Arterial Blood Gas Interpretation

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45 Arterial Blood Gas Interpretation

Arterial blood gas (ABG) analysis plays a pivotal role in the management of critically ill patients. Although no randomized controlled study has ever been performed evaluating the benefit of ABG analysis in the intensive care unit (ICU), it is likely this technology stands alone as the diagnostic test which has had the greatest impact on the management of critically ill patients; this has likely been translated into improved outcomes. Prior to the 1960s, clinicians were unable to detect hypoxemia until clinical cyanosis developed. ABG analysis became available in the late 1950s when techniques developed by Clark, Stow and coworkers, and Severinghaus and Bradley permitted measurement of the partial pressures of oxygen (PaO₂) and carbon dioxide (PaCO₂) in arterial blood.¹^–³ The ABG remains the definitive method to diagnose, categorize, and quantitate respiratory failure. In addition, ABG analysis is the only clinically applicable method of assessing a patient’s acid-base status. ABGs are the most frequently ordered test in the ICU and have become essential to the management of critically ill patients.⁴ Indeed, a defining requirement of an ICU is that a clinical laboratory should be available on a 24-hour basis to provide blood gas analysis.⁵

Indications for Arterial Blood Gas Sampling

ABGs are reported to be the most frequently performed test in the ICU.⁴ There are, however, no published guidelines and few clinical studies that provide guidance as to the indications for ABG sampling.⁶ It is likely that many ABGs are performed unnecessarily. Muakkassa and coworkers studied the relationship between the presence of an arterial line and ABG sampling.⁷ These authors demonstrated that patients with an arterial line had more ABGs drawn than those who did not, regardless of the value of the PaO₂, PaCO₂, the Acute Physiology and Chronic Health Evaluation (APACHE) II score, or the use of a ventilator. In that study, multivariate analysis demonstrated that the presence of an arterial line was the most powerful predictor of the number of ABGs drawn per patient independent of all other measures of the patient’s clinical status. Roberts and Ostryznuik demonstrated that with use of a protocol they were able to reduce the number of ABGs by 44%, with no negative effects on patient outcomes.⁴

The ubiquitous use of pulse oximetry in the ICU has made the need for frequent ABG sampling to monitor arterial oxygenation unnecessary. Furthermore (as discussed later), venous blood gas analysis can be used to estimate arterial pH and bicarbonate (HCO₃⁻) but not arterial carbon dioxide tension (PaCO₂). Previously, ABGs were drawn after every ventilator change and with each step of the weaning process; such an approach is no longer recommended.

The indications for ABG analysis should be guided by clinical circumstances. However, as a “general rule” all patients should have an ABG performed on admission to the ICU and/or following (10-15 minutes) endotracheal intubation. Patients with respiratory failure should have an ABG performed at least every 24 to 48 hours. Patients with type II respiratory failure (see definitions later in this chapter) will require more frequent ABG sampling than those with type I respiratory failure. Furthermore, patients with complex acid-base disorders and patients undergoing permissive hypoventilation will require more frequent ABG sampling.

Arterial Blood Gas Sampling

ABG specimens may be obtained from an indwelling arterial catheter or by direct arterial puncture using a heparinized 1- to 5-mL syringe. Indwelling arterial catheters should generally not be placed for the sole purpose of ABG sampling, as they are associated with rare but serious complications. Arterial puncture is usually performed at the radial site. When a radial pulse is not palpable, the brachial or femoral arteries are suitable alternatives. Serious complications from arterial puncture are uncommon; the most common include pain and hematoma formation at the puncture site. Laceration of the artery (with bleeding), thrombosis, and aneurismal formation are rare but serious complications.^8,⁹

ABG analysis is typically performed on whole blood. The partial pressure of oxygen (PaO_2,), partial pressure of carbon dioxide (PaCO₂), and pH are directly measured with standard electrodes and digital analyzers; oxygen saturation is calculated from standard O₂ dissociation curves and may be directly measured with a co-oximeter. The bicarbonate (HCO₃⁻) concentration is calculated using the Henderson-Hasselbalch equation:

where pK_A is the negative logarithm of the dissociation constant of carbonic acid. The base excess is defined as the quantity of strong acid required to titrate blood to pH 7.40 with a PaCO₂ of 40 mm Hg at 37°C. In practice, acid is not titrated as suggested but calculated using a variety of established formulae or normograms. The base excess thus “removes” the respiratory element of acid-base disturbance and identifies the metabolic contribution to interpret with pH and [H⁺]. The standard bicarbonate is broadly similar and is the calculated [HCO₃⁻] at a PaCO₂ of 40 mm Hg. Although the base excess and standard bicarbonate allow for a metabolic acidosis to be diagnosed, they provide few clues as to the pathophysiology or underlying diagnosis.

