Monitoring Oxygen Delivery in the Critically Ill

Monitoring Oxygen Delivery in the Critically Ill* Yuh-Chin Tony Huang, MD, MHS, FCCP

An accurate assessment of regional tissue oxygen delivery (DO2) may help the intensivist to attenuate end-organ damage in critically ill patients. Transport of oxygen from the ambient air to the mitochondria occurs by convection and diffusion, and is tightly regulated by neural and humoral factors. This article reviews the basic principles of DO2 and the abnormal oxygen supply-demand relationship seen in patients with shock. It also discusses approaches to monitoring DO2, including clinical symptoms/signs, acid-base status, and gas exchange, which provide global assessment, as well as gastric tonometry, which may reflect regional DO2. Some new experimental methods, such as near-infrared spectroscopy and positron emission tomography, are still in development but may in the future provide useful clinical devices for quantifying the adequacy of regional tissue oxygenation in critically ill patients. (CHEST 2005; 128:554S–560S) Key words: gastric tonometry; near-infrared spectroscopy; oxygen delivery; positron emission tomography Abbreviations: ATP ⫽ adenosine triphosphate; Cao2 ⫽ oxygen content in arterial blood; CO ⫽ cardiac output; Cvo2 ⫽ oxygen content in mixed venous blood; Do2 ⫽ oxygen delivery; NIRS ⫽ near-infrared spectroscopy; OEC ⫽ oxygen equilibrium curve; OER ⫽ oxygen extraction ratio; PET ⫽ positron emission tomography; pHi ⫽ intramucosal pH; Pvo2 ⫽ mixed venous Po2; Sao2 ⫽ arterial oxygen saturation; V˙o2 ⫽ oxygen consumption Learning Objectives: 1. To understand the basics of oxygen delivery, particularly as it pertains to critically ill patients. 2. To summarize the standard and investigational methods used to measure regional oxygen delivery, including gastric tonometry, near-infrared spectroscopy, and metabolic positron emission tomography.

cells require oxygen for aerobic metabolism to A llmaintain normal cellular function. Because oxygen cannot be stored in the cells, a constant supply that matches the metabolic needs of each cell is required. Failure to deliver sufficient oxygen to the tissues may result in organ dysfunction, as seen in many forms of underresuscitated shock. Therefore, early detection and correction of tissue hypoxia is essential in the management of critically ill patients. This overview focuses on the basic concepts of oxygen delivery (Do2) and utilization by tissues. It also discusses methods for monitoring Do2 and recent advances in the measurement of regional deficiencies in Do2. *From the Division of Pulmonary & Critical Care Medicine, Duke University Medical Center, Durham, NC. This publication is supported by an educational grant from Ortho Biotech Products, L.P. The following authors have indicated to the ACCP that no significant relationships exist with any company/organization whose products or services may be discussed in their article: Yuh-Chin T. Huang, MD, FCCP. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Yuh-Chin Tony Huang, MD, MHS, FCCP, Division of Pulmonary & Critical Care Medicine, Box 3315, Duke University Medical Center, Durham, NC 27710; e-mail: [email protected] 554S

Do2 and Oxygen Consumption Transport of oxygen from the atmosphere to the cells of organs follows a relatively simple physical pathway involving convection (bulk flow), diffusion, and chemical combination with hemoglobin. During inspiration, oxygen is transported from the atmosphere by convective flow (ventilation) to the alveoli, where it diffuses into the blood and binds rapidly and reversibly to hemoglobin within the RBC (oxygen uptake). Oxygen bound to hemoglobin is then transported in the RBC by a convective process (cardiac output [CO]) to the tissues, where oxygen dissociates from hemoglobin and diffuses down its concentration gradient into the cells and ultimately reaches the mitochondria (Do2), where the bulk (approximately 90%) of molecular oxygen is consumed. These gastransport mechanisms use the physical processes of convection (between atmosphere and lungs and between lungs and tissues), diffusion (between lungs and blood and between blood and tissues), and chemical reactions (between oxygen and hemoglobin). The following equations are relevant in describing Do2: O2 diffusion ⫽ K ⫻ S/␶ ⫻ ⌬P

