β The hydrogen-ion concentration is tightly regulated because changes in hydrogen ions (H+) alter virtually all protein and membrane functions. Since the concentration of hydrogen ions in plasma is normally very low (approximately 40 nmol per liter), the pH, which is the negative logarithm of the hydrogen-ion concentration, is generally used in clinical medicine to indicate acidβ€"base status.
β— The terms β€acidemiaβ€ and β€alkalemiaβ€ refer to states in which the blood pH is abnormally low (acidic) or abnormally high (alkaline). The process in which the hydrogen-ion concentration is increased is called acidosis, and the process in which the hydrogen-ion concentration is decreased is called alkalosis.
The three major methods of quantifying acidβ€"base disorders are the physiological (traditional) approach, which is used here as the chosen quantification method; the base-excess approach; and the physicochemical approach (also called the Stewart method).
β The physiological traditional approach uses the carbonic acidβ€"bicarbonate buffer system and its values based on the Hendersonβ€"Hasselbalch equation.
β— pH = pK + log10 (bicarbonate [HCO3-] Γ· [0.03 Γ— partial pressure of arterial carbon dioxide (PaCO2)]).
β— Based on the isohydric principle, this system characterizes acids as hydrogen-ion donors and bases as hydrogen-ion acceptors and all the buffer systems within the body exist in equilibrium with each other; therefore, analysis of any one buffer system of the body mirrors the state of all the other buffer systems.
β— The carbonic acidβ€"bicarbonate system is important in maintaining homeostatic control.
β" This buffer system acts like a sponge, taking up hydrogen ions when there is too much and releasing hydrogen ions when there is too little.
β— In the physiological approach, a primary change in the partial pressure of carbon dioxide (PCO2) causes a secondary β€adaptiveβ€ response in the bicarbonate concentration (HCO₃β») and vice versa; further changes in carbon dioxide or bicarbonate reflect additional changes in acidβ€"base status.
β" Empirical observations suggest that the homeostatic response to acidβ€"base disorders is predictable and can be calculated.
The current prediction equations that are used to assess the homeostatic response are approximations based on nearly 40-year-old studies involving humans and dogs.
β" In response to metabolic acidβ€"base disturbances, changes in the respiratory rate develop quickly, and a new steady-state PCO2 is reached within hours.
β" The kidneys generally complete the metabolic response to respiratory acidβ€"base disturbances within days by retaining bicarbonate and excreting acid.
β— The four recognized primary acidβ€"base disorders comprise two metabolic disorders (acidosis and alkalosis) and two respiratory disorders (acidosis and alkalosis).
β" An acidβ€"base disorder is called β€respiratoryβ€ when it is caused by a primary abnormality in respiratory function (i.e., a change in the PaCO2) and β€metabolicβ€ when the primary change is attributed to a variation in the bicarbonate concentration.
Detailed instructions on how to apply the physiological approach to analyzing acid-base disorders, including calculations and interpretation of results.
A logarithm consists of two sets of numbers; the digits to the left of the decimal point are called the characteristic. The numbers after the decimal are the mantissa.
β In wide (high) anion gap metabolic acidosis, it is principally the decrease in the bicarbonate that accounts for the increase in the anion gap. If the decrease in the bicarbonate is disproportionate to the increase in the anion gap, this implies the presence of an additional acid-base disorder. The difference between the increase in the anion gap (Ξ"AG) and the decrease in the bicarbonate (Ξ"HCO3- ) is termed the Delta β€" Delta Gap (Syn.: Bicarbonate Gap, Delta Gap, Delta Ratio).
• In a pure wide anion gap metabolic acidosis, the fall in the bicarbonate need not always exactly parallel the rise in the AG: although the bicarbonate is the principal extracellular buffer, it is not the only buffer; there are other buffer systems that are also participating in the buffering process.
The Aβ€"a O2 gradient, or the alveolar-arterial gradient, measures the difference between the oxygen concentration in the alveoli (PaO2) and arterial system (PaO2). The Aβ€"a O2gradient hzimportant clinical utility as it can help narrow the differential diagnosis for hypoxemia. The A-a gradient calculation is as follows:
Aβ€"a O2 Gradient = PaO2 β€" PaO2.
• High Aβ€"a O2gradients are associated with oxygen transfer / gas exchange problems. These are usually associated with alveolar membrane diseases, interstitial diseases or V/Q mismatch.
• Hypoxemia in the face of a normal A-a gradient implies hypoventilation with displacement of alveolar O2 by CO2 or other substance.
