9 Acid-base balance and blood gases

Oswald Müller-Plathe, Lothar Thomas

9.1 Acid-base homeostasis

The acid-base homeostasis is the homeostatic regulation of the pH of the extracellular fluid of the body. Normally systemic acid-base balance is regulated with arterial pH between 7.36 and 7.44. The proper balance between acids and bases is maintained by the integrated function of kidneys, lungs and liver. The liver is the principal organ responsible for hydrogen ion (H⁺ ) metabolism from the body’s daily protein intake and a resulting acid loading on the body. The H⁺ must be buffered and cleared to maintain acid-base homeostasis /1, 2/.

Intracellular and extracellular buffers are the optimal mechanisms of defense against changes in the pH. The HCO₃^–/CO₂ buffer system is the clinically most significant extracellular buffer system. Buffering of H⁺ leads to the formation of CO₂ that is expired by the lung:

H+ + HCO3– ═ H2CO3 ═ H2O + CO2

The HCO₃^–/CO₂ buffer system is physiologically most important because of its quantitative capacity to buffer acid or alkali loads and because of the capacity for independent regulation of HCO₃^– and PCO₂ by the kidneys and lungs, respectively /2/. The HCO₃^– consumed in this process must be regenerated by the kidneys. In this way, 20–30 mVal of acids from food and the same amount from the endogenous metabolism as well as HCO₃^– losses are compensated via excretion.

Arterial CO₂ is predominantly regulated by alveolar ventilation after production in peripheral tissues.

Disorders of HCO₃^– or non-volatile acids (fixed acids) are usually referred to as metabolic disorders. Disorders of CO₂ are referred to as respiratory disorders /2/. Fixed acids are lactic acid, phosphoric acid and sulfuric acid.

Under physiological conditions, the acid-base balance is kept constant within a tight range. Normal H⁺ concentration is 40 nmol/L; expressed as negative logarithm, this corresponds to pH 7.4. The reference intervals of the acid-base parameters in arterial blood are pH 7.36–7.44, PCO₂ 36–44 mmHg and HCO₃^– 21–26 mmol/L. However, the critical parameter ensuring normal physiology and cell metabolism of the organism is the intracellular pH that does not change until the extracellular pH undergoes significant changes. A decrease in pH is referred to as acidemia and an increase as alkalemia. In contrast, the terms “acidosis” and “alkalosis” designate the conditions that cause a decrease (acidosis) or increase (alkalosis) in pH.

9.2 Blood gases

Blood gases are the gases dissolved in the blood. They comprise the main constituents of atmospheric air such as nitrogen (N₂), oxygen (O₂), as well as carbon dioxide produced in metabolic processes (CO₂). The partial pressure (P) of a mixture of gases is defined as the pressure exerted by a gas as an individual component of the gas mixture /3/.

Arterial blood gas analysis is an essential part of diagnosing and managing a patient’s oxygenation status and acid-base balance. Blood gas analysis is performed in patients with acid-base disorders to detect concurrently existing pulmonary changes /4/.

The widely used investigations to acid-base disorders are /4/:

• The HCO₃^- (in the context of PCO₂)
• The standard base excess
• The strong ion difference (refer to Section 8.3.5.1).

9.2.1 CO₂ transport in blood

The arterial blood supplying the tissues contains much O₂ bound to hemoglobin (HbO₂) and little CO₂. Due to the partial pressure gradient between tissue and plasma, CO₂ diffuses from the tissue into the plasma and from there the majority shifts into the red blood cells. In the red blood cells:

• 20% of the CO₂ bind to the amino groups of the Hb as carbamino CO₂
• 70% of the CO₂ are hydrated to H₂CO₃ by carbonic anhydrase. The H₂CO₃ dissociates into HCO₃^– and H⁺. The HCO₃^– are released to the plasma in exchange for Cl^– and the H⁺ bind to hemoglobin
• 10% of the CO₂ remain physically dissolved.

Hypercapnia refers to an increase in PCO₂ and occurs in cases of respiratory insufficiency with hypo ventilation.

9.2.2 O₂ transport in blood

The oxygen in the blood is transported bound to hemoglobin (Hb). The transport capacity is dependent on the O₂ partial pressure (PO₂) and the Hb level, and the Hb saturation with O₂ is dependent on the PO₂. The relation between PO₂ and HbO₂ is expressed by the HbO₂ dissociation curve. The curve is not linear but S-shaped. The affinity of O₂ to Hb and, thus, the course of the dissociation curve is dependent on the temperature, H⁺ concentration and PCO₂ (Fig. 9-1 – HbO₂ dissociation curve and effects of temperature, H⁺ and PCO₂).

