INTRODUCTION
No animal can live in an atmosphere where a flame does not burn.
Leonardo da Vinci, 1500
Despite good intentions, much of what we do to patients in the name of aerobic support is without documented need or documented benefit. This is a reflection of the inability to obtain a direct measurement of tissue oxygen tensions. As a result, decisions about oxygen are often based on surrogate measures of tissue oxygenation that are inappropriate (such as arterial blood gases).
The invasive nature of patient care in the ICU creates approaches to evaluating tissue oxygenation that are not available in other areas of the hospital. This chapter reviews some of these approaches, along with a more standard marker of tissue oxygen balance (i.e., blood lactate). The oxygen transport variables in this chapter are described in more detail in Chapter 2.
TISSUE OXYGEN BALANCE
The determinants of tissue oxygenation are illustrated in Figure 13.1. The oxygen supply to tissues is shown as the rate of O2 uptake from the microcirculation (i.e., VO2). The metabolic requirement for oxygen (MRO2) is the rate at which oxygen is metabolized to water in the mitochondria. Because oxygen is not stored in tissues, VO2 must match MRO2 for aerobic metabolism to continue undisturbed. When this occurs, glucose is completely oxidized, as shown in Figure 13.1, and the energy yield is 36 moles of ATP (673 kcal) per mole glucose. When VO2 cannot match MRO2, a portion of the glucose metabolism is diverted to the production of lactate, with an energy yield of 2 moles ATP (47 kcal) per mole glucose. Thus, when the O2 supply is inadequate, the energy yield from substrate metabolism drops precipitously. This condition, in which the production of ATP is limited by the supply of oxygen, is called dysoxia (1), and when cell dysoxia produces a measurable change in organ function, the condition is commonly known as shock.
OXYGEN TRANSPORT MONITORING
As described in Chapter 2, two variables are used to describe oxygen transport: the rate of oxygen delivery (DO2) and the rate of oxygen uptake (VO2), also known as oxygen consumption. These are global measures of the oxygen supply (DO2) and oxygen utilization (VO2) in the systemic circulation. Oxygen uptake (VO2) is equivalent to the oxygen supply identified in Figure 13.1. Oxygen transport monitoring therefore provides information about the oxygen supply to tissues (2), but it provides no information about the adequacy of tissue oxygenation (because that requires a measurement of metabolic rate).
INTERPRETATIONS
The important transport parameter is VO2, which can be interpreted as follows (see Table 13.1):
Low VO2: indicates tissue oxygen deficits (oxygen debt)
Normal VO2: A blood lactate level is required to determine whether tissue oxygenation is adequate.
VO2 DEFICIT
If a decrease in oxygen uptake is not accompanied by a proportional decrease in metabolic rate, the oxygen supply will be inadequate to support aerobic metabolism. Because hypometabolism is uncommon in critically ill patients, a VO2 that falls below the normal range (below 100 mL/minute/m2) can be used as evidence of impaired tissue oxygenation.
An example of a low VO2 that serves as a marker of inadequate tissue oxygenation is shown in Figure 13.2. The data in this figure are taken from a patient who underwent abdominal aortic aneurysm surgery. At the first postoperative recording (2 hours), VO2 is below normal, and thereafter, VO2 never returns to the normal range. At 6 hours, the serum lactate rises above the normal range. The lactate levels continue to rise steadily thereafter, reaching 9 mEq/L at 24 hours after surgery. The progressive rise in blood lactate is evidence that the low VO2 indicates a widespread tissue oxygen deficit. Note that the cardiac index remains normal despite the ongoing ischemia. This highlights the fact that cardiac output monitoring does not evaluate tissue oxygenation.
OXYGEN DEBT
The area under the dotted line in the VO2 curve reflects the total VO2 deficit over time. The cumulative VO2 deficit (derived by integrating the VO2 deficit over time) is known as the oxygen debt. Studies of the oxygen debt after resuscitation from hemorrhagic shock (3) and in postoperative patients (4) show a direct relationship between the magnitude of the oxygen debt and the risk of multiorgan failure and death. These correlations are evidence that the VO2 deficit is a marker of tissue ischemia and that early correction of VO2 deficits is warranted to limit the magnitude of the ischemic insult.
