Basic science

Analysis of blood gases and acidbase balance

andrew smith chris Taylor

pH units and concentration of hydrogen ions

pH 8.00 7.70 7.44 7.40 7.36 7.10 7.00 Table 1 [H+] (mmol/l) 10 20 36 40 44 80 100

Abstract
Regulation of the concentration of hydrogen ions is important for the maintenance of the function and integrity of cells. Many pathological processes impact on the ability to maintain homeostasis of hydrogen ion concentration. This contribution dicusses some of the concepts involved in the measurement of acidbase balance and blood gas concentrations.

Keywords acidosis; alkalosis; anion gap; base excess; blood gases;

buffering system; haemoglobin; mixed venous saturation; oxygen saturation; standard bicarbonate

Biological buffering systems A buffer is a substance that minimizes a change in pH by releasing or absorbing H+ when an acid or alkali is added to a solution, thus maintaining the pH within normal limits. The effectiveness of a buffer is dependent on its concentration and its pKa (the pH at which a buffer solution is ionized by 50%). The closer the pKa to the biological pH, the more effective is the buffer. For example, an undissociated acid (HA) and its dissociated forms (H+ and A) can be represented by the equation: HA [H+] + [A] The equation shifts to the right when base is added or to the left when acid is added. The HendersonHasselbach equation describes this relationship:
pH = pKa + log [A ] [HA]

Body fluids require a stable pH for the normal function of enzymes, and the maintenance of protein structure and ion distribution. In health, body metabolism generates about 60 mmols of H+ in the form of organic acids (e.g. lactic acid, pyruvic acid) released into the extracellular fluid every 24 hours. The concentration of H+ is maintained relatively stable at 4535 nmol/l (pH 7.357.45). This exact regulation of acidbase balance is attributed to buffering (and ultimately the excretion) of H+ ions from the body.

Terminology and definitions

Activity of hydrogen ions and pH The term pH comes from the French puissance dhydrogne (strength of hydrogen) and is how hydrogen activity is expressed; pH is the negative logarithm (base-10) of the hydrogen ion concentration i.e.
pH = log [H + ] = log 1 [H + ]

Maximal buffering takes place when the pK of the buffer system equals the pH. This occurs when the acid (A) and base (HA) are in equal amounts (the log of one is zero). Buffering systems in the body There are buffering systems in: blood (carbonic acid (H2CO3)/bicarbonate (HCO3), haemoglobin, plasma proteins, phosphate (PO43)) intracellular fluid (proteins, PO43). The HCO3 system with a pKa at 6.1 is (by definition) not efficient at body pH, but CO2 is eliminated in the lungs, and so can be regulated by changes in respiration. HCO3 can be filtered and reabsorbed by the kidneys. These mechanisms (as well as the large quantity of HCO3 in the plasma) make it the main buffering system in the blood. Carbonic acid dissociates or is catalysed by carbonic anhydrase to carbon dioxide and water, that is: H2O + CO2 H2CO3 + H+ HCO3 The HendersonHasselbach equation can be derived from this:

A small change in pH represents a relatively large change in [H+] in the opposite direction (Table 1). A pH change of 0.3 units is equivalent to doubling or halving the [H+]. The range of [H+] compatible with life is 20160 nmol/l (pH 7.706.80).

Andrew Smith FRCA is a Consultant Anaesthetist at the Heart Hospital, London, UK. Conflicts of interest: none declared. Chris Taylor MRCP(Paed) FRCA is a Consultant in Neuro-anaesthesia and Neurocritical care at the National Hospital for Neurology and Neurosurgery, University College Hospitals NHS Trust, UK. Conflicts of interest: none declared.