The following applies:

• An increase in the above-mentioned parameters causes the HbO₂ dissociation curve to shift to the right (lower affinity of O₂ to Hb)
• A decrease in the above-mentioned parameters causes the curve to shift to the left (higher affinity of O₂ to Hb).

Within the PO₂ range in the pulmonary alveoli (about 100 mmHg), the Hb saturation changes little even at greater partial pressure gradients. In the other tissues with a PO₂ of about 40 mmHg, the steep course of the HbO₂ dissociation curve maintains the necessary pressure gradient even at lower Hb saturation. Parameters to be measured for analyzing the acid-base homeostasis and oxygen supply are shown in Tab. 9-1 – Parameters to be measured for analyzing the acid-base homeostasis and oxygen supply.

9.3 Indication

• Obstructive and restrictive ventilation disorders
• Disease of lung parenchyma and bronchi
• Disorders of lung perfusion (e.g., right-to-left shunt)
• Circulatory insufficiency, hypovolemia, shock
• Renal insufficiency, renal tubular dysfunction
• Decompensated diabetes mellitus
• Coma, intoxication
• Gastroenterological disorders (vomiting, diarrhea)
• Gallbladder and pancreatic fistula
• Hypokalemia and hyperkalemia
• Hypochloremia and hyperchloremia
• Dysfunction of the adrenal cortex
• Therapy monitoring, such as infusion treatment, artificial respiration, parenteral feeding, hemodialysis, hemofiltration, massive transfusion, treatment with diuretics, corticosteroids.

9.4 Method of determination

The pH, PCO₂ and PO₂ are determined in anaerobically sampled, heparin anticoagulated whole blood in a single measuring chamber at 37 °C /5/.

9.4.1 pH measurement

The pH value is measured with a glass electrode chain. The outer glass membrane is placed in direct contact with the blood, whilst the inner membrane is in contact with a solution of constant H⁺ activity. A conductive electrode is placed within this solution. At 37 °C a potential difference between the electrodes arises, that changes in 61.5 mV per increase or decrease of one pH unit. For the measurement of voltage change a conductive reference electrode in contact with the blood sample is required. Calibration is performed with two buffer solutions traceable to the primary standards of the National Institute of Standards and Technology.

9.4.2 PCO₂ measurement

The PCO₂ is measured with the CO₂ electrode. This glass electrode is placed in a sodium bicarbonate solution together with the reference electrode. The solution is separated from the blood by a CO₂-permeable membrane. The pH of the solution changes in proportion to the PCO₂ of the blood sample according to the following equation:

9.4.3 PO₂ measurement

The PO₂ is measured amperometrically with a platinum electrode covered with an O₂ permeable membrane. Molecular O₂ diffuses across the membrane to the surface of the platinum cathode where it is reduced according to the following equation:

O₂ + 2 H₂O + 4e^– → 4 HO^–

A reductive current of minimal intensity is created due to the charge transfer to the reference electrode. The intensity of the current is dependent upon the pO₂ of the blood sample.

9.4.4 Bicarbonate in serum/plasma

The determination of the bicarbonate (HCO₃^–) concentration is important for the determination of the acid-base status and the electrolyte balance /6/. HCO₃^– is calculated using the following transformation of the Henderson-Hasselbalch equation:

cHCO₃^– (mmol/L) = 0.0307 PCO₂ (mmHg) × 10^{(pH – 6.1)}

PCO₂ is the partial pressure of arterial CO₂, and 0.037 describes the solubility of CO₂ in blood.

9.4.5 Base excess

The base excess /6, 7/:

• Is used as an indicator of the degree of metabolic disturbances
• Is the dose of acid or alkali to return the extracellular fluid to normal pH (7.40) under standard conditions (at 37 °C at a PCO₂ of 40 mmHg)
• Is defined as equal to zero (–3 to +3 mmol/l) when pH = 7.40, PCO₂ = 40 mmHg (5.33 kPa) at 37 °C (98.6 °F)
• Is often assessed in association with the anion gap and the PCO₂ to make reliable statements of either metabolic or respiratory components of acid-base disturbance, because it can be affected by both
• Is calculated by arterial blood gas analyzers according to the van Slike equation

BE_(ECF) (mmol/L) = (HCO₃^– – 24.4) + (2.3 × Hb + 7.7) × (pH – 7.4) × (1 – 0.023 × Hb)

For further information refer to Tab. 9-1 – Parameters to be measured for analyzing the acid-base homeostasis and oxygen supply.