(1)

where diffusion of oxygen from the alveolar air into

Improving Outcomes in Respiratory Failure: Ventilation, Blood Use, and Anemia Management

the blood or from the blood into the tissue is described by the Fick law, which states that diffusion of oxygen is directly proportional to the permeability of oxygen within the diffusion medium (K), surface area for diffusion (S), and pressure gradient (⌬P) across the diffusion barrier, and is inversely proportional to the diffusion distance (␶). In the lung, the diffusion barrier is the alveolar-capillary membrane, where Po2 is approximately 100 mm Hg on the alveolar side and approximately 90 mm Hg on the capillary side. In other organs and tissues, the capillary wall forms the primary barrier. Intercellular and intracellular distances also contribute to the kinetics of oxygen transport to the mitochondria. The diffusion gradient ranges from a Po2 in the arterial end of the capillary of approximately 90 mm Hg to only 1 mm Hg or less near the mitochondria. Once oxygen diffuses into the pulmonary capillaries, it binds rapidly to hemoglobin. The affinity of hemoglobin for oxygen increases with increasing arterial oxygen saturation (Sao2) [cooperativity]. As a result, the oxygen hemoglobin equilibrium curve has a sigmoid shape (Fig 1).1 The amount of oxygen transported to the peripheral tissues by the blood can be described by the Fick CO equation: Do2共mL/min兲 ⫽ 10 ⫻ CO 共L/min兲 ⫻ Cao2 (2) where Cao2 is the oxygen content of arterial blood (1.34 ⫻ Hb ⫻ Sao2 ⫹ 0.003 ⫻ Pao2), where 1.34 is the amount of oxygen (in milliliters) carried by 1 g of hemoglobin, Hb is the hemoglobin concentration

(grams per 100 mL), and 0.003 is the solubility of oxygen in the plasma. In a normal resting adult at sea level, Do2 is approximately 1,000 mL/min based on a CO of 5 L/min, a hemoglobin level of 15 g/100 mL, and Sao2 of 100%. The majority of oxygen is carried by the hemoglobin (21 mL/100 mL) compared with the plasma (0.3 mL/100 mL). Without hemoglobin, a CO of at least 80 L/min would be needed to support the normal resting oxygen consumption (V˙o2) of approximately 250 mL/min in adult humans. Thus, from the equation, increases in Do2 to the peripheral tissues are most efficiently achieved through increases in hemoglobin concentration and CO (Fig 2).2 When hemoglobin oxygen saturation is ⬎ 90% (ie, at the plateau of the oxygen equilibrium curve [OEC]), additional oxygen does not significantly enhance Do2. It simply increases the amount of oxygen dissolved in the plasma, which is small unless hyperbaric pressures of oxygen are used. A number of conditions can displace the OEC to the right or the left, affecting Sao2 and thus Do2 (Fig 1). Increased 2,3-diglycerophosphate, acidosis, and hyperthermia shift the curve to the right and decrease hemoglobin saturation for any given Po2. In contrast, decreased 2,3-diglycerophosphate, alkalosis, and hypothermia shift the curve to the left and increase hemoglobin saturation at any given Po2. Some abnormal hemoglobins, such as carboxyhemoglobin, not only have decreased oxygen-binding capacity but also shift the OEC to the left, resulting in severe tissue hypoxia. Global V˙o2 is the total amount of oxygen consumed by the tissues per unit of time and can be described by the following equation: V˙o2共mL/min兲 ⫽ 10 ⫻ CO 共L/min兲 ⫻ 共Cao2 ⫺ Cvo2兲 (3)

