in ventilation.

What must not be inferred is that one can determine the adequacy of alveolar ventilation and thus PaCO2 – at the bedside.

Though VE can be readily determined with a spirometer (tidal volume x respiratory rate), one cannot know VD or the patient's rate of CO2 production. One would err in presuming that a patient breathing fast, hard and/or deep is hyperventilating.

The overnight physician was bleeped to the bedside of a man in his seventies, who had been admitted two days earlier on the Friday, for investigation of bilateral lower limb swelling. He was noted to be anxious and dysponeic with a clear chest, normotensive, heart rate of 102 bpm and respiratory rate of 32 bpm. The nurse informed the physician that this was common for him at night and that he may benefit from some night sedation, which the doctor duly prescribed for 'hyperventilation and anxiety'. One hour subsequently he stopped breathing and could not be resuscitated.

Dalton’s Law

A rise in PCO2 leads to a fall in PO2 for a fixed inspired O2 (FiO2) as the preservation of pressures is dictated by Dalton’s law.

Dalton’s Law

Each gas in a mixed gas environment produces its own partial pressure with the result that the sum of the pressures of the different gases provides the total pressure created by the mixture. This is defined in Dalton’s law of partial pressure. The pressure of a mixture of gases is equal to the sum of the pressures of all of the constituent gases alone.

Mathematically P Total = P1 + P2 … Pn

The higher the baseline PaCO2, the more it will rise for a given fall in VA, e.g. a 1 L/min decrease in VA will raise PaCO2 a larger amount when the baseline PaCO2 is 6.7 kPa than when it is 5.3 kPa. A direct consequence of raised CO2 is the rise in [H+] as previously outlined, leading to respiratory acidosis. This acidification has varying consequences:

Respiratory

Pulmonary vasoconstriction which, in a hypoxic environment, contributes even further to reducing the availability of O2 with potential life threatening consequences. Therefore, in the situation of a normal or raised PCO2 with acidosis, non invasive ventilation (NIV) is indicated so as to assist the excretion of CO2 thus preventing further increases in pulmonary vascular resistance which would reduce oxygenation yet further.

Cardiovascular

There is augmented release of adrenaline and noradrenaline in acute respiratory acidosis and in the milieu of proton excess and hypoxia the myocardium becomes irritable and is prone to arrhythmias.

Acute onset of hypocarbia can cause cerebral vasoconstriction and though, in the past, there was a vogue for hyperventilating head injured patients so reducing CBF, the current practice is to maintain normal/low normal levels of PCO2. This is because acute decline in CBF flow can cause symptoms of dizziness, mental confusion, syncope and seizures.

One positive of hypocarbia is the rise in PO2 as oxygen replaces the CO2 expired. This interrelationship is represented by the alveolar gas equation (AGE):

Where FiO2 is the inspired oxygen concentration.

This principle is utilised by free divers who hyperventilate prior to their descent thus replacing the CO2 with O2 allowing more protracted breath holding.

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