9.4.6 Total carbon dioxide (tCO₂) in blood serum/plasma

The CO₂ is present in blood as dissolved carbonic acid (H₂CO₃), bicarbonate (HCO₃^–), carbonate (CO₃^2–), carbamate (CO₂ bound to free amino groups of proteins, mainly hemoglobin; RNHCOO^–) and complex bound ion pairs. The concentration is 16–25 mmol/L. Lower levels are measured in acidosis and higher ones in alkalosis. HCO₃^– account for up to 95% of tCO₂. The selected reference measurement procedure for tCO₂ is an extraction method. In this procedure, the CO₂ set free from the sample by the acid reagent (lactic acid; pH 2) shifts to a vessel for titration.

9.4.7 Oxygen saturation (SO₂) and oxyhemoglobin fraction

The SO₂ is calculated by approximation from PO₂ and pH. The calculation for the range in venous blood (PO₂ below 55 mmHg) is not accurate enough in many cases. In this range, the SO₂ should be measured by oximetry. In oximetry, the spectrophotometric absorption of the blood sample is measured in a cuvette of approximately 0.1 mm path length at 6–7 wavelengths after gentle erythrocytolysis such that the total Hb, oxy-Hb, deoxy-Hb, COHb and metHb are measured individually. Appropriate calculation procedures either yield the free oxy-Hb fraction (fHbO₂) related to the total Hb /4/:

or the oxygen saturation based on Hb capable of binding (SO₂):

9.4.8 Oxygen concentration

The total oxygen concentration (tO₂) is calculated as follows:

tO₂ (mL/L) = 1.39 HbO₂ (g/L) + 0.03 PO₂ (mmHg)

All calculations described above are performed automatically by the analyzers.

9.5 Specimen

Arterial blood

The blood is usually collected with a specially prepared plastic syringe containing a dry heparin salt /9/. Immediately after removing the syringe from the puncture site, air bubbles should be expelled and the tip of the syringe sealed with a cap. The analysis must be performed within 15 min. at the most because plastic syringes are not gas-tight /6/.

If the period until analysis is expected to exceed 15 min., a glass syringe is required. Its dead space must be filled with liquid heparin to a final concentration below 50 IU/mL blood. The liquid must be free of air bubbles. The syringe is filled with blood to its nominal volume, and sealed promptly and stored on ice slush until analyzed. This procedure provides stability for 1 hour.

Arterialized capillary blood

After hyperemization of the relevant skin area, tap the blood from the earlobe or the finger tip or, in infants, from the side of the heel into a heparinized glass capillary /8/. Fill the capillary completely. Insert a flee for mixing. Seal the capillary with caps on both ends and perform the analysis immediately; if the sample is stored between cooling elements, the analysis should be performed within 1 hour.

Venous blood

The only diagnostically relevant venous specimen for the analysis of PCO₂, PaO₂, and SO₂ is mixed venous blood (pulmonary artery catheder) /8/. Venous blood collected from a peripheral vein can only be used explicitly for determination of the base parameters: in this case, collection is done without application of a tourniquet. The arm from which the sample is collected must be at complete rest (no muscular activity).

Venous plasma or serum

In order to determine bicarbonate or total CO₂ in plasma or serum the collecting tubes are completely filled and immediately sealed with a cap /8/. Furthermore they must be centrifuged while the tube is still closed. Serum or plasma must be analyzed without delay with as little exposure to atmospheric air as possible.

9.6 Reference intervals

Refer to Ref. /9, 10, 11/ and Tab. 9-2 – Reference intervals for acid-base markers.

9.7 Clinical significance

Disorders of acid-base homeostasis may be suspected based on the medical and medication history and clinical examinations. In many cases, however, acid-base disorders are not associated with any clinical symptoms, and laboratory findings provide initial evidence. Basic assays include /12, 13/:

• Blood gas analysis, pH, PCO₂, PaO₂ and bicarbonate
• In plasma: Na⁺, K⁺, Cl^– and calculation of the anion gap.

9.7.1 Acid-base parameters

9.7.1.1 Interpretive approach

After history and clinical examination of the patient the second step is to determine the primary acid-base disorder and the secondary response /1/. The diagnosis of acid-base disorders is done in two phases.

Phase one

Determination of pH, PaCO₂ and bicarbonate. The four acid-base disturbances are defined as primary acid-base disorders.

Metabolic acidosis	Respiratory acidosis
Metabolic alkalosis	Respiratory alkalosis

Determination of the degree of compensation of the disorder. The assumed duration of the acid-base disorder is to be considered in this context. Respiratory compensation of metabolic disorders starts almost immediately and is fully developed after approximately 12 hours. Renal compensation of respiratory disorders does not become manifested until the second day and is complete after about six days. Fig. 9-2 – The principal constellation of values in acid-base disorders and Fig. 9-3 – Nomogram for diagnosing acid-base disorders considering the degree of compensation refer to this first phase of the diagnostic approach.