Figure 1. Oxyhemoglobin equilibrium (dissociation) curve of hemoglobin.1 The normal P50 value is indicated by the dashed lines. The changes in position of the curve associated with various effector molecules are indicated by the dashed arrows. DPG ⫽ diglycerophosphate; P50 ⫽ oxygen tension at which hemoglobin is 50% saturated; CO ⫽ carbon monoxide. Used with permission from Piantadosi and Huang.1 www.chestjournal.org

where Cvo2 is the oxygen content of mixed venous blood (1.34 ⫻ hemoglobin ⫻ Svo2 ⫹ 0.003 ⫻ Pvo2), and Pvo2 is mixed venous Po2. In a normal adult, V˙o2 is approximately 250 mL/min if the CO is 5 L/min. Thus, under normal resting conditions, the tissues extract about 25% of oxygen delivered to them. This ratio of V˙o2/Do2, termed the oxygen extraction ratio (OER), can increase during exercise,2 congestive heart failure, or severe anemia, leading to a lower Cvo2. The OER can decrease in disease states such as sepsis leading to a higher Cvo2. Because each organ has its own characteristic metabolic needs, individual organ OERs vary. Resting blood and oxygen supply of various organs are shown in Table 1.3 Brain tissue and cardiac muscle extract much more oxygen from the blood than other organs. These two organs also are most susceptible to oxygen deprivation, and their functions are critically CHEST / 128 / 5 / NOVEMBER, 2005 SUPPLEMENT

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Figure 2. Relative effects of changes in Pao2, hemoglobin, and CO on Do2 in a critically ill patient. Do2 in a normal 75-kg subject at rest is shown in the white bar, and Do2 in a patient with hypoxemia, anemia, and reduced CO is shown in the black bar. The gray bars show the effect of sequential interventions on Do2. The numbers in each bar represent the calculated increase in Do2 compared with the preceding value. Fio2 ⫽ fraction of inspired oxygen; Hb ⫽ hemoglobin; CO ⫽ cardiac output. Data are from Leach and Treacher.2

V˙o2 begins to decline has been termed the critical DO2. When oxygen transport is reduced to below the critical Do2, V˙o2 becomes supply dependent. The tissues begin to consume energy stores preferentially in the form of phosphocreatine, eventually turning to anaerobic glycolysis to generate adenosine triphosphate (ATP), resulting in lactic acidosis. The level of critical Do2 has been determined in humans. In one study4 of 17 critically ill septic and nonseptic patients, this critical level of Do2 ranged from 2.1 to 6.2 mL/min/kg, with a mean (⫾ SD) value of 4.16 ⫾ 0.34 mL/min/kg (or approximately 300 mL/ min for a 75-kg patient). Patients whose critical Do2 is higher would be at a greater risk for tissue hypoxia

dependent on adequate delivery of oxygen. Oxygen content in a mixed venous blood sample is a blood flow-weighted average of venous oxygen content of different organs, and thus may not accurately reflect changes in tissue V˙o2 and OER. Shock As noted above, in the normal state Do2 is more than sufficient to meet V˙o2 demands of all tissues and organs (Fig 3). Even in states of moderate reductions in Do2, the OER increases to satisfy V˙o2. This biphasic Do2-V˙o2 relationship is shown in Figure 3.2 The level of oxygen transport at which the

Table 1—Oxygen Supply and Consumption of Various Organs* Organs

Blood Flow, mL/min (% of CO)

Blood Flow, mL/100 g

Arterial-Venous Difference, Volume %

V˙o2, mL/min

Heart Brain Kidney Liver GI tract Skeletal muscle Skin Other organs†

210 (4) 760 (15) 1220 (24) 510 (10) 715 (14) 760 (15) 215 (4) 715 (14)

70 50 400 29 35 2.5 9.5

11.4 6.3 1.3 4.1 4.1 6.4 1.0

23.9 47.9 15.9 20.9 29.3 60.8 2.15

*Data used with permission from Jain and Fischer.3 †Other organs include fat, bone, and lungs. 556S

Improving Outcomes in Respiratory Failure: Ventilation, Blood Use, and Anemia Management

sensitive nor specific. These parameters are slow to change during the compensation phase, and abnormal values may be seen only in the late stages of diminished Do2. Serum lactate, anion gap, base excess, and pH may be used to assess the severity of metabolic acidosis and shock, but they are global measurements and are not sensitive to regional hypoperfusion.6