CORRECTING VO2 DEFICITS
The flow diagram in Figure 13.3 shows a management strategy that can be used to correct a VO2 deficit. This approach begins with a focus on blood volume.
Step 1: Central Venous Pressure or Wedge Pressure
1. If low, infuse volume to normalize the filling pressures.
2. For normal or high pressures, go to Step 2.
Correcting volume deficits is essential to maintain cardiac filling volume.
Step 2: Cardiac Output
1. If low, and filling pressures not high, infuse volume until central venous pressure (CVP) is 10 to 12 mm Hg or wedge pressure is 18 to 20 mm Hg.
2. If low, and filling pressures high, start dobutamine infusion at 3 ug/kg/minute and titrate to cardiac index above 3.0 L/min/m2. If blood pressure (BP) is low, use dopamine at starting dose of 5 ug/kg/minute.
3. For cardiac index over 3.0 L/min/m2, go to Step 3.
Volume is preferred to adrenergic drugs, so volume is infused to high filling pressures, if needed. Dobutamine is the preferred inotrope and is also less thermogenic than the other adrenergic drugs (and thus has less tendency to stimulate metabolism).
Step 3: Oxygen Uptake
1. If VO2 is less than 100 mL/min/m2, use volume (to CVP = 8 to 10 or wedge pressure = 18 to 20) and inotropic therapy to achieve a cardiac index above 4.5 L/min/m2. Correct anemia if Hb is less than 8 g/dL.
2. For VO2 greater than 100 mL/min/m2, go to Step 4.
If VO2 does not readily increase when volume is adequate and cardiac index is high, the prognosis is poor. Correcting anemia usually does not increase VO2, but it can be used as a last resort. When VO2 is normal, the lactate is used to determine whether VO2 is matched to the metabolic rate.
Step 4: Blood Lactate Level
1. If lactate is greater than 4 mmol/L and other signs of shock (organ failure, low BP) are present, options include decreasing metabolic rate (through sedation or stopping feedings) and increasing VO2 above 160 mL/min/m2 (if possible).
2. For lactate below 4 mmol/L, observe.
An elevated lactate indicates that VO2 is less than the metabolic rate, so the approach is to either decrease the metabolic rate or increase VO2. Achieving a supranormal VO2 is difficult to accomplish and can lead to unwanted cardiac and metabolic stimulation. Therefore, decreasing metabolic rate is preferred if possible. At this point in the management, if the prognosis is poor, there may be nothing more to do.
IMPENDING VO2 DEFICIT
As described in Chapter 2 and shown in Figure 13.4, VO2 is kept constant when DO2 is reduced because of reciprocal adjustments in O2ER (5,6). When O2ER increases to a level of 0.5 to 0.6, VO2 becomes supply dependent as DO2 is further reduced. When this occurs, cellular energy production is oxygen-limited (dysoxia). Thus, in the setting of impaired O2 delivery (e.g., low cardiac output or anemia) an O2ER above 0.5 indicates a high risk of developing impaired tissue oxygenation. In this situation, measures aimed at increasing the DO2 are protective. This principle has been applied to patients with normovolemic anemia, where an O2ER above 50% is recommended as an indication for blood transfusion (7).
SUPPLY-DEPENDENT VO2
The DO2-VO2 relationship in critically ill patients can differ from the normal pattern, as shown in Figure 13.4. The normal DO2-VO2 relationship (described in Chapter 2) shows a constant VO2 over a wide range of variations in DO2. In critically ill patients, the DO2-VO2 curve is predominantly linear, and the slope is reduced (indicating a low O2ER). This covariance was originally attributed to dysoxia and was called pathologic supply dependency. However, it now seems that in most cases, this phenomenon is not the result of a pathologic derangement in oxygen metabolism, but it is a manifestation of the processes described below (5,6,8,9).