As with any diagnostic test, it is important that the specimen for an ABG measurement be collected and processed correctly and that quality assurance methods exist to ensure the accuracy of the measurements. Aside from interlaboratory variation, errors in calibration and electrode contamination with protein or other fluids may alter results. Heparin is usually added to the blood to prevent coagulation, and dilution with older liquid solutions previously caused spuriously low PaCO₂. Sample preparation is important because air bubbles falsely elevate PaO₂.

To avoid errors in blood gas interpretation, the following points must be considered before obtaining the sample:

1 Steady state: Blood sampling must be done during steady state following the initiation or change in oxygen therapy or changes in ventilatory parameters in patients on mechanical ventilation. In most ICU patients, a steady state is reached between 3 and 10 minutes and in about 20 to 30 minutes in patients with chronic airway obstruction.¹⁰

2 Anticoagulants: Excess of heparin may affect the pH. Only 0.05 mL is required to anticoagulate 1 mL of blood. The dead space volume of a standard 5-mL syringe with 1-inch, 22-gauge needle is 0.02 mL; filling the syringe dead space with heparin provides sufficient volume to anticoagulate a 5-mL blood sample. Today, calibrated volumes of dry (sodium or lithium) heparin are used in ABG kits, minimizing this problem.

3 Delay in processing of the sample: Because blood is a living tissue, O₂ is being consumed and CO₂ is produced in the blood sample. Red blood cell glycolysis may generate lactic acid and change pH. Significant increases in PaCO₂ and decreases in pH occur when samples are stored at room temperature for more than 20 minutes. In circumstances when a delay in excess of 20 minutes is anticipated, the sample should be placed in ice; iced samples can be processed up to 2 hours after collection without affecting the blood gas values.

4 Venous sampling: Arterial blood provides more information than venous blood with regard to acid-base and oxygenation status (see later discussion). At times it may be difficult to distinguish arterial from venous blood. The following points may help in recognizing inadvertent venous sampling:

• Failure to observe a flash of blood on entry into vessel or pulsation during syringe filling

• Incompatibility of values with clinical condition

• Low PaO₂ and high PaCO₂

• SpO₂ by pulse oximetry more than SaO₂ by ABG analysis

When in doubt, simultaneous sampling of arterial and venous blood should help solve this problem.

5 Collection equipment and technique: Increased dead space in the syringe lowers PaCO₂ content. Needle size rarely causes variability; however, a smaller (25 g) needle is recommended. In patients with an indwelling arterial line, a discard volume of at least twice the dead space (priming volume from sample port to catheter tip) is required to prevent sample dilution.¹¹

6 Hypotension: Severe hypotension may require forceful aspiration, and results—particularly for PaO₂—may be falsely low.

7 Hyperventilation: Hyperventilation resulting from anxiety and/or pain may acutely alter results from baseline values.

8 Leukocytosis: Leukocytosis accelerates the decline of PaO₂ and pH and elevation of PaCO₂ within a stored sample. This PaO₂ decrease is more pronounced at higher PaO₂ levels, is attributable to cellular oxygen consumption, and may be attenuated when samples are stored at colder temperatures.

9 Hypothermia: Blood gas values are temperature dependent, and if blood samples are warmed to 37°C before analysis (as is common in most laboratories), PO₂ and PCO₂ will be overestimated and pH underestimated in hypothermic patients. The following correction formulas can be used:

• Subtract 5 mm Hg PO₂ per 1°C that the patient’s temperature is less than 37°C.

• Subtract 2 mm Hg PCO₂ per 1°C that the patient’s temperature is less than 37°C.

• Add 0.012 pH units per 1°C that the patient’s temperature is less than 37°C.

Arterial Blood Gas Analysis

An ABG provides a rapid and accurate assessment of oxygenation, ventilation, and acid-base status. These three processes are closely interrelated with each other, and an alteration in one process will affect the other two. However, for the sake of simplicity and ease of understanding, each will be discussed separately.

Alveolar Ventilation

The arterial CO₂ content as reflected by arterial CO₂ tension (PaCO₂) at any given moment depends on the quantity of CO₂ produced and its excretion through alveolar ventilation (VA) and can be expressed by the equation, PaCO₂ ∼ CO₂/VA. The alveolar ventilation is that portion of total ventilation that participates in gas exchange with pulmonary blood. If it is assumed that CO₂ production is constant, then CO₂ homeostasis can be simplified to 1/VA ∼ PaCO₂. Thus PaCO₂ becomes very useful for the assessment of alveolar ventilation. High PaCO₂ (>45 mm Hg) indicates alveolar hypoventilation, and low PaCO₂ (<35 mm Hg) implies alveolar hyperventilation.