H2CO3 H+ + HCO3 The dissociation is governed by the dissociation constant (K)

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K=

[H+][[HCO3 ] [H2CO3 ]

Rearranging the above equation:

1 [HCO3 ] 1 = [H+] K [H2CO3 ]

Taking logarithms:
log [HCO3 ] 1 1 = log + log [H+] K [H2CO3 ] [HCO3 ] [H2CO3 ]

pH = pKa + log

[H2CO3] is related to [CO2] in the original reaction and [CO2] is related to its partial pressure (PCO2) and a solubility factor (0.23 mmol/l per kPa or 0.03 mmol/l per mmHg). A more useful form of the equation is:
pH = pKa + log [HCO3 ] PCO2 0.23

acidosis (e.g. diabetic ketoacidosis), the elevated concentration of H+ stimulates the medullary respiratory centre, resulting in hyperventilation, which tends to restore the pH towards normal; thus, a compensatory respiratory alkalosis results. With a primary metabolic alkalosis (e.g. excessive vomiting with loss of hydrochloric acid), the respiratory system compensates by hypoventilation. This results in less CO2 being excreted by the lungs. The subsequent rise in H+ concentration tends to restore the pH towards normal i.e. a compensatory respiratory acidosis. The kidneys can compensate by altering the net acid (in the form of ammonium ions (NH4), sulphate ions (SO42), PO43 or net HCO3 excreted per day). For example, in primary respiratory acidosis (e.g. chronic obstructive sleep apnoea), a compensatory retention of more filtered HCO3 at the tubular level occurs, resulting in a compensatory metabolic alkalosis. Alternatively, a respiratory alkalosis (e.g. as in anxiety) will be compensated by a reduction of retention of HCO3 at the tubular level, and a compensatory metabolic acidosis results. These compensatory changes make the change in pH less than it would otherwise be, but they do not necessarily return the pH to normal.

Thus, if CO2 rises, so will HCO3, (in order to keep [HCO3]/ PCO2 constant). Similarly, a fall in HCO3 will be accompanied by a fall in PCO2 (in order to prevent a change in pH). Acidosis and alkalosis Acidosis is a condition in which [H+] is raised or would be in the absence of compensatory mechanisms. An acidosis leads to an acidaemia, but the terms are often used interchangeably. (Alkalosis and alkalaemia are defined in a similar way.) A pH of <7.35 in blood or plasma is an acidaemia. Respiratory acidosis is a fall in pH resulting from a rise in PCO2 due to hypoventilation. Respiratory alkalosis is a rise in pH resulting from a fall in PCO2 due to hyperventilation. Metabolic acidosis is a fall in pH due to metabolic causes resulting in a low pH for a given PCO2. Causes include: an increase in acid production; ketones in diabetes mellitus or lactic acid in shock acid ingestion (e.g. salicylate poisoning) failure to excrete H+ (e.g. renal failure, renal tubular acidosis, carbonic anhydrase inhibitors) loss of HCO3 (e.g. diarrhoea, gastrointestinal fistula, proximal renal tubular acidosis, ureterostomy). Metabolic alkalosis is an inappropriately high pH for a given PCO2. There is a loss of acid (e.g. due to vomiting, nasogastric aspiration) or a gain in bicarbonate. Compensatory mechanisms The buffering system acts as an immediate control of pH but a variety of compensatory changes occur in order to effect longerterm control. The concentration of H+ in the body is regulated by respiratory and renal compensatory methods. (However, recent concepts of physiochemical approaches to acidbase compensation have been proposed, see below). The ability of the respiratory system to excrete acid in the form of CO2 allows it to compensate for a metabolic disturbance more rapidly than the kidneys for a respiratory disturbance. If the primary disturbance is metabolic
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Analysis of blood gases (Table 2)

PO2, pH, and PCO2 are directly measured from a blood gas machine; [HCO3] is calculated from the Henderson Hasselbach equation. Blood gas machines can also derive other variables useful in the interpretation of acidbase status (e.g. electrolyte concentrations (Na+, K+, Cl), lactate, glucose, creatinine).

Data from a blood gas machine showing normal values in an adult

Temp pH PcO2 PO2 HcO3 TcO2 sBc Be sBe O2 sat Hb cOHb MetHb Lactate 37c 7.367.44 4.65.6 kPa 10.013.3 kPa 2226 mmol/l 2428 mmol/l 2226 mmol/l 2 to +2 mmol/l 3 to +3 mmol/l > 95% 11.516.5 g/dl

(4436 mmol/l) (3542 mmHg) (75100 mmHg)

02 mmol/l

PcO2, partial pressure of carbon dioxide; PO2, partial pressure of oxygen; HcO3, bicarbonate; TcO2, total carbon dioxide; sBc, standard bicarbonate concentration; Be, base excess; sBe, standard base excess; O2 sat, oxygen saturation; Hb, haemoglobin; cOHb, carboxyhaemoglobin, MetHb, methaemoglobin.