Physiologic Coupling
A linear DO2-VO2 relationship can occur when there is a primary change in metabolic rate and DO2 changes proportionally to match the newly created oxygen requirements. In this situation, the covariance of DO2 and VO2 is a normal adaptive response and is not a sign of impaired tissue oxygenation. Changes in metabolic rate occur commonly in patients in the ICU. The metabolic response to activity is often exaggerated in critically ill patients, and even routine ICU interventions (e.g., portable chest x-ray) can cause significant (20% or greater) increases in metabolic rate (9).
Mathematical Coupling
The abnormal supply dependency in patients in the ICU occurs almost exclusively when DO2 and VO2 are calculated, and it disappears when VO2 is directly measured by gas exchange (8,10-13). This indicates that the abnormal link between DO2 and VO2 is an artifact related to the calculations used to derive these parameters. One possible source of the problem is mathematical coupling because the equations for DO2 and VO2 share three variables (i.e., hemoglobin, cardiac output, and arterial O2 saturation). Thus, a change in any of these shared variables could affect both calculations and produce an artifactual link.
The source of the artifactual link between DO2 and VO2 is still not clear, but the problem demonstrates that the calculations used to derive O2 delivery and O2 uptake can affect the reliability of oxygen transport monitoring. This warrants a brief look at calculated versus measured transport variables.
CALCULATED VERSUS MEASURED VO2
The VO2 is usually derived (and not measured) using Equation 13.1.
VO2 = Q x 13.4 x Hb x (SaO2 – SvO2)
(13.1)
The derivation is based on four measured variables: cardiac output (Q), hemoglobin concentration (Hb), arterial O2 saturation (SaO2), and mixed venous O2 saturation (SvO2). Each of these measurements varies, and their summed contribution can lead to considerable variability in the calculated VO2. This is shown in Table 13.2 (14).
The variability of each component is expressed by the coefficient of variation (CV), which is the standard deviation expressed as a percentage of the mean. Because the standard deviation is expressed on either side of the mean, the CV also expresses a range that is 2 ยด CV, and this range is indicated for each measurement. Laboratory measurements are considered reproducible if they have a CV below 5%, and each of the individual measurements has a CV that is within this range or not far removed. However, the sum of the individual variations creates a large variability in the calculated VO2. Considering the range of variation, the calculated VO2 could change by 30% without a change in the metabolic condition of the patient.
The calculated VO2 is considered to have a range of error that is 15% on either side of the mean for individual determinations (15). This is consistent with the variability in Table 13.2 and forms the basis for the recommendation that the calculated VO2 should change at least 15% to be considered a physiologically significant change.
Gas Exchange
VO2 can also be measured as the oxygen concentration difference in inhaled and exhaled gas multiplied by the respiratory rate. A number of instruments are available that can measure VO2 at the bedside. Many of these instruments can also measure carbon dioxide production (VCO2) and are used by nutrition support services to measure daily energy requirements. As shown in Table 13.2, the measured VO2 is much less variable than the calculated VO2, and thus has less of a tendency for error. Because gas exchange measurements have a CV below 5%, a change in the measured VO2 that exceeds 5% can be considered physiologically significant.
Whole Body versus Systemic VO2
Although the calculated and measured VO2 are often compared, they should not be considered equivalent because the gas exchange method measures the whole body VO2, whereas the calculated VO2 measures only systemic VO2. Thus, the measured VO2 is higher than the calculated VO2 by the VO2 in the lungs. Normally, the VO2 in the lungs accounts for less than 5% of the whole body VO2 (16). However, in patients with inflammatory lung injury (i.e., acute respiratory distress syndrome), 20% of the whole body VO2 can take place in the lungs (17). This corresponds to a difference of 25 mL/minute/m2 between whole body VO2 and calculated VO2. This difference deserves consideration when comparing measured and calculated parameters.
BLOOD LACTATE CONCENTRATION
As mentioned, blood lactate levels help determine whether VO2 is adequate for the needs of aerobic metabolism. Thus, adding lactate determinations to oxygen transport monitoring provides a more complete assessment of tissue oxygen balance. Because lactate levels in whole blood and plasma are equivalent (18), both measurements are called blood lactate.