• The FiO2 (fraction of inspired oxygen) is equal to the Percent Inspired O2 / 100. The estimate of the precise FiO2 that the patient is breathing, is often inaccurate. Variable performance devices like nasal prongs and non-venturi masks provide unreliable estimates of FiO2. FiO2 estimates can be misleading on conventional oxygen devices if a patient has an irregular pattern of breathing.
• pATM is dependent on altitude above sea level. The barometric pressure does not remain constant throughout the day though it is invariably assumed to be.
• pH2O (water vapor pressure) actually changes slightly with body temperature.
• The Respiratory Quotient Ratio is not always 0.8, especially in critically ill patients with altered body metabolism and on complex nutritive supplementation.The RQ may, also, change slightly depending upon the FiO2 administered, in order to compensate for the Nitrogen that is washed out with higher fractions of O2. At FiO2’s of 100% the RQ approximates 1.0.
β" Use RQ = 0.8 when FiO2 < 0.6
β" Use RQ = 1 when FiO2 > 0.6
Aβ€"a O2 Gradient Helps in Differentiating Between the Different Mechanisms of Hypoxemia
| Causes of Hypoxemia | Aβ€"a O2 Gradient Shift |
|---|---|
| V/Q Mismatch (ex: PNA, CHF, PE, ARDS, atelectasis, etc). Decreased ventilation relative to perfusion or vice versa. It is the most commonly encountered mechanism for hypoxemia | Widened |
| Shunt (ex: PFO, ASD, pulmonary AVMs). An extreme form of V/Q mismatch. Due to lack of regional ventilation, unoxygenated blood returns to the left-heart, increasing the shunt fraction ( | Widened |
| Diffusion defect (ex: interstitial lung dz, environmental lung dz, PCP, PNA). Hypoxemia caused by a limitation of the diffusion of gas (oxygen) through the alveolar capillary membrane | Widened |
| Hypoventilation (ex: COPD, CNS d/o, neuromuscular dz, etc). Decreased bulk flow in and out of the lungs. Hypoventilation leads to a buildup of CO2 in the blood. Hypercapnia is its defining feature | Not Widened |
| High altitude. A decreased inspired fraction of O2 would produce the same effect as a low barometric pressure | Not Widened |
β The Law of Electroneutrality states that the sum of all the anions should equal the sum of all the cations. In practice the measured anions are Sodium (Na+) and Potassium (K+), and the measured cations are Bicarbonate (HCO3-) and Chloride (Cl-).
• The anion gap is the difference between the unmeasured anions and the unmeasured cations.
β" Anion Gap = [Na+] + [K+] β€" [HCO3-] β€" [Cl-]
• The anion gap exists because some anions are not measured. It is an artefact of measurement and not a physiological reality. In other words, if all ions were measurable, there would simply be no anion gap!
• In wide anion gap metabolic acidosis, there is a relative excess in the concentration of unmeasured anions. Although these anions are not directly measured, the increased H+ in acidosis leads to consumption in the HCO3β€".
• The Law of Electroneutrality can also be written as follows:
β" Total cations β' total anions = 0
β" [Na+] + [K+] β€" [Cl-] β€" [HCO3-] β€" [A-] β€" [unmeasured anions] = 0
β For the calculation of anion gap either of the two following formulae can be used:
• [Na+] - [Cl -] - [HCO3-]. Normal range: 12±4 mEq/L. This is the generally used formula. K+is excluded from the formula on the grounds that the value of K+is generally small enough to be disregarded.
• [Na+] + [K+] - [Cl-] - [HCO3-].Normal range: 16±mEq/L. This is the formula used when the value of K+is expected to vary significantly, as in renal patients.
• Newer autoanalysers report the normal serum Cl- at a higher value (than did the β€olderβ€ machines); the normal range for the anion gap with the newer machines is lower, usually ranging between 3 and 11 mEq/L. However, given that its measurement hinges on multiple factors, a wide AG can be diagnosed with assurance when above 17β€"18 mEq/L.
β Certain factors can limit the diagnostic accuracy of the AG:
• Errors of measurement
Since the measurement of three to four ions is required in its computation, there are greater chances of errors in its measurement
• Lactic acidosis
In lactic acidosis the AG may sometimes remain normal in spite of the presence of a significant acidosis.
• Hypoalbuminemia
The albumin molecule carries a large number of negative charges on its surface; therefore, albumin accounts for most of the unmeasured anions. Albumin is normally responsible for virtually all of the value of the AG.
β€Low Albumin, Low Anion gap’: For every gram per dL decrease in albumin below 4.4 g/dL, the AG narrows by 2.5β€"3 mmol/L. The anion gap can be spuriously low when significant hypoalbuminemia exists. In severe hypoalbuminemia (such as in the nephrotic syndrome and cirrhosis), a wide anion gap metabolic acidosis may exist, masked by hypoalbuminemia.