Oxygenation

The ultimate aim of the cardiorespiratory system is to provide adequate delivery of oxygen to the tissues. This is largely dependent upon cardiac output, hemoglobin (Hb) concentration, and Hb saturation. The PaO₂ is a measure of the oxygen tension in plasma; while the dissolved fraction makes a negligible contribution to oxygen delivery (<2%), it is a major factor affecting Hb saturation. In turn, the PaO₂ is dependent on the concentration of oxygen in the inspired air (FIO₂), oxygen exchange in the lung (V/Q mismatching), and the venous oxygen saturation (SmvO₂). The PaO₂ must always be interpreted in conjunction with the FIO₂ and age.

Relation Between PaO₂ and FIO₂

The PaO₂ alone provides little information regarding the efficiency of oxygen loading into the pulmonary capillary blood. The PaO₂ is determined largely by the FIO₂ and the degree of intrapulmonary shunting (Figure 45-1). The PaO₂ must therefore always be interpreted in conjunction with the FIO₂. The PaO₂ alone does not quantitate the degree of intrapulmonary shunt, which is required for assessing the severity of the underlying lung disease and in guiding the approach to oxygen therapy and respiratory support. There are various formulas for calculating the intrapulmonary shunt, including the classic “shunt equation,” which is the gold standard but requires mixed venous sampling through a pulmonary artery catheter, and the alveolar-arterial oxygen gradient equation (Table 45-1). Clinically the PaO₂-to-FIO₂ ratio (PaO₂/FIO₂) is most commonly used to quantitate the degree of ventilation/perfusion mismatching (V/Q). Since the normal PaO₂ in an adult breathing room air with an FIO₂ of 0.21 is 80 to 100 mm Hg, the normal value for PaO₂/FIO₂ is between 400 and 500 mm Hg. A PaO₂/FIO₂ ratio of less than 200 most often indicates a shunt of greater than 20%. A notable limitation of the PaO₂/FIO₂ is that it does not take into account changes in PaCO₂ at a low FIO₂, which tends to have a considerable effect on the ratio.

Figure 45-1 The effect on PaO₂ of increasing FIO₂ according to shunt fraction.

TABLE 45-1 Formulas for Evaluating Patients in Respiratory Failure

Age-predicted PaO₂ = Expected PaO₂ − 0.3(age − 25) [expected PaO₂ at sea level is 100 mg/Hg]

As a rough rule of thumb: Expected PaO₂ ≈ FIO₂ (%) × 5

AaDO₂ = (FIO₂ × [BP*− 47]) − (PaO₂ + PaCO₂), where BP = barometric pressure

PaO₂/FIO₂ ratio

Oxygenation index = [(mean airway pressure × FIO₂)/PaO₂] × 100

Vd/Vt = (PaCO₂ − PECO₂)/PaCO₂ (N = 0.2-0.4)

Age

The normal arterial oxygen tension decreases with age (see Table 45-1). The normal PaO₂ at sea level and breathing room air is approximately 85 to 90 mm Hg at the age of 60 and 80 to 85 mm Hg at the age of 80 years.

The PaO₂ is primarily used for assessment of oxygenation status, since PaO₂ accurately assesses arterial oxygenation from 30 to 200 mm Hg, whereas SaO₂ is normally a reliable predictor of PaO₂ only in the range of 30 to 60 mm Hg. However, oxygen saturation as measured by pulse oximetry (SpO₂) or by ABG analysis (SaO₂) is a better indicator of arterial oxygen content than PaO₂, since approximately 98% of oxygen is carried in blood combined with Hb. Hypoxemia is defined as a PaO₂ of less than 80 mm Hg at sea level in an adult patient breathing room air; the concomitant decrease in cell/tissue oxygen tension is known as hypoxia (or tissue hypoxia). The degree of hypoxia in patients with hypoxemia depends on the severity of the hypoxemia and the ability of the cardiovascular system to compensate. Hypoxia is unlikely in mild hypoxemia (PaO₂ = 60-79 mm Hg). Moderate hypoxemia (PaO₂ = 45-59 mm Hg) may be associated with hypoxia in patients with anemia or cardiovascular dysfunction. Hypoxia is almost always (but with a few exceptions) associated with severe hypoxemia (PaO₂ <45 mm Hg). However, it must be recognized that the human body has an extraordinary capacity to adapt to hypoxemia. Indeed, patients with cyanotic heart disease do not have evidence of tissue hypoxia at rest. Most remarkably, at the top of Mount Everest (29,028 ft; 253 torr) and without supplemental oxygen, experienced mountain climbers have been reported to have a mean PaO₂ of between 24 and 28 mm Hg in the absence of tissue hypoxia.^12,¹³

Acute respiratory failure occurs when the pulmonary system is no longer able to meet the metabolic demands of the body. Respiratory failure is classically divided into two types:

• Type I, hypoxemic respiratory failure: PaO₂ ≤ 60 mm Hg when breathing room air (sea level).

• Type II, hypercapnic respiratory failure: PaCO₂ ≥ 50 mm Hg.