Phase two

The cause of the acid-base disorder is to be determined based on the following findings:

• A general overview of the patient’s clinical situation, especially his history, state of consciousness, state of hydration, and current medication
• The electrolyte status, especially the levels of Na⁺, K⁺, Cl^– and the anion gap in plasma
• The oxygen parameters PaO₂ and SO₂
• Urine pH, ketone bodies, blood glucose, serum creatinine, blood lactate and more clinical laboratory measurements if needed.

9.7.1.2 Mixed acid-base disorders

Empirical observations suggest that the homeostatic response to acid-base disorders is predictable and can be calculated. They are diagnosed when the secondary response differs from that which would be expected. Primary disorder and secondary response can either combine to impede pH compensation; or if they are of opposing influence, they can lead to an overcompensation. The clarification of mixed disorders can be achieved by taking into account the clinical context, current medication and further laboratory findings. An increased anion gap, for example, suggests a primary decrease in bicarbonate. At atmospheric pressure a greatly decreased PaO₂ implies the primary character of an increased PaCO_2.. Nomograms alone are not sufficient to clarify mixed disorders, but from the location of the status point one can detect an under compensation or overcompensation which raises the possibility that a combined disorder is present.

The following combinations are possible:

• Respiratory and metabolic acidosis
• Respiratory acidosis and metabolic alkalosis
• Respiratory and metabolic alkalosis
• Respiratory alkalosis and metabolic acidosis.

An example is provided for each of the combined disorders (Case 1, Case 2, Case 3, and Case 4). The respective status points can be plotted in Fig. 9-2 – The principal constellation of values in acid-base disorders.

9.7.1.3 Quantitative assessment of measurement results

pH

Deviations from normal behavior within the range 7.3–7.5 are to be considered as mild, but should be clarified. pH values of 7.1–7.3 and 7.5–7.6 characterize severe decompensated acidosis and/or alkalosis, respectively. Values below 7.1 and above 7.6 are critical, especially if they are of acute respiratory origin. The range of pH that is compatible with life is 7.80 to 6.80 /3/.

PaCO₂

Primarily induced deviations from the reference interval within the limits of 30–50 mmHg are to be considered as mild, but should be diagnostically clarified. An uncompensated acute primary change of PaCO₂ is considered life threatening if it is below 25 mmHg or above 60 mmHg.

Significantly higher PaCO₂ values (80 mmHg and higher) are relatively well tolerated in many cases of chronic hypercapnia developed over weeks or months. Compensatory increases in PaCO₂ in cases of metabolic alkalosis rarely exceed 50 mmHg. In contrast, PaCO₂ can for a short period of time be reduced to values around 15 mmHg and lower to compensate metabolic acidosis with intact lung function: for example, Kussmaul respiration.

Bicarbonate

Values below 10 or above 40 mmol/L are rarely found. The extreme limits are around 5 and 55 mmol/L. The degree of risk from pathological bicarbonate concentrations is indicated by the resulting pH shift. The same applies by analogy to the other base parameters.

9.7.1.4 Metabolic acidosis

The H⁺ concentration of the organism is tightly regulated because changes in the H⁺ alter protein and membrane functions. Metabolic acidosis is a disorder that reduces the HCO₃^– concentration and occurs if the H⁺ production exceeds the body’s capacity for adequate compensation by buffering or increased respiration.

Metabolic acidosis /8/ may be attributed to Tab. 9-3 – Metabolic acidosis due to acid addition or bicarbonate subtraction:

• The addition of H⁺ with the consumption of HCO₃^– as the reaction shifts to the left: increased production or supply of acids such as keto acids, lactic acid, chloride, various intoxications
• Removal of HCO₃^– from the body resulting in increased H⁺ concentration as the reaction shifts to the right: enteral or renal loss of HCO₃^–
• Acid retention: reduced renal clearance of H⁺ and/or reduced HCO₃^– production in the kidney in renal insufficiency, tubular dysfunction or hormonal disorder. For causes, see Tab. 9-4 – Metabolic acidosis due to renal acid retention or base subtraction. See also chloride in urine (Section 8.8.4 – Disturbances of chloride excretion).

Calculation of the anion gap is useful in the initial evaluation for the presence of mixed metabolic acid-base disturbances /1/.

9.7.1.5 Metabolic alkalosis

Metabolic alkalosis develops if a net loss of acids or a net increase in bases cannot be compensated by increased renal clearance of bicarbonate. Clinical laboratory results are a pH higher than 7.4 and an HCO₃^– concentration higher than 26 mmol/L.