Serum Anion Gap adjusted for the albumin = [Na+] β€" [Cl-] β€" [HCO3-] + 2.5 Γ— (4 - albumin in g/dL).
β Corrected Anion Gap (AGc):
• The Corrected Anion Gap (AGc) is the anion gap adjusted for the albumin and phosphate, altogether:
β" AGc= ([Na+ + K+] β' [Cl- + HCOFiO3-]) β' (2 [Albumin in g/dL]) + 0.5 [Phosphate in mg/dL] β€" Lactate, or
β" AGc= ([Na++ K+] β' [Cl- + HCO3-]) β' (2 [Albumin in g/dL]) + 1.5[Phosphate in mmol/L] β€" Lactate
β Oh MS, Carroll HJ. The anion gap. N Engl J Med. 1977 Oct 13;297(15):814-7.
β The concept of pH as an expression for the hydrogen-ion concentration was proposed in two papers in 1909 by the Danish chemist SΓΈren Peter Lauritz SΓΈrensen, director of the Chemical Department of the Carlsberg Laboratories between 1901 and 1938.
Soren Peter SΓΈrensen observed that enzymatic activity produced tiny but measurable changes in the H+ concentration. The intent behind the use of the pH scale is to make the handling of very small numbers more convenient. The pH range 6.8β€"7.8 (corresponding to a H + ion concentration of 160 β€"16 nmol/L) is generally considered to be the range of pH within which life can exist. On a logarithmic scale, a relatively small change in pH can reflect a large change in the H+ ion concentration.
• "pH", is a short form for what he called the β€Puissance hydrogenβ€ or β€Wasserstoffionenexponentβ€ or simply the β€Potenzβ€, ie β€Potentialβ€ of hydrogen.
• SΓΈrensen, S.P.L. (1909) Γ‰tudes enzymatiques. II. Sur la mesure et l’importance de la concentration des ions hydrogΓ¨ne dans les rΓ©actions enzymatiques. Compt. rend. du Lab. de Carlsberg 8, 1β€"168
• SΓΈrensen, S.P.L. (1909) Enzymstudien. II. Mitteilung. Γber die Messung und die Bedeutung der Wasserstoffionenkoncentration bei enzymatischen Prozessen. Biochem. Zeitschr. 21, 131β€"304, and 22, 352β€"356
β The Aβ€"a O2 Gradient is the difference between the alveolar O2 tension (PaO2) and the arterial oxygen tension (PaO2). Aβ€"a O2 Gradient represents the ease with which the inspired oxygen diffuses into the blood, and therefore reflects the efficiency of the lungs in oxygenating the blood.
• To estimate the Aβ€"a O2 Gradient it is necessary to calculate the PaO2, from the modified alveolar gas equation: PaO2 = FiO2 x (Pb - Pw) - PaCO2 / R where, PaO2 = alveolar oxygen tension, FiO2 = fraction of inspired oxygen, Pb = atmospheric pressure in mmHg, Pw = partial pressure of water, PaCO2 = arterial CO2 tension and R = respiratory quotient.
β Limitations of the simplified formula in Aβ€"a O2 Gradient calculation
• FiO2: The estimate of the precise FiO2 that the patient is breathing, is often inaccurate. Variable performance devices like nasal prongs and non-venturi masks provide unreliable estimates of FiO2. FiO2 estimates can be misleading on conventional oxygen devices if a patient has an irregular pattern of breathing.
• Pb: The barometric pressure does not remain constant throughout the day though it is invariably assumed to be. Pb = 760 x e(Altitude / -7000).
• Pw: Water vapour pressure is assumed to be 47 mmHg: actually, the water vapor pressure changes slightly with body temperature. Pw = 47 x e((Patient Temperature in °C - 37) / 18.4).
• The Respiratory Quotient Ratio is not always 0.8, especially in critically ill patients with altered body metabolism and on complex nutritive supplementation.
β" Use RQ = 0.8 when FiO2 < 0.6
β" Use RQ = 1 when FiO2 > 0.6
β If the Aβ€"a O2 Gradient is elevated, it suggests the presence of a diffusion defect, a V/Q mismatch, or a shunt. Further tests would then be needed to ascertain the underlying cause.
β Gradient A-a O2 = PaO2 - PaO2 = (PB - PH2O) Γ— FIO2 - PACO2 / RQ - PaO2
• Barometric pressure decreases with increasing altitude, which reduces the absolute amount of inspired oxygen molecules, resulting in hypoxia at high altitudes.
β" PB at sea level is 760 mm Hg, and FiO2 at sea level is 21%.