Acid-Base Balance

The normal diet generates volatile acid (CO₂), primarily from carbohydrate metabolism, and nonvolatile acid (hydrogen ion, H⁺) from protein metabolism. The aim of the body’s homeostatic system is to maintain pH within a narrow range, and pH homeostasis is accomplished through the interaction of the lungs, kidneys, and blood buffers. Alveolar ventilation allows for excretion of CO₂. The kidneys must reclaim filtered bicarbonate (HCO₃⁻), because any urinary loss leads to gain of H⁺. In addition, the kidney must excrete the daily acid load generated from dietary protein intake. Less than half of this acid load is excreted as titratable acids (i.e., phosphoric and sulfuric acids); the remaining acid load is excreted as ammonium. The blood pH is determined by the occurrence of these physiologic processes and by the buffer systems present in the body.

The history of assessing the acid-base equilibrium and associated disorders is intertwined with the evolution of the definition of an acid. In the 1950s, clinical chemists combined the Henderson-Hasselbalch equation and the Brønsted-Lowry definition of an acid to produce the current bicarbonate ion–centered approach to metabolic acid-base disorders.¹⁴ Stewart repackaged pre-1950 ideas of acid-base in the late 1970s, including the Van Slyke definition of an acid.¹⁵ Stewart also used laws of physical chemistry to produce a new acid-base approach.¹⁴ This approach, using the strong ion difference (SID) and the concentration of weak acids (particularly albumin), pushes bicarbonate into a minor role as an acid-base indicator rather than as an important mechanism:

The SID is not identical to anion gap (AG) and contains [lactate], although it does share a number of parameters, and the trends will often be close. The normal SID has not been well established, but the quoted range is 40 to 42 mEq/L.

As the SID approaches zero, anions “accumulate” and acidity increases. This approach provides a physicochemical model for “hyperchloremic acidosis” following 0.9% saline administration,²¹ and the systemic alkalosis of hypoalbuminemia (regarded as a weak acid).

Most clinicians use the bicarbonate ion–centered approach for the diagnosis and management of acid-base disorders; this approach is easier to understand and more practical. Furthermore, there are no clinical data to suggest that the Steward approach has any advantages over the classic (bicarbonate) approach.¹⁶ The Henderson-Hasselbalch equation describes the fixed interrelationship between PaCO₂, pH, and HCO₃⁻ being described as pH = pK_c log HCO₃⁻/dissCO₂. If all the constants are removed, the equation can be simplified to pH = HCO₃⁻/PaCO₂ (∼Kidney/Lung). The HCO₃⁻ is controlled mainly by the kidney and blood buffers. The lungs control the level of PaCO₂ by regulating the level of volatile acid, carbonic acid, in the blood. Buffer systems can act within a fraction of a second to prevent excessive change in pH. The respiratory system takes about 1 to 15 minutes and kidneys many minutes to days to readjust H⁺ ion concentration.

The Anion Gap

Following the principle of electrochemical neutrality, total [cations] must equal total [anions], and so in considering the commonly measured cations and anions and subtracting them, a fixed number should be derived. The measured cations are in excess; mathematically this “gap” is filled with unmeasured anions ensuring electrochemical neutrality. There is never a “real” AG, in line with the law of electrochemical neutrality; it is rather an index of nonroutinely measured anions. The anion gap is calculated using the following formula ¹⁷:

Critical illness is typically associated with a rapid fall in the plasma albumin concentration. Albumin is an important contributor of the “normal” AG. Therefore, as the albumin concentration falls, it tends to reduce the size of the AG, or have an alkalinizing effect. Various corrections are available; however, Figge’s AG correction (AGcorr) is most commonly used ¹⁷:

A Stepwise Approach to Acid-Base Disorders

Step 1: Do a Comprehensive History and Physical Exam

A comprehensive history and physical examination can often give clues as to the underlying acid-base disorder (Table 45-2). For example, patients who present with gastroenteritis manifested as diarrhea typically have a non–anion gap metabolic acidosis from loss of fluid containing HCO₃⁻. Patients who present with chronic obstructive lung disease usually have underlying chronic respiratory acidosis from retention of CO₂.

TABLE 45-2 Common Clinical States and Associated Acid-Base Disorders

Clinical State	Acid-Base Disorder
Pulmonary embolus	Respiratory alkalosis
Hypotension/shock	Metabolic acidosis (lactic acidosis)
Severe sepsis	Metabolic acidosis, respiratory alkalosis
Vomiting	Metabolic alkalosis
Severe diarrhea	Metabolic acidosis
Renal failure	Metabolic acidosis
Cirrhosis	Respiratory alkalosis
Pregnancy	Respiratory alkalosis
Diuretic use	Metabolic alkalosis
COPD	Respiratory acidosis
Diabetes	Metabolic acidosis (ketoacidosis)
Ethylene glycol poisoning	Metabolic acidosis
Post normal saline resuscitation	Metabolic acidosis (non–anion gap)

Step 2: Order Simultaneous Arterial Blood Gas Measurement and Chemistry Profile

Step 3: Check the Consistency and Validity of the Results

Normal ABG results are provided in Table 45-3.