The main causes are /14/:

• Gastrointestinal acid loss due to vomiting. The gastric juice contains up to 100 mmol/L of H⁺ and the secretory volume is 1–2 liters per day. Since the loss of H⁺ is stoichiometrically associated with an increase in HCO₃^– in the blood, it undergoes glomerular filtration together with Na⁺ as NaHCO₃^–. The clearance of NaHCO₃^– theoretically leads to a loss of Na⁺. Due to the loss of volume as a result of vomiting, however, the Na⁺ are replaced by H⁺ and K⁺ in the distal nephron; this additionally results in a loss of K⁺.
• Renal acid loss due to primary or secondary hyperaldosteronism. In the distal nephron, the H⁺ are increasingly secreted in exchange for Na⁺. This situation also occurs in the Liddle syndrome (activated epithelial Na⁺ channels, ENaC). Renal-induced alkalosis can also occur due to compensation of respiratory acidosis. During hypercapnia, renal acid secretion generates new HCO₃^– to attenuate the decrease in pH in the blood. However, the increase in renal acid clearance is also associated with a loss of NH₄Cl. If, after the correction of hypercapnia, the replenishment of Cl^– is impaired by insufficient NaCl uptake or diuretics medication, renal clearance of HCO₃^– is not possible and metabolic alkalosis occurs as a result.
• Exogenous supply of bases through the administration of large quantities of HCO₃^– during cardiopulmonary resuscitation or treatment of ketoacidosis or lactic acidosis. However, HCO₃^– loading alone does not result in metabolic alkalosis unless renal HCO₃^– clearance is impaired by hypochloremia or renal failure at the same time.

For further causes, see Tab. 9-5 – Metabolic alkalosis.

9.7.1.6 Respiratory acidosis, respiratory alkalosis

These are conditions characterized by the retention and/or increased release of CO₂. Accordingly, any such case is associated with a corresponding change in PaCO₂. The deviation of the pH value characteristic of acidemia (pH decrease) and/or alkalemia (pH increase) can be significantly reduced by compensation processes. Please refer to:

• Tab. 9-6 – Respiratory acidosis
• Tab. 9-7 – Respiratory alkalosis.

Chronic respiratory acidosis

In this condition, the kidney gradually increases H⁺ clearance and bicarbonate reabsorption. As a result, increasing amounts of bicarbonate are produced from the back-diffusing CO₂ and are shifted to the extracellular space or the plasma. Thus, contrary to acute respiratory acidosis, chronic respiratory acidosis is characterized by an increase in bicarbonate concentration and base excess. This adaptation process starts on the first day and reaches its peak after 5–6 days.

9.7.1.7 Respiratory compensation of metabolic disorders

Metabolic disorders are always associated with a primary decrease in HCO₃^– and are compensated by respiration. In this process, alveolar ventilation is increased (PaCO₂ decreased) or reduced (PaCO₂ increased) to approach the HCO₃^–/H₂CO₃ ratio of 20 : 1.

To achieve this, the respiratory center is stimulated centrally by chemoreceptors on the anterior surface of the medulla oblongata and peripherally by chemoreceptors in the aorta and carotid arteries.

Adaptation of respiration starts immediately and is completed after 12–24 hours due to the slow diffusion of ions across the blood-brain barrier into the plasma. Normalization of respiration is delayed by several hours compared to therapeutic normalization of the bicarbonate concentration for the same reasons.

9.7.1.8 Renal compensation of respiratory disorders

Acute respiratory acidosis

In this situation, the buffering effect of Hb immediately results in a pronounced increase in bicarbonate in the plasma. As this occurs at the expense of the Hb buffer, the concentration of the buffer bases and, as a result, the extracellular base excess remain unchanged. Nevertheless, the blood base excess is slightly decreased because the newly produced bicarbonate is distributed to the entire extracellular compartment and thereby in part removed as a base equivalent from the blood. This could appear to be an accompanying metabolic acidosis. To prevent misdiagnosis only the extracellular base excess (in-vivo base excess) should be used.

Respiratory alkalosis

As in all alkaloses, the kidney is capable to compensate reduced CO₂ expiration by increased excretion of bicarbonate.

9.7.2 Oxygen parameters

Besides specific aspects in pulmonology and cardiology, the O₂ parameters are mainly analyzed to assess the degree of arterialization of the blood in the lungs /5/. Arterialization depends on the following factors:

• Pulmonary function
• O₂ content of inspired air
• Atmospheric pressure.