Measurement of Systemic Do2 Figure 3. Schematic representation of the relationship between Do2 and V˙o2 in healthy and critically ill individuals.2 Used with permission from Leach and Treacher.2

when Do2 is reduced (dashed line in Fig 3). Do2 may be reduced in several pathologic states and may occur due to decreased oxygen uptake by the lung (which decreases oxygen saturation), reduced CO, or impaired diffusion from blood to tissue.5 In addition, a reduction in the oxygen-carrying capacity of blood due to hemorrhage or anemia can also reduce Do2. The physiologic consequences of oxygen deprivation are complex and depend on the mechanisms responsible for the reduction in Do2. Many cellular and circulatory mechanisms can be activated to compensate for the oxygen deprivation state. A typical example is shock. In response to shock, sympathetic stimulation, release of vasopressin, and formation of angiotensin II serve to maintain CO by maintaining preload (through venoconstriction) and increasing heart rate. These neural and humoral responses also produce systemic arterial vasoconstriction, which maintains arterial BP and perfusion to vital organs. During the initial phase of shock, blood flow to the heart and brain is preserved, but it occurs at the expense of Do2 to other organs (eg, kidney, gut, skeletal muscle). Once these compensatory mechanisms fail, hypoperfusion of all organs occurs, including the heart and brain, which ultimately may lead to multisystem organ failure.5 At this late stage of shock, treatments become futile even if the inciting events are controlled. Monitoring Do2 Because recovery from irreversible shock is difficult, it is important to diagnose and treat shock early so that Do2 to the organs can be preserved. Clinical indications of shock and inadequate Do2, such as increased heart rate, decreased BP, reduced urine output, and reduced skin temperature, are neither www.chestjournal.org

The adequacy of systemic or global Do2 is most commonly assessed directly by measuring the oxygen content of arterial and mixed venous blood, estimating CO, and calculating Do2 and V˙o2 using equations 2 and 3. Mixed venous blood is sampled using a pulmonary artery catheter. CO is most often estimated by the thermal dilution technique, and arterial and venous oxygen contents are determined optically with a CO oximeter. Besides the fact that Do2 and V˙o2 are global measurements, there may be errors in the measurements, especially in critically ill patients.7 The accepted accuracy of CO measured by thermodilution is ⫾ 10%.8 However, this error tends to be larger at extremely high or low values, such as those commonly observed in critically ill patients with septic or hypovolemic shock, respectively.7 Errors in the determination of oxygen content of arterial and mixed venous blood may also contribute to the overall errors in the estimate of Do2 and V˙o2, increasing the scatter of repeat measurements. Previous studies2,5 have also seemed to suggest that, in critically ill patients, interventions that increase Do2 also appear to increase V˙o2, creating a more linear relationship between Do2 and V˙o2 than that seen in healthy subjects. This “oxygen supply dependency,” however, is highly artificial and confounded by mathematical coupling.2,5,7,9 In studies4,10 in which V˙o2 has been measured independently by indirect calorimetry, the apparent supply dependence is not seen. Blood lactate levels are also commonly used clinically for monitoring systemic Do2. When Do2 is adequate and there is no tissue oxygen deficit, adequate ATP (38 mol/L) is produced from glucose via the tricarboxylic acid cycle to support the metabolic functions of the cell. During hypovolemic shock, the energy source for the cell turns primarily to anaerobic glycolysis, which produces only 2 mol/L of ATP. Instead of entering the tricarboxylic acid cycle, pyruvate is converted to lactate. Blood lactate begins to accumulate, and in the presence of increased hydrogen ion (H⫹) from hydrolysis of ATP, lactic acidosis ensues. The lactate level in arterial blood during lactic acidosis is usually elevated above the normal 2 mmol/L. The lactate level in the blood, CHEST / 128 / 5 / NOVEMBER, 2005 SUPPLEMENT