TABLE 45-3 Normal Acid-Base Values

Step 4: Identify the Primary Disturbance

The next step is to determine whether the patient is acidemic (pH <7.35) or alkalemic (pH >7.45) and whether the primary process is metabolic (initiated by change in HCO₃⁻) or respiratory (initiated by a change in PaCO₂) (Table 45-4).

TABLE 45-4 Acid-Base Disorders

Acid-Base Disorder	Criteria
Respiratory acidosis	PaCO₂ >45 mm Hg
Respiratory alkalosis	PaCO₂ <35 mm Hg
Acute respiratory failure	PaCO₂ >45 mm Hg; pH < 7.35
Chronic respiratory failure	PaCO₂ >45 mm Hg; pH 7.36-7.44
Acute respiratory alkalosis	PaCO₂ <35 mm Hg; pH > 7.45
Chronic respiratory alkalosis	PaCO₂ <35 mm Hg; pH 7.36-7.44
Acidemia	pH <7.35
Alkalemia	pH >7.45
Acidosis	HCO₃ <22 mEq/L
Alkalosis	HCO₃ >26 mEq/L

Step 5: Calculate the Expected Compensation

Any alteration in acid-base equilibrium sets into motion a compensatory response by either the lungs or the kidneys. The compensatory response attempts to return the ratio between PaCO₂ and HCO₃⁻ to normal and thereby normalize the pH. Compensation is predictable; the adaptive responses for the simple acid-base disorders have been quantified experimentally ¹⁸ (Table 45-5). Determine whether the compensatory response is of the magnitude expected—that is, is there a secondary (uncompensated) acid-base disturbance?

TABLE 45-5 Compensation Formulas for Simple Acid-Base Disorders

Acid-Base Disorder	Compensation Formula
Metabolic acidosis	Change in PaCO₂ = 1.2 × change in HCO₃⁻
Metabolic alkalosis	Change in PaCO₂ = 0.6 × change in HCO₃⁻
Acute respiratory acidosis	Change in HCO₃⁻ = 0.1 × change in PaCO₂
Chronic respiratory acidosis	Change in HCO₃⁻ = 0.35 × change in PaCO₂
Acute respiratory alkalosis	Change in HCO₃⁻ = 0.2 × change in PaCO₂
Chronic respiratory alkalosis	Change in HCO₃⁻ = 0.5 × change in PaCO₂

Step 6. Calculate the “Gaps”

Calculate the Anion Gap

In high-AG metabolic acidosis, acid dissociates into H⁺ and an unmeasured anion. H⁺ is buffered by HCO₃⁻, and the unmeasured anion accumulates in the serum, resulting in an increase in AG. In non–AG metabolic acidosis, H⁺ is accompanied by Cl⁻ (a measured anion); therefore, there is no change in AG. Acid-base disorders may present as two or three coexisting disorders. It is possible for a patient to have an acid-base disorder with normal pH, PCO₂, and HCO₃⁻, the only clue to an acid-base disorder being an increased AG. If the AG is increased by more than 5 meq/L (i.e., an AG > 15 meq/L), the patient most likely has a metabolic acidosis. Compare the fall in plasma HCO₃⁻ (25 − HCO₃⁻) with the increase in the plasma AG (ΔAG); these should be of similar magnitude. If there is a gross discrepancy (>5 meq/L), then a mixed disturbance is present:

• If increase in AG > fall in HCO₃⁻: suggests that a component of the metabolic acidosis is due to HCO₃⁻ loss.

• If increase in AG < fall in HCO₃⁻: suggests coexistent metabolic alkalosis.

Common Acid Base Disturbances in the ICU

Metabolic Acidosis

The clinical manifestations of a metabolic acidosis are largely dependent on the underlying cause and the rapidity with which the condition develops. An acute, severe metabolic acidosis results in myocardial depression with a reduction in cardiac output, decreased blood pressure, and decreased hepatic and renal blood flow. Reentrant arrhythmias and a reduction in the ventricular fibrillation threshold can occur. Brain metabolism becomes impaired, with progressive obtundation and coma.