Table 2

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Base excess is the amount (in mmol) of acid or base required to restore 1 l of blood to normal pH at a PCO2 of 5.3 kPa at 37C. The value is negative in metabolic acidosis (also called base deficit) and positive in metabolic alkalosis. Base excess is a useful indicator of the metabolic component of an acidbase disturbance. Base excess is an in vitro determination of the whole blood that goes into the blood gas machine. Base excess is described on the blood gas result in a number of ways: base excess (BE) actual base excess (ABE) base excess-blood (BEb) standard base excess (SBE) extracellular fluid base excess (BEe). There is little clinical difference between the different values. Standard base excess is similar to base excess, but includes an estimate of the in vivo base excess of extracellular fluid, which has lower buffering capacity than whole blood, hence its value is 12 mEq/l greater than base excess. If it is appropriate to correct metabolic acidosis by treating with HCO3 (not always the case), then calculate:
Base excess body weight (kg) 3

is about 75%; it is an indication of the matching of total oxygen supply to total oxygen demand of the body in critical care patients. If SvO2 is >75%, the oxygen supply to the tissues may exceed the oxygen utilization. During a period of severe sepsis, there may be adequate oxygen supply to the tissues but poor oxygen uptake and utilization by the cells. If SvO2 is <75%, demand exceeds supply (e.g. in cardiogenic shock with reduced delivery of oxygen to the peripheral tissues). In a hypotensive critical care patient, the SvO2 can therefore be useful in differentiating septic shock from cardiogenic shock as the cause of the low blood pressure. PO2 and Aa gradient: the inspired oxygen concentration and the age of the patient must be known when interpreting PO2 otherwise results have little meaning. Normal PO2 declines with age. In general, PO2 = 13.30.044 age (kPa). A PO2 of 10 kPa is reasonable for a patient until it is discovered that he has an inspired oxygen fraction (FIO2) of 40%, hence the importance of knowing the FIO2. To calculate the alveolar partial pressure of O2 (PAO2), a simplified alveolar gas equation may be used. The expected alveolar PO2 (PACO2) can be predicted from the FIO2:
PA O2=PlO2 PCO2 R

This gives the amount (in mmols) of HCO3 needed to restore the pH to normal (1 ml of 8.4% of sodium bicarbonate contains 1 mmol). In practice, this value is not calculated and a standard aliquot of HCO3 is given (usually 50 ml of 8.4% sodium bicarbonate), the pH and base deficit rechecked and further doses given if required. Standard bicarbonate is the plasma concentration of HCO3 when arterial PCO2 has been corrected to 5.3 kPa with fully saturated haemoglobin at a temperature of 37 C (i.e. denotes what the HCO3 concentration would be if the respiratory component was absent). Standard base excess and base excess provide similar information and often no clinical distinction is made between the two values. Standard bicarbonate is represented as SBC on the blood gas machine. Total carbon dioxide is the total concentration of CO2 in the plasma as HCO3 and dissolved CO2 (about 95% of total carbon dioxide is contributed by HCO3). This measurement rarely provides any useful information and is represented as TCO2 on the blood gas machine. Oxygen saturation is the percentage of haemoglobin saturated with oxygen. It is derived from the haemoglobin dissociation curve and the measured PO2. However, inaccuracies may occur because other forms of haemoglobin (e.g. carboxyhaemoglobin) will be included as oxyhaemoglobin; co-oximetry should be used if this is suspected (e.g. in burns patients). Oxygen saturation is represented as O2 sat on the blood gas machine. Mixed venous saturation (SvO2) is the percentage of haemoglobin saturated with oxygen in blood derived from the superior and inferior vena cava (different in composition) after it has mixed together during passage through the heart. True SvO2 is obtained from the right ventricle or the pulmonary artery by using a pulmonary artery flotation catheter. In health, SvO2
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Where R is the respiratory exchange ratio (normally 0.8). In dry gas, FIO2 is equal to PIO2 (kPa). Alveolar gas is saturated with water vapour (6.3 kPa), for which an allowance must be made. If the FIO2 = 40% and the PCO2 = 5.3, then:
PA O2=40 (101.3 6.3) 5.3 = 30.85 kPa 100 0.8