β The Urine Anion Gap (UAG) is the difference between measured cations (sodium and potassium) and measured anions (chloride) in the urine, often expressed as:
• UAG = (Na+ + K+) - (Cl-).
• A positive UAG suggests impaired ammonium excretion, often due to renal tubular acidosis.
• A negative UAG suggests an intact ability to excrete ammonium, often due to non-renal causes of metabolic acidosis (e.g., diarrhea).
• UAG is primarily used to assess the kidney’s response to metabolic acidosis and can help distinguish between renal and non-renal causes of acidosis.
β Note: A positive UAG in the setting of metabolic acidosis may indicate renal tubular acidosis, whereas a negative UAG suggests an appropriate renal response to acidosis.
β The intent behind the use of the pH scale is to make the handling of very small hydrogen ion concentration of the blood more convenient.
• The pH range 6.8β€"7.8 (corresponding to a H+ ion concentration of 160 β€"16 nmol/L) is generally considered to be the range of pH within which life can exist.
β The Henderson Equation, which is derived from the Law of Mass Action, can be modified with respect to the bicarbonate buffering system to yield a simpler equation that provides a quick approximation of the H+ or HCO3- concentration without the need to calculate logarithms.
• The modified Henderson Equation, also known as Kassirer and Bleich’s equation is as follows: [H+] = 24 x PCO2/HCO3-.
• Kassirer and Bleich’s equation is used to calculate the hydrogen ion concentration and from that pH is calculated. This pH is then compared to the measured pH. If the values are similar the sample is valid and if the values are far apart, there may be a measurement error.
β The interpretation follows the physiological approach, pioneered by Van Slyke and co-workers. This approach, which remains the simplest, most rigorous, and most serviceable approach to assessing acidβ€"base disorders, considers acids as hydrogen ion (H+) donors and bases as H+ acceptors. It uses solely the carbonic acid/bicarbonate buffer system for assessing acid-base status, a position rooted in the isohydric principle. Adoption of this buffer system reflects its abundance, physiological preeminence, and the fact that its two components undergo homeostatic control.
• Blood pH is viewed as being determined by the prevailing levels of carbonic acid (that is, PaCO2, the respiratory component) and plasma bicarbonate concentration ([HCO3-], the metabolic component, as stipulated by the Henderson equation, [H+] = 24 × PaCO2/[HCO3-].
• The physiological approach recognizes four acidβ€"base disorders. Metabolic disorders are expressed as primary changes in plasma [HCO3-], whereas respiratory disorders are expressed as primary changes in PaCO2. Each primary change in either plasma [HCO3-] or PaCO2 elicits in vivo a secondary response in the other variable that tends to minimize the change in acidity.
β" These secondary responses, otherwise referred to as compensatory, have been quantitated in animals and humans. The use of the term compensatory is discouraged, because the secondary responses occasionally can yield a maladaptive effect on blood pH. Absence of an appropriate secondary response denotes the co-existence of an additional simple acidβ€"base disorder.
β" Use of ventilator support in critically ill patients can, of course, alter or prevent expression of the secondary changes in PaCO2 in response to metabolic acidβ€"base disorders. These ventilator-induced alterations are viewed as complicating primary respiratory acidβ€"base disorders.
• The simultaneous presence of two or more simple acidβ€"base disorders defines a mixed acidβ€"base disorder.
• Assessment of the metabolic component is complemented by evaluating the plasma anion gap (AG), defined as [Na+] - ([Cl-]+[TCO2]), where [TCO2] indicates venous total CO2 concentration. The average normal value for plasma AG differs among health-care facilities because of methodological variation. Normally, approximately 75% of the plasma AG is determined by plasma albumin concentration. Thus, the plasma AG must be adjusted by subtracting or adding 2.5 mEq/l from the calculated value for each 1 g/dl of plasma albumin below or above the average normal value of 4.5 g/dl, respectively.
β The standard blood gas analyzer measures pH and PaCO2, from which plasma [HCO3-] is calculated.
β The response for respiratory disorders is by renal processes and vice versa. It is worth re-emphasizing that interpretation of acid-base disorders should always be made in the clinical context. If the response is less or more than expected, an independent second disorder exists.
• An alternative term often used for secondary responses is 'compensatory'. However, this term can lead to confusion, as it suggests a distinction between partial and complete compensation. While secondary responses do help mitigate the effects of primary changes on blood acidity, they never fully restore blood acidity to its original levels.
β Considerable uncertainty exists regarding the time course for completion and eradication of the secondary responsesin humans.
• A mixed acid-base disorder might be diagnosed incorrectly because insufficient time has elapsed for the secondary response to a single primarydisorder to develop or resolve.