A metabolic acidosis in the critically ill patient is an ominous sign and warrants an aggressive approach to the diagnosis and management of the cause(s) of the disorder (Figure 45-2 and Table 45-7). In the vast majority of patients the cause(s) of the metabolic acidosis are usually clinically obvious, with lactic acidosis (from tissue hypoxia/hypermetabolism), ketoacidosis, and renal failure being the most common causes. In patients with an unexplained AG, metabolic acidosis methanol or ethylene-glycol toxicity should always be considered.¹⁹ Accumulation of 5-oxoproline related to the use of acetaminophen is a rare cause of an anion-gap metabolic acidosis.²⁰ Prolonged high-dose administration of lorazepam can result in the accumulation of the vehicle, propylene glycol, resulting in worsening renal function, metabolic acidosis, and altered mental status.^21,²² Toxicity is typically observed after prolonged (>7 days), high-dose (average 14 mg/h), continuous lorazepam infusion and can be recognized by an increased osmolal gap.²³ Similarly, prolonged high-dose propofol (>100 µg/kg/min) is rarely associated with the “propofol infusion syndrome” characterized by rhabdomyolysis, metabolic acidosis, and renal and cardiac failure.²⁴

Figure 45-2 Diagnostic approach to metabolic acidosis.

TABLE 45-7 Causes of Metabolic Acidosis

Elevated Anion Gap

• Defects in gluconeogenesis

Normal Anion Gap

• Renal tubular acidosis

• Diarrhea

• Posthypocapnic acidosis

• Carbonic anhydrase inhibitors

• Ureteral diversions

Normal to hyperkalemic acidosis

• Early renal failure

• Excessive 0.9% NaCl

• Hydronephrosis

• Addition of HCl

• Sulfur toxicity

The prognosis is related to the underlying disorder causing the acidosis. In almost all circumstances, the treatment of a metabolic acidosis involves treatment of the underlying disorder. Except in specific circumstances (outlined later), there is no scientific evidence to support treating a metabolic or respiratory acidosis with sodium bicarbonate.²⁵ Furthermore, it is the intracellular pH which is of importance in determining cellular function. The intracellular buffering system is much more effective in restoring pH to normal than the extracellular buffers. Consequently, patients have tolerated a pH as low as 7.0 during sustained hypercapnia, without obvious adverse effects. Paradoxically, sodium bicarbonate can decrease intracellular pH (in circumstances where CO₂ elimination is fixed). The infusion of bicarbonate can lead to a variety of problems in patients with acidosis, including fluid overload, a postrecovery metabolic alkalosis, and hypernatremia. Furthermore, studies in both animals and humans suggest that alkali therapy may only transiently raise the plasma bicarbonate concentration. This finding appears to be related in part to CO₂ generated as the administered bicarbonate buffers excess hydrogen ions. Unless the minute ventilation is increased (in ventilated patients), CO₂ elimination will not be increased, and this will paradoxically worsen the intracellular acidosis. Currently, there are no data to support the use of bicarbonate in patients with lactic acidosis.^25,²⁶

Bicarbonate is frequently administered to “correct the acidosis” in patients with diabetic ketoacidosis (DKA). However, paradoxically, bicarbonate has been demonstrated to increase ketone and lactate production. Studies have demonstrated an increase in acetoacetate levels during alkali administration, followed by an increase in 3-hydroxybutyrate levels after its completion.^27,²⁸ In pediatric patients, treatment with bicarbonate has been demonstrated to prolong hospitalization.²⁹ In addition, bicarbonate may decrease CSF pH, as increased CO₂ produced by buffering acid crosses the blood-brain barrier, combines with H₂O, and regenerates H⁺. It is generally believed that adjunctive bicarbonate is unnecessary and potentially disadvantageous in severe DKA.³⁰

Bicarbonate is considered “life saving” in patients with severe ethylene glycol and methanol toxicity. In hyperchloremic acidosis, endogenous regeneration of bicarbonate cannot occur (bicarbonate has been lost rather than buffered). Therefore, even if the cause of the acidosis can be reversed, exogenous alkali is often required for prompt attenuation of severe acidemia. Bicarbonate therapy is therefore indicated in patients with severe hyperchloremic acidosis when the pH is less than 7.2; this includes patients with severe diarrhea, high-output fistulas, and renal tubular acidosis. To prevent sodium overload, we suggest that 2 × 50 mL ampules of NaHCO₃⁻ (each containing 50 mmol of NaHCO₃⁻) be added to 1 L of 5% D/W and infused at a rate of 100 to 200 mL/h.

Lactic Acidosis

Lactic acid, like most substances with a pKa of less than 4 (pKa 3.78), circulates almost entirely as the freely dissociated anion, lactate (i.e., it releases its proton), at physiological pH—strongly favoring the right of the equation below:

Hyperlactatemia refers to an elevated plasma concentration of lactate anions. In clinical practice, lactic acidemia is defined as a pH less than 7.35 with a lactate concentration greater than 4 mmol/L. Lactic acidemia typically develops as a result of endogenously produced lactic acid, with lactate being measured as the dissociated base. During critical illness, the source of lactate is often believed to be ischemic anaerobically metabolizing tissues, such as the gut and muscle. However, lactate metabolism in critical illness is complex and often does not indicate ischemic tissues.³¹ The anatomic source of lactate in critical illness is not consistent and may be dependent on the disease process and timing. Furthermore, it should be noted that both the pH and AG are insensitive markers of an elevated lactate; patients with an elevated lactate may have a normal pH and AG.³²

D-Lactic Acidosis

Certain bacteria in the GI tract may convert carbohydrate into organic acids. The two factors that make this possible are slow GI transit (blind loops, obstruction) and change of the normal flora (usually with antibiotic therapy). The most prevalent organic acid is D-lactic acid. Since humans metabolize this isomer more slowly than L-lactate, and production rates can be very rapid, life-threatening acidosis can be produced.³³ The usual laboratory test for lactate is specific for the L-lactate isomer. Therefore, to confirm the diagnosis, the plasma D-lactate must be measured.