In general, one can deduct 10 from the FIO2 percentage to give the expected PAO2 in kPa (e.g. if FIO2 = 50%, PAO2 is about 40 kPa). The difference between estimated PAO2 and measured arterial PO2 is called the (Aa) gradient; it is normally 0.52 kPa. Using the above example, a FIO2 of 40%, the PA02 will be about 30 kPa. Therefore, the Aa gradient will be 3010 kPa, far from normal. Temperature correction: samples of arterial blood gas are analysed at 37C. CO2 becomes more soluble as blood is cooled, reducing its PCO2 by about 4.5% per C. Debate exists as to whether temperature corrections should be made (a facililty available in most machines); common practice in the UK is that a correction is not made. Anion gap: the sum of the positive and negative charges in plasma is equal. The main cations are Na+ and K+ and the main anions are Cl, HCO3, proteins, PO43, SO42, and organic acids. Of these, only Na+, K+, Cl and HCO3 tend to be measured so, when normal values are added, they do not balance:
Anion gap=([Na+] +[K+]) ([Cl ] +[HCO3 ]) = (140+5) (105+25)=15 (10 18) mmol ion charge/l

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Guide for interpreting blood gas measurements (see Figure 1)

interpret results with knowledge of the clinical condition. check for consistency within the blood gas sample. The derived variables will be misleading if any of the three measurements (pH, PcO2 and PO2) are incorrect. Observe the pH for the primary acidbase disorder. Observe the PcO2. abnormality may indicate a respiratory component (e.g. a high PcO2 may be seen in acute respiratory failure secondary to pneumonia). Observe the standard bicarbonate or base excess for metabolic acidbase status. evidence of secondary compensation or of mixed acidbase disorder may be apparent. if the acidosis is thought to be metabolic in origin, calculate the anion gap or strong ion difference, and look at the lactate and chloride values to suggest a cause for the metabolic element. Look at the PO2 (in relation to the F1O2), determine hypoxia (using the modified alveolar gas equation) and calculate the aa gradient. Table 3

Strong ion difference and strong ion gap: there is an increasingly popular, alternative method of considering acidbase balance, in particular metabolic disturbances. In 1983, Stewart (see Further reading) showed that HCO3 varies with pCO2, leading to errors in the metabolic component of acidbase measurement. The physiochemical laws of mass action and electroneutrality were used to derive a mathematical model that would predict the concentration of H+ in complex solutions (e.g. plasma). This equation has three independent determinants of H+ concentration. The PCO2, the concentration of weak acids (e.g. PO43, albumin) and the strong ion difference. [HCO3] are not independent variables. Ion difference = ([Na+]+[K+] + [Mg2+] + [Ca2+]) ([Cl] + [lactate]) = 4046 mmol/l Electroneutrality must be maintained; if there is a difference in the balance of concentrations of the positively charged ions and the negatively charged ions, the difference (gap) must be compensated by additional (usually) negative ions. The negative ions that usually make up this gap (expressed as the strong ion difference) are HCO3, albumin, and PO43. For example, if the serum [Na+] is 137 mmol/l, the [K+] is 4 mmol/l, the [Ca2+] is 2.2 mmol/l, [Mg2+] is 1 mmol/l and [Cl] 107 mmol/l and [lactate] is 0 mmol/l, the strong ion difference is about 37 mmol. If the HCO3 is 26 mmol/l, then 11 mmol of negative ions remain. If the [albumin] is 46 g/l and the [phosphate] is 1 mmol/l, their contribution can be estimated by 0.2 [albumin] + 1.5 [phosphate], which equals 10.7 (about 11 mmol/l). An acidosis with a strong ion difference of >46 suggests a possible metabolic acidosis of: overproduction of endogenous organic acid or under-clearance of lactic acid or ketoacid

The difference (the anion gap) is due to anions that are not usually measured. It is useful in the differential diagnosis of metabolic acidosis. When organic anions accumulate, the anion gap increases (e.g. lactic acidosis, ketosis, renal failure). Conversely, in the situation of metabolic acidosis due to loss of HCO3 (e.g. due to diarrhoea), the HCO3 is replaced by Cl and the anion gap is normal.