Reduced arterialization

Reduced arterialization is most sensitively detected by arterial PaO₂. If the PaO₂ decreases from 90 to 60 mmHg in cases of pneumonia, the SO₂ only decreases from 97 to 91%. On the other hand, the SO₂ reflects the situation regarding the O₂ supply in a quantitatively adequate manner. In the example above, the oxygen available to the organs is only reduced by 6% and not by a third because, at the same Hb content, the oxygen concentration is much more strongly influenced by saturation than by partial pressure (Tab. 9-8 – Arterial hypoxemia; decreased PaO₂ and SO₂).

Oxygen supply to the organs

The oxygen supply to the organs depends not only on arterialization of the blood, but also on cardiac output and Hb content. Thus, a normal arterial PaO₂ or even an elevated one observed under mechanical ventilation does not, in any way, exclude a situation of poor supply with oxygen. Hypoxemia can only be detected by determining the oxygen difference (mL/L) between arterial and mixed venous blood (avDO₂). If the threshold value of 50–60 mL/L is exceeded while the arterial PaO₂ is normal, this indicates hypoxia caused by reduced cardiac output, anemia or dyshemoglobinemia. Lactate determination can provide initial evidence of hypoxia.

The arterial O₂ parameters must, of course, always be evaluated together with the PaCO₂.

In most cases, pulmonary and/or respiratory diseases that mainly impair the ventilation/blood flow relationship, diffusion or perfusion (right-to-left shunt) lead to a decrease in arterial PaO₂ without a concomitant increase in PaCO₂. This pattern is referred to as partial pulmonary insufficiency. Arterial PaCO₂ can even be low in this case due to hypoxic stimulation of the respiratory center.

If the decrease in PaO₂ is associated with an increase in PaCO₂, this is referred to as generalized pulmonary insufficiency. It occurs in all diseases with alveolar hypo ventilation, is common in obstructive ventilation disorders and manifests in advanced stages of restrictive ventilation disorders. Illnesses normally accompanied by partial insufficiency, such as pneumonia or tumors, may also be observed with generalized insufficiency when these diseases are more extensive or advanced.

9.7.2.1 Assessment of PaO₂

The arterial PaO₂ in healthy individuals is 75–95 mmHg and the values can range from 65–105 mmHg depending on the age of the individual. Values of 50–65 mmHg are considered to be potentially dangerous, because PaO₂ changes very rapidly. Precautionary measures and diagnostic clarification are necessary. Values below 50 mmHg, corresponding to less than 85% oxygen saturation, are to be considered as critical and may require immediate intervention.

Elevated arterial PO₂ is only found in spontaneous or mechanical ventilation with oxygen-enriched air and/or gas mixtures. In theory, a maximal PO₂ of about 670 mmHg can be reached with pure oxygen respiration at normal atmospheric pressure. Since pure oxygen may only be administered for a short period of time, values above 500 mmHg are rarely measured. In such cases, the O₂ saturation reaches approximately 100%.

Patients with chronic obstructive pulmonary disease (COPD) have tissue hypoxia due to arterial hypoxemia, which is largely the result of a ventilation-perfusion imbalance in the lung. Hypoxia-inducible factors constitute the master switch in the human response to hypoxia /18/.

Environmental hypoxia leads to hypoxemia as well as tissue hypoxia. For every 1% increase in the inspired oxygen concentration, the physiological altitude is reduced by approximately 300 meters.

Hypobaric hypoxia

Decreased humidity and air temperature and increased exposure to ultraviolet light are important features of high altitude travel /25/. The reduction in barometric pressure decreases the PO₂ all along the oxygen transport chain, from inspired air to organs and tissues, which sets in motion the increase in bicarbonaturia (in hours), increase of erythropoietin and plasma volume (in days) and the ventilation (in hours to days). Contraindications to travel above 2500 meters are shown in Tab. 9-9 – Contraindications to travel above 2500 meters.

9.7.3 PaCO₂-Parameters

Normocapnia in arterial blood is 35 to 45 mmHg. In a study /26/ patients with coma who were resuscitated after out-of-hospital cardiac arrest targeted mild hypercapnia (arterial carbon dioxide; PaCO₂ 50–55 mmHg) did not lead to better neurologic outcomes at 6 months than targeted normocapnia.

9.8 Comments and problems

Pre analytical factors are of great significance in blood gas analysis /2, 6/.

Specimen

Syringe: the lack of pulsation during blood collection indicates inadvertent venipuncture if a syringe with an easily moving plunger is used. This affects the acid-base parameters slightly; however, the oxygen quantities are altered to the point of being useless.

Capillary: practically pure arteriolar blood emerges if the skin in the hyperemized region is tapped in a professional manner. Any squeezing, however, leads to contamination with venous blood.