Metabolic Alkalosis

Metabolic alkalosis is a common acid-base disturbance in ICU patients, characterized by an elevated serum pH (>7.45) secondary to plasma bicarbonate (HCO₃⁻) retention. Metabolic alkalosis is usually the result of several therapeutic interventions in the critically ill patient (Table 45-8). Nasogastric drainage, diuretic-induced intravascular volume depletion, hypokalemia, and the use of corticosteroids are common causes of metabolic alkalosis in these patients. In addition, citrate in transfused blood is metabolized to bicarbonate, which may compound the metabolic alkalosis. Overventilation in patients with type II respiratory failure may result in a posthypercapnic metabolic alkalosis. In many patients, the events that generated the metabolic alkalosis may not be present at the time of diagnosis.

TABLE 45-8 Causes of Metabolic Alkalosis

Low Urine Chloride (Volume or Saline Responsive)

Gastric volume loss

Diuretics

Post hypercapnia

Villous adenoma (uncommon)

Cystic fibrosis (if there has been excessive sweating)

High Urine Chloride with Hypertension

Primary and secondary hyperaldosteronism

Apparent mineralocorticoid excess

Liddle’s syndrome

Conn’s syndrome

Cushing disease

High Urine Chloride without Hypertension

Bartter syndrome

Gitelman syndrome

Excess bicarbonate administration

Metabolic alkalosis may have adverse effects on cardiovascular, pulmonary, and metabolic function. It can decrease cardiac output, depress central ventilation, shift the oxyhemoglobin saturation curve to the left, worsen hypokalemia and hypophosphatemia, and negatively affect the ability to wean patients from mechanical ventilation. Increasing serum pH has been shown to correlate with ICU mortality. Correction of metabolic alkalosis has been shown to increase minute ventilation, increase arterial oxygen tension and mixed venous oxygen tension, and decrease oxygen consumption. It is therefore important to correct metabolic alkalosis in all critically ill patients.

The first therapeutic maneuver in patients with a metabolic alkalosis is to replace any fluid deficit with normal saline and correct electrolyte deficits. Aggressive potassium supplementation is warranted to achieve a K⁺ above 4.5 mEq/L. If these interventions fail, ammonium chloride, hydrochloric acid, or arginine hydrochloride may be given. The disadvantage of these solutions is that they are difficult to use and require the administration of a large volume of hypotonic fluid. Extravasation of hydrochloric acid may result in severe tissue necrosis, mandating administration through a well-functioning central line. Acetazolamide is a carbonic anhydrase inhibitor that promotes the renal excretion of bicarbonate and has been demonstrated to be effective in treating metabolic alkalosis in ICU patients. A single dose of 500 mg is recommended. The onset of action is within 1.5 hours, with duration of approximately 24 hours.³⁴^–³⁷ Repeat doses may be required as necessary.

Venous Blood Gas Analysis

Studies performed in the emergency room have demonstrated a strong correlation between arterial and venous blood pH and HCO₃⁻ levels in patients with DKA and uremia.^36,³⁷ In these studies, the difference between arterial and venous pH varied from 0.04 to 0.05, and the difference in bicarbonate levels varied from −1.72 to 1.88. However, as one would anticipate, the correlation between arterial and venous PCO₂ was poor. These observations have been confirmed in a cohort of unselected emergency room patients³⁸ and patients with tricyclic antidepressant poisoning.³⁹ Similarly, an excellent correlation has been demonstrated between mixed venous pH and HCO₃⁻ with arterial pH and HCO₃⁻ in ICU patients.^40,⁴¹ The association between arterial and venous pH, HCO₃⁻ and PCO₂ is, however, not valid in patients with shock. In a now classic study, Weil and coauthors reported that during cardiopulmonary resuscitation, the arterial blood pH averaged 7.41, whereas the average mixed venous blood pH was 7.15.⁴² Similarly, the PaCO₂ was 32 mm Hg, whereas the mixed venous PCO₂ was 74 mm Hg. Androgue and colleagues have reported similar findings in patients with circulatory failure.⁴³

In hemodynamically stable (and resuscitated patients) without known hypercarbia, ABG analysis may not be required; pulse oximetry and venous blood gas analysis should suffice in most circumstances. Furthermore, a venous blood gas can be useful to screen for arterial hypercarbia, with a venous PCO₂ level > 45 mm Hg being highly predictive of arterial hypercarbia (sensitivity and negative predictive value of 100%). ⁴⁴ In hemodynamically unstable patients and those with complex acid-base disorders, a venous blood gas cannot be substituted for an ABG analysis. In these situations, both arterial and mixed venous/central venous blood gas analysis provides useful information (see later discussion).