Interpreting blood gas measurements (see Figure 3)

Look at pH to classify primary acidbase disorder See Figure 2 for explanation of abbreviations

Low pH (acidosis)

Raised pH (alkalosis)

High PCO2 Respiratory acidosis

Low SBC or negative BE

Low CO2 Respiratory alkalosis

High SBC or positive BE

Metabolic acidosis

Metabolic alkalosis

Is SBC raised? Yes No

Is PCO2 low? Yes No Yes

Is SBC low? No

Is PCO2 raised? Yes No

Metabolic No acute compensation compensation Figure 1

Respiratory No acute compensation compensation

Metabolic No acute compensation compensation

Respiratory No acute compensation compensation

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Case studies using blood gas data

Patient 1 pH PcO2 PO2 HcO3 O2 sat

7.22 (7.367.44) 4.0 (4.65.6) 12.8 (10.013.3) 11.8 (2226) 97%

TcO2 13.0 (2428) sBc 9.7 (226) Be 13.7 (2 +2) sBe 14.6 (3 +3) (F1O2 air)

acidaemia is present (low pH), primarily due to a metabolic acidosis (low sBc and a negative Be). some respiratory compensation has occurred (low PcO2), although pH has not reached normal. PO2 is normal. Patient 2 pH PcO2 PO2 HcO3 O2 sat

intake of exogenous acid or acid precursors (e.g. methanol, salicylates). The metabolic acidosis seen with hypoalbuminaemia is due to a lower concentration of a weak acid (albumin). The acidosis seen with hyperchloraemia (e.g. due to excess infusion of saline) results in a lowering of the strong ion difference. A strong ion difference (e.g. <40) is consistent with a metabolic alkalosis or a surplus of unmeasured cations (as in cationic paraproteinaemias or ingestion of cations such as Mg2+, Ba2+). Strong ion difference has been used as a marker to predict outcome and is strongly predictive of death following major vascular trauma. The concentration of lactic acid in blood has a normal range of 0.62.0 mmol/l and is often quoted on blood gas results. Lactic acid is the end product of anaerobic glycolysis and therefore can help to decide the cause of a metabolic acidosis. Elevated concentrations of lactic acid may indicate insufficient supply of blood to tissues, resulting in hypoxia (the resultant anaerobic metabolism of pyruvate generates lactic acid instead of CO2 and water). This may occur with inadequate delivery of oxygen in cardiogenic shock or in sepsis, where there is inadequate utilization of oxygen in tissue. Elevated concentrations of lactic acid in trauma patients have been shown to predict mortality. A guide and an algorithm for interpreting blood gas measurements are given in Table 3 and Figure 1 respectively; case studies using blood gas data are given in Table 4.

7.35 (7.367.44) 9.44 (4.65.6) 7.3 39.8 (226) 87%

TcO2 41.8 (248) sBc 33.5 (2226) Be +9.4 (2 +2) sBe +10.2 (3 +3) (F102 24%)

Respiratory acidosis is present (raised PcO2) compensated by a metabolic alkalosis (high sBc and positive Be). pH is at the lower part of the normal range. The PO2 breathing 24% oxygen would be expected to be (2410) = 14. it is low due to hypoventilation. This is a typical picture seen in chronic obstructive airways disease with renal compensation. There is an exception to the rule. For patient 2, longstanding respiratory acidosis has been compensated by renal (metabolic) compensation, leading to a raised HcO3. The picture may become confused if this patient were to develop a metabolic acidosis due to another cause (e.g. hepatic failure). This case underlines the importance of interpreting the blood gas results with knowledge of the clinical history (see Table 3).
F1O2, inspired oxygen fraction. see Table 2 for explanation of abbreviations.

Table 4

FurTHer reADinG Kaplan LJ, Kellum Ja. initial pH, base deficit, lactate, anion gap, strong ion difference, and strong ion gap predict outcome from major vascular injury. Crit Care Med 2004; 32: 112024. stewart Pa. Modern quantitative acid-base chemistry. Can J Physiol Pharm 1983; 61: 144161.

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