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however, is also influenced by the elimination and the distribution of lactate. The liver plays a central role in eliminating lactate from the blood, so in patients with poor liver function (eg, cirrhosis), the blood lactate level can increase without lactic acidosis. Lactic acidosis may also be present without an increase in blood lactate level. This may occur when the blood flow to an organ is completely blocked (eg, limb ischemia). Transient increases in blood lactate are only observed after successful reperfusion because of washout of lactate from the ischemic tissues. Thus, it is usually more advantageous to follow the changes in the blood lactate level rather than the absolute values. A continuous fall in the blood lactate level during resuscitation from hypovolemic shock is usually a favorable sign and is associated with survival. Persistent increase in blood lactate, however, almost always indicates the continuous presence of ischemic tissues and correlates with multiorgan system failure and poor outcome.11,12 Pvo2 (or Svo2) is another parameter that is used clinically to monitor systemic Do2. Svo2 can be measured in the pulmonary artery blood samples obtained from a pulmonary artery catheter. For a given rate of V˙o2, Svo2 is determined by CO, hemoglobin concentration, and Sao2. Svo2 is reduced in low Do2 (low CO, hypoxia, severe anemia) or increased V˙o2 (fever, thyrotoxicosis). It is increased in sepsis and cytotoxic tissue hypoxia (eg, cyanide poisoning). Svo2 can now be monitored continuously via an intravascular sensor in a specialized pulmonary arterial catheter. Decreases in Svo2 may be an earliest signs that the clinical condition of the patient is deteriorating.13,14

Measurement of Regional Do2 Because of the regional differences in the circulatory response during shock, measurement of global Do2 and V˙o2 may not adequately reflect oxygenation status in individual tissues and organs. For example, splanchnic organ blood flow may be disproportionately reduced during shock without affecting global tissue oxygenation.6,10 During periods of hypoperfusion, gut barrier functions may become compromised, increasing its permeability and resulting in the introduction of endotoxin, microorganisms, and inflammatory cytokines into the systemic circulation, contributing to multiple organ failure.5 The ability to monitor the adequacy of local tissue Do2 thus may allow early detection of oxygen deprivation and early intervention that might prevent the progression to multiple organ failure. Gastric tonometry, which measures gastric Pco2 and calculates gastric intramucosal pH (pHi), was 558S

developed based on the principle that fluid in a hollow organ can be used to measure the gas tension of the surrounding tissue.15,16 During periods of oxygen debt, anaerobic metabolism produces organic acids, but regional acidosis is difficult to measure directly because of the acid-buffering capacity of plasma and other fluids. However, one can measure Pco2 in the intramucosal fluid and calculate the local pH based on this value and the arterial bicarbonate concentration using the Henderson-Hasselbalch equation: pHi ⫽ 6.1 ⫹ log10共关HCO⫺ 3 兴/共0.03 ⫻ Pco2兲兲 (4) where 6.1 is the negative logarithm of ionization constant of carbonic acid, [HCO3–] is the concentration of bicarbonate ion in arterial plasma; and 0.03 is the solubility of carbon dioxide in plasma. In practice, intraluminal Pco2 is measured by introducing a carbon dioxide-permeable balloon into the gut and filling it with saline solution. After an equilibrium period, the saline solution is sampled anaerobically, and Pco2 in the saline solution is measured by standard methods. Animal experiments have shown that this indirect estimate of pHi within the stomach correlates well with pHi measured directly with a microelectrode (r2 ⫽ 0.76),17 and that pHi of the intact intestine calculated by tonometry falls as Do2 is reduced below a critical level.18 Clinical studies have been performed to validate the use of gastric tonometry in surgical and critically ill patients. Fiddian-Green and Baker19 measured stomach wall pH in 85 patients undergoing elective cardiac surgery and found that decreased pHi was a sensitive predictor of complications. In a prospective study of 83 consecutive critically ill patients, Maynard and colleagues10 reported that mortality was higher in patients with low gastric pHi (⬍ 7.35) on admission to the ICU than in those who had admission gastric pHi in the normal range (59% vs 21% mortality, p ⬍ 0.001). Abnormal gastric pHi was a better predictor of outcomes than other global measures of Do2 and utilization (eg, arterial pH, Do2, V˙o2, arterial lactate concentration). Although gastric tonometry may provide the physician with additional information regarding the metabolic state of the gastric mucosa, the accuracy and reliability of pHi measurement is affected by several local factors, including equilibration time, choice of buffer in the balloon, and the secretion of hydrogen ions by the parietal cells.20 The measurement is also intermittent. Newer methods that measure Pco2 in the air circulating through a gastric balloon may allow for automatic and continuous determination of pHi.20,21 Despite frequent study, no clinical data