BLOOD LACTATE AND SURVIVAL
One of the reasons the blood lactate is such popular test is its ability to predict outcome. A comparison of lactate with cardiac output and oxygen uptake is shown in Table 13.3 for patients with septic shock (19). Neither cardiac output nor oxygen uptake differs significantly in survivors and nonsurvivors, whereas the lactate levels are three times as high in the nonsurvivors. The predictive value of blood lactate levels is consistently better than any measure of hemodynamics or oxygen transport (20), but the ability of lactate to predict mortality is limited mostly to patients with shock.
Optimal Threshold
As shown in Table 13.1, the normal blood lactate concentration is less than 2 mmol/L, but the threshold for an elevated blood lactate is higher, at 4 mmol/L. The reason for this difference is shown in Table 13.4 (18). This table shows the relationship between the cutoff level for an elevated blood lactate and the reliability of an elevated lactate level for predicting mortality. The lower threshold of 2 mmol/L is very sensitive but not specific, which means that a considerable fraction of lactate levels in this range will be false positives. On moving to the higher threshold of 4 mmol/L, sensitivity declines by 27% but specificity is much (46%) higher, as is the ability to predict outcome (i.e., the positive predictive value). Thus, the higher threshold is preferred for the clinical definition of hyperlactatemia.
OTHER SOURCES OF LACTATE
Anaerobic metabolism is not the only source of lactate. Other causes of hyperlactatemia include hepatic insufficiency (caused by impaired clearance of lactate by the liver), thiamine deficiency (blocks pyruvate entry into mitochondria), alkalosis (stimulates glycolysis), and production by enteric microbes (D-lactic acid).
Sepsis
Evidence suggests that the lactate accumulation in sepsis is not the result of oxygen deprivation. The culprit may be endotoxin, which blocks the actions of the pyruvate dehydrogenase enzyme that moves pyruvate into mitochondria. Pyruvate then accumulates in the cell cytoplasm and is converted to lactate. The ability of endotoxin to promote lactate formation is shown in the graph in Figure 13.5 (21). This graph is taken from a study in which animals were subjected to a 1-hour infusion of endotoxin. As indicated on the graph, the endotoxin infusion was associated with a progressive rise in blood lactate. After the endotoxin infusion, the animals were given dichloroacetate, a substance that activates pyruvate dehydrogenase, but only in the presence of oxygen. The dichloroacetate was able to reduce the lactate levels to normal, indicating that oxygen was present in cells to permit the activation of pyruvate dehydrogenase. Furthermore, when hypoxia was induced by having the animals breathe a low-oxygen gas mixture (on the right side of the graph), the lactate levels failed to rise. This study shows that oxygen deprivation can be unrelated to lactate production in a setting that mimics sepsis.
LACTATE AS A FUEL
A final word about lactate that deserves mention is the possibility that lactate might serve as an oxidative fuel. The energy yield from the oxidation of lactate is shown in Table 13.5. Also shown is the energy yield from the oxidation of glucose. The energy yield from glucose oxidation is twice that of lactate, but glucose is twice the size of lactate (i.e., 6 carbons versus 3 carbons, respectively). Because each mole of glucose produces 2 moles of lactate, the energy yield from glucose metabolism is about the same when glucose is directly oxidized and when glucose is converted to lactate and the lactate is oxidized. A number of organs can oxidize lactate to derive energy, including the heart, brain, liver, and skeletal muscle (22,23).
If the lactate generated during periods of oxygen deprivation can undergo oxidation at a later time, when tissue oxygenation is restored, then the energy yield of glucose oxidation (i.e., oxidative metabolism) will be preserved. In this context, lactate production would be a mechanism for preserving nutrient energy during periods of hypoxia or ischemia, when prevailing conditions do not favor oxidation.
GASTRIC TONOMETRY
The oxygen transport variables and blood lactate levels are global (whole body) measures that cannot identify oxygen deficits in individual organs. This limitation became a concern upon the discovery that splanchnic hypoperfusion is common in critically ill patients and may be the prelude to multiorgan failure (24). This led to the development of the method described here for evaluating oxygenation in the gastrointestinal tract (25,26).