Contact with air

Syringe: any air bubbles in the syringe must be expelled at once and the syringe itself must be immediately capped once the specimen has been obtained. Plastic syringes are only to be considered sufficiently gas-tight for 10–15 min. at the most.

Capillary: if the puncture in the appropriate region is sufficiently deep, the emerging drop of blood is large enough to quickly fill a capillary immersed into the middle of the drop. Seal the capillary immediately at both ends.

Acidification and dilution by heparin

In excess, both factors result in imitation of metabolic acidosis. The heparin concentration per mL of blood should be below 50 IU in syringes and below 80 IU in capillaries. The volume of the heparin solution in syringes should not be more than 6% of the total volume of the blood sample.

Metabolic processes in the sample

If the analysis is not performed within 15 min., the sample must be cooled to minimize glycolysis and O₂ consumption. Syringes are stored in ice water and capillaries are stored horizontally between cooling elements.

Incomplete resuspension

Before the sample is analyzed it is warmed to 37 °C in the blood gas analyzer, because its original composition with its plasma and erythrocyte buffer systems must be restored. Resuspension of the erythrocytes is especially important if Hb determination is performed simultaneously within the scope of the blood gas analysis.

Syringe: slowly move and turn the syringe vertically up and down ten times and then roll it back and forth horizontally for 10 sec.

Capillary: move the wire flea inserted after sampling back and forth from the outside with a magnet.

Clotting

Insufficient heparin content or (more commonly) inadequate mixing of the specimen after sampling leads to clot formation, either already in the syringe or capillary or during warming in the blood gas analyzer. Clots can render an analyzer useless for an extended period of time.

Body temperature of the patient

The body temperature of the patient is still subject of debate whether or not the results found in hypothermic patients should be converted to those of normothermic conditions. The debate centers around whether the reference values applying to normothermia are still valid under hypothermic conditions. Conversion is available in blood gas analyzers but can also be performed with nomograms /16/.

Determination of tCO₂

Principle: in order to measure tCO₂, HCO₃^– is determined enzymatically using phosphoenolpyruvate carboxylase. Catalyzed by malate dehydrogenase, the oxalo acetate formed is converted into malate and NAD in the presence of NADH /17/.

High LD activity in the sample results in elevated values of tCO₂. This is the case in samples with an LD activity > 845 U/L, because the pyruvate present in the sample is converted into lactate and NAD under NADH consumption. The decrease in NADH falsely indicates the concentration of tCO₂ as too high. In a case report, instead of a HCO₃^– concentration of 6 mmol/L, a tCO₂ concentration of 16 mmol/L at an LD activity of 4490 U/L was determined.

Stability of acid/base parameters in venous blood samples

Venous blood gas analysis including pH, PaCO₂ and calculated HCO₃^– are an alternative to arterial blood gas analysis. Studies have documented a close correlation between arterial and venous acid/base samples /21/.

A study /22/ investigating the stability of the acid/base parameters at room temperature versus slushed ice demonstrated the following findings:

• pCO₂: pH was stable at room up to 60 min at room temperature and up to 3 h in slushed ice.
• pO₂ became unstable (from 40 to 20 min) and the instability increased when baseline pO₂ was ≥ 60 mmHg.
• The storage time for pCO₂, pO₂, pH, and CO-Oximetry, when measured together, were limited by the pO₂.

Hemolysis

Hemolysis can frequently be found in heparinized blood gas samples and affects parameters, e.g. K⁺, Ca²⁺, PO₂ and PaCO₂ /23/. In a study /24/ 3.6% of samples were excluded because of sample hemolysis. The K⁺ was low (< 3.5 mmol/L) in 5.5%, normal (3.5 to 5.0 mmol/L) in 90%, and elevated (> 5.0 mmol/L) in 3.6% of patients. Elevated concentrations of K⁺ can indicate hemolysis in blood gas samples.

9.9 Pathophysiology

9.9.1 Acid-base elimination of the body

Normally the equivalent of 40–60 mmol of acid is ingested daily in the diet, metabolized and eliminated by the kidneys. About 24 moles of CO₂ are generated and pulmonally eliminated within the same period. Despite these turnovers, the body is capable of keeping the H⁺ concentration stable at 40 nmol/L, corresponding to pH 7.4.

Even under stress conditions acting on the acid-base system that may ultimately lead to acidosis or alkalosis, the pH deviation can be kept within relatively tight limits for a long time.

This is achieved by the following organs:

• The lungs can increase CO₂ expiration to more than ten-fold for a short period of time
• The clearance capacity of healthy kidneys for acids is 400–500 mmol/24 h.

Metabolic acidosis cannot occur until metabolic acid formation has reached this magnitude or the acid clearance capacity of the kidneys is reduced.