Improving Outcomes in Respiratory Failure: Ventilation, Blood Use, and Anemia Management

have demonstrated that outcome in critically ill patients is improved by the use of gastric tonometry.5 Near-infrared spectroscopy (NIRS) is an experimental method that has been used to determine the oxygenation state of light-absorbing materials, and to measure local tissue blood flow and oxygen utilization at the cellular level. Three relevant compounds change their absorption spectra when oxygenated: hemoglobin, myoglobin, and cytochrome aa3. Local Do2 and Sao2 can be determined because the absorption spectra of oxyhemoglobin and deoxyhemoglobin differ.22–24 A number of investigators have tested NIRS in models of shock. For example, Rhee and co-workers25 monitored cytochrome aa3 redox shifts with NIRS during hemorrhagic shock and resuscitation in rabbits, and reported significant correlations between global measures of Do2 and cytochrome aa3 redox state in skeletal muscle, kidney, and liver. Gastric cytochrome oxidation, however, did not recover during resuscitation, suggesting that local monitoring of this organ with NIRS may be useful in evaluating the regions that remain hypoxic. Similar findings using NIRS were reported in experiments with anesthetized female pigs.26 NIRS can also be used to estimate tissue pH, and NIRS-obtained pH in the gut measured during experimental shock correlates well with those measured with microelectrodes.27 Since light in the near-infrared region (700 to 1,000 nm) is transmitted through skin, bone, and muscle with little attenuation, NIRS can be used noninvasively to monitor skeletal muscle oxygenation. In eight severely injured trauma patients, skeletal muscle hemoglobin oxygen saturation measured by NIRS was found to correlate significantly with Do2 over 36 h of resuscitation.28 Although NIRS remains an experimental tool, its ease of use and its noninvasive nature are attractive, and it continues to show promise as a trend-monitoring method for assessment of regional oxygenation in a number of tissues during shock. However, intratissue hemoglobin saturation measurements will remain difficult to interpret with respect to local energy metabolism until more quantitative information can be obtained about the mitochondrial oxidation-reduction state. Metabolic positron emission tomography (PET) imaging is another noninvasive experimental method for measuring Do2 and tissue oxygenation. In the brain of nine healthy subjects, tissue levels of oxygen are independent of blood flow and Do2 using 15O water as the isotope tracer.29 Regional oxygenation within the porcine liver could be assessed based on the accumulation of [18F]fluoromisonidazole.30 Myocardial blood flow and V˙o2 in normal humans could be estimated simultaneously by dynamic PET with www.chestjournal.org

[11C]acetate.31 The major limitation for PET scan is that it lacks the portability needed for most ICU applications.

Conclusions Maintaining adequate Do2 to the peripheral tissues in critically ill patients is essential in preventing shock-related multisystem organ failure. Measuring Cao2 and CO to calculate Do2 remains the most common method for assessing global Do2. This method is invasive and is not sensitive enough to detect oxygenation deficiencies in important tissues and organs. Although methods such as gastric tonometry exist for the evaluation of regional Do2, they offer only intermittent monitoring and have yet to influence clinical outcomes. New methods such as NIRS may allow continuous and simultaneous monitoring of oxygenation of several organs and tissues, but the metabolic assessment remains qualitative and we have been limited to trend monitoring, which has clear clinical constraints. More research on the new devices and approaches to monitor regional Do2 will be essential for assessing the effectiveness of Do2-based therapies.

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