Mixed Venous/Central Venous Oxygen Saturation

Monitoring of the mixed venous oxygen saturation (SmvO₂) has been used as a surrogate for the balance between systemic oxygen delivery and consumption during the treatment of critically ill patients. Generally an SvO₂ of less than 65% is indicative of inadequate oxygen delivery. Measurement of SvO₂ involves placement of a pulmonary artery catheter (PAC); this is an invasive device that has not been shown to improve patient outcome, so its use has fallen out of favor. However, since most critically ill patients have a central venous catheter in situ, the central venous oxygen saturation (ScvO₂) has been used as an alternative to the SmvO₂.

Regional variations in the balance between DO₂ and VO₂ result in differences in the Hb saturation of blood in the superior and inferior venae cavae. Streaming of caval blood continues within the right atrium and ventricle, and complete mixing only occurs during ventricular contraction. The drainage of myocardial venous blood directly into the right atrium via the coronary sinus and cardiac chambers via the thebesian veins results in further discrepancies.^45,⁴⁶ Consequently, SmvO₂ reflects the balance between oxygen supply and demand averaged across the entire body, but ScvO₂ is affected disproportionately by changes in the upper body. In healthy individuals, ScvO₂ is usually 2% to 5% less than SvO₂, largely because of the high oxygen content of effluent venous blood from the kidneys.⁴⁷ This relationship changes during periods of hemodynamic instability, because blood is redistributed to the upper body at the expense of the splanchnic and renal circulations. In shock states, therefore, the observed relationship between ScvO₂ and SvO₂ may reverse, and the absolute value of ScvO₂ may exceed that of SvO₂ by up to 20%.⁴⁸ This lack of numerical equivalence has been demonstrated in various groups of critically ill patients, including those with cardiogenic, septic, and hemorrhagic shock. Based on these data, the Surviving Sepsis Campaign has recommended achieving an SmvO₂ level of 65% or a ScvO₂ level of 70% in patients with severe sepsis and septic shock.⁴⁹ Although trends in ScvO₂ may reflect those of SmvO₂, the absolute values differ, and the variables cannot be used interchangeably.^48,⁵⁰^–⁵² In addition to guiding resuscitation, ScvO₂ may have prognostic significance, with low values during the first 24 hours of hospitalization or in the postoperative period being predictive of a worse outcome.⁵³^–⁵⁵

In patients with sepsis and liver failure, a low ScvO₂/SmvO₂ is usually indicative of decreased cardiac output (oxygen delivery)⁵⁶; however, normal values do not exclude adequate resuscitation or tissue hypoxia.^57,⁵⁸ The presence of functional and/or anatomic shunting results in “arterialization” of venous blood. In addition, cytopathic hypoxia may further decrease oxygen uptake and result in a “spuriously high” ScvO₂.⁵⁹ Indeed, patients dying of both sepsis and liver failure usually have a high ScvO₂/SmvO₂. In an intriguing study, Pope and colleagues demonstrated that in patients with sepsis, a high ScvO₂ (90%-100%) at any time during hospitalization was an independent predictor of mortality, whereas a low ScvO₂ (<70%) was only predictive of mortality if this value remained low following resuscitation.⁶⁰ It is noteworthy that in a recent goal-directed sepsis study, the mean ScvO₂ was 74% at enrollment, and less than 10% of patients required specific interventions to achieve ScvO₂ above 70%.⁶¹

Experimental models have demonstrated that a high mixed venous–to-arterial PCO₂ gradient is a reliable marker of decreased cardiac output and global tissue ischemia.^62,⁶³ This observation has been confirmed by Weil et al. and Androgue et al., who demonstrated that a high mixed venous–to-arterial PCO₂ gradient is a sensitive marker of global tissue ischemia during cardiopulmonary resuscitation and in patients with circulatory failure.^43,^64,⁶⁵ In patients with septic shock, Bakker and colleagues demonstrated that the venous-to-arterial PCO₂ gradient was directly related to cardiac output.⁶⁶ In resuscitated patients (ScvO₂ > 70%) with septic shock, Vallee and coworkers demonstrated that a widened central venous-to-arterial PCO₂ gradient (>6 mm Hg) identified patients with a low cardiac index who were inadequately resuscitated.⁵⁸ The central venous-to-arterial PCO₂ gradient may prove to be a better endpoint for resuscitation of septic patients than the ScvO₂.