9.9.2 Renal acid-base regulation

Bicarbonate reabsorption

The cells of the proximal tubule reabsorb 80% of the glomerularly filtered bicarbonate. The membrane-bound and cytoplasmic carbonic anhydrases catalyze the formation of CO₂ as follows:

H⁺ + HCO₃^– → H₂CO₃ → H₂O + CO₂

By transmembrane diffusion, the CO₂ passes from the lumen into the tubule cell (see also Fig. 8.8-3 – Maintaining the acid-base homeostasis in the proximal tubulus). Usually balanced at an extracellular HCO₃^– concentration of 26 mmol/L, this process is stimulated by hypercapnia (see compensation of respiratory acidosis). The capacity is approximately 4500 mmol/24 h.

Adaptive H⁺ elimination

This process takes place in the distal tubule and the cortical part of the collecting ducts. At the luminal side, the cells involved have H⁺-transporting ATPase that is capable of secreting H⁺ against a gradient of three pH units (see also Fig. 8.8-4 – H⁺ secretion into the cortical collecting ducts). This process is stimulated by hypercapnia and aldosterone. The capacity is 70–100 mmol/24 h.

Elimination of ammonium

Acid loading leads to the increased formation of glutamine in the hepatocyte at the expense of urea synthesis /19/; from the glutamine, NH₃ is formed in the proximal tubule cells. H⁺ secreted into the lumen of the collecting ducts are bound as NH₄⁺ and excreted (see also Fig. 8.8.4). The capacity is 300–400 mmol/24 h.

9.9.3 Urinary buffer system

The H⁺ are buffered by NH₃ and hydrogen phosphate:

NH₃ + H⁺ → NH₄⁺
HPO₄^2- + H⁺ → H₂PO₄^–

The H₂PO₄^– are determined by measuring the titratable acidity of the urine; the NH₄⁺ are measured directly.

9.9.4 Blood buffer system

At pH 7.4, the blood contains approximately 48 mmol/L of buffer bases. Two buffer systems are significant:

• The HCO₃^–/H₂CO₃ system that accounts for about 75% of the buffering of fixed acids
• The Hb buffer system that accounts for about 20% of the buffering of fixed acids but is primarily responsible for H⁺ transport and buffering.

H₂CO₃ + Hb^– → HCO₃^– + HHb

Bicarbonate produced by the H₂CO₃ buffering process is released from the erythrocyte into the plasma in exchange for chloride. The components of the HCO₃^–/H₂CO₃ system are used for the quantitative assessment of the acid-base status. Their relationship is described by the Henderson-Hasselbalch equation.

or

When the ratio between HCO₃^– and H₂CO₃ is 20 : 1 or the numeric ratio between bicabonate concentration (mmol/L) and PCO₂ (mmHg) is 0.6, the result in a pH of 7.4.

Buffering within the cells is based on the bicarbonate and hydrogen phosphate systems and the plasma proteins. The buffering function of these systems is not available for routine analysis.

9.9.5 Pulmonary function tests for prediction of postoperative pulmonary complications

Pulmonary function tests such as spirometry and blood gas analysis have been claimed to improve preoperative risk assessment. According to a study /27/ it is currently unknown if pulmonary function tests improve risk assessment before non-thoracic surgery.

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22. Zavorsky GS, van Wijk XMR. The stability of blood gases and CO-oximetry under slushed ice and room temperature conditions. Clin Chem Lab Med 2023; 61 (10): 1750–9.

23. Möckel M, Luppa PB. Why hemolysis detection should be an integral part of any near-patient blood gas analysis. J Lab Med 2021; 45 (4–5): 193–5.

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9.10 Asthma

Lothar Thomas

Asthma is a chronic inflammatory disease of the airways with variable expiratory airflow limitation and diverse respiratory symptoms. The clinical spectrum of symptoms includes coughing, wheezing, breathlessness, and chest tightness.

Asthma affects a substantial number of people globally. The estimated prevalence of asthma cases and related symptoms including reported wheezing was 755 million. Asthma mortality is 5.96 per 100.000 inhabitants.

The cause of death in asthma patients ranges and includes /1/:

• benign conditions ,e.g. respiratory tract infections, chronic obstructive pulmonary disease (COPD), cardiovasvascular disease (CVD), diseases of the musculoskeletal system, connective tissue diseases, genitourinary diseases, metabolic, and immunity disorders
• malignant diseases, e.g. lung cancer.

Comorbidities refers to the coexistance of additional diseases and holds significant relevance to the management of asthma /1/. Asthma-related comorbidities are shown in Tab. 9.10 – Asthma-related comorbidities.

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