METHOD
The basic elements of this method are outlined in Table 13.6. This method uses an indirect measurement of the pH in the gastric mucosa to evaluate the adequacy of tissue oxygenation (i.e., oxygen deficits produce a local acidosis). This measurement is derived using the Henderson-Hasselbach equation and an indirect measure of the gastric mucosal carbon dioxide pressure (PCO2), obtained with a tonometer.
The tonometer is a CO2-permeable silicone balloon affixed to the distal end of a standard 16-French nasogastric tube. The apparatus is placed in the stomach in the usual fashion, and the balloon is partially filled with saline (2.5 mL) and left that way for at least 30 minutes. During this time, the balloon is in contact with the gastric mucosa, and the CO2 in the adjacent mucosa moves into the balloon. The CO2 eventually equilibrates between the tissues and the saline in the balloon. When this occurs, the PCO2 in the saline approximates the PCO2 in the gastric mucosa, and thus the saline PCO2 is measured and used as the intramucosal PCO2. The pH calculation also requires a measure of the tissue bicarbonate, and the bicarbonate concentration in an arterial blood sample is used for this purpose. The normal gastric intramucosal pH has a mean of 7.38 and a standard deviation (SD) of 0.3, so the range is 7.35 to 7.41 (1 SD on either side of the mean). The threshold for an abnormal pH is 7.32, which is 2 SDs from the mean (Table 13.1).
PERFORMANCE
The advantage of monitoring pH in the gastric mucosa is illustrated by the case depicted in Figure 13.6. The line plots represent the temporal changes in the systemic oxygen uptake (VO2) and the gastric intramucosal pH (pHi) in the early postoperative period following renal transplantation. Both measures are in the normal range during the first postoperative day. However, at approximately 30 hours after surgery, the patient developed a sepsis syndrome (indicated by the dashed line). Thereafter, the intramucosal pH dropped precipitously, while the VO2 remained unchanged. The patient was returned to the operating room 12 hours after the onset of sepsis, and an infected renal implant was removed. The sepsis subsequently resolved and the patient survived. At no time during this rocky postoperative course did the VO2 provide any hint of danger, whereas the gastric mucosal pH showed evidence of progressive ischemia as the sepsis progressed.
In keeping with the observations in Figure 13.6, the gastric mucosal pH has proven superior to the global measures of tissue oxygenation (O2 transport variables and lactate) for predicting outcome in critically ill patients (25-28).
PROBLEMS
A number of shortcomings associated with gastric tonometry deserve mention. Descriptions of the major ones follow.
Gastric Acid Secretion
Acid secretion in the stomach is a confounding variable that must be eliminated when using gastric mucosal pH as a marker of tissue oxygenation. Routine doses of histamine H2 blockers may not achieve adequate acid suppression. Administration of ranitidine 100 mg intravenously 1 hour before measurements effectively blocks acid secretion for 2 to 4 hours (29). Raising gastric pH carries the risk of gastric colonization, which is not a desirable condition in critically ill patients (as discussed in Chapter 6).
Acid-Base Disorders
Systemic acid-base disorders can also influence the pH of the gastric mucosa (30). This is a particular concern because metabolic acidosis can be common in patients with circulatory shock, and these patients represent a large target population for gastric mucosal pH monitoring. Also of concern is respiratory alkalosis, which is common in mechanically ventilated patients.
Arterial versus Mucosal Bicarbonate
The use of arterial bicarbonate as a measure of mucosal bicarbonate is problematic because the two are not equivalent in low flow states (because of local accumulation of acid) (24). Thus, in low flow states, where accuracy is most important, arterial bicarbonate measurements are likely to produce the least accurate results.
MANAGEMENT
The treatment of abnormal mucosal pH is not well defined. The few studies available on treatment use volume infusions followed by dobutamine. The volume is given in aliquots, with no clear endpoint. Dobutamine has consistently increased mucosal blood flow, but its effects on mucosal pH are variable. Individual studies of dobutamine show increased pH (31,32), no change in pH (33), and even decreased pH (34). The response to dobutamine therefore must be determined on an individual basis.
