AACN Clinical Issues Volume 15, Number 4, pp.

506524 2004, AACN

Diagnostic Measures to Evaluate Oxygenation in Critically Ill Adults

Implications and Limitations
Karen L. Johnson, RN, PhD, CCRN

Accurate assessment and treatment of disturbances in oxygenation are crucial to optimal outcomes in critically ill patients. Oxygenation is dependent upon adequate pulmonary gas exchange, oxygen delivery, and oxygen consumption. Each of these physiologic processes may vary independently in response to pathophysiologic conditions and therapeutic interventions. The author reviews diagnostic measures available to evaluate pulmonary gas exchange, oxygen delivery, and oxygen consumption in critically ill patients. Currently available tools and their potential value as well as key methodological limitations are addressed. Failure on behalf of clinicians to fully appreciate these limitations can lead to misdiagnoses and inappropriate treatment. The aim of this article is to help advanced practice nurses more fully understand the implications and limitations of these diagnostic measures to ensure accurate assessment and treatment of disturbances in oxygenation. (KEY WORDS: assessment of oxygen consumption, assessment of oxygen delivery, assessment of oxygenation, assessment of pulmonary gas exchange)
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Tissue

Oxygenation

The outcome of critical illness depends on the adequacy of oxygenation; therefore, accurate assessment and treatment of oxygenation disturbances is critical to optimal patient outcomes. A thorough evaluation of oxygenation is one of the most important components of the advanced practice nurses assessment abilities. Oxygenation is a physiologic process that is dependent upon the integration and coordination of multiple body systems including the pulmonary, cardiovascular, neurologic, hematologic, and metabolic systems. Adequacy of oxygenation depends on the integration of three physiologic components: pulmonary gas exchange, oxygen delivery, and oxygen consumption (Figure 1). Pulmonary gas exchange physiology involves the physiologic processes of ventilation, diffusion, and perfusion as oxygen is brought from the atmosphere to the pulmonary capillary bed. Delivery of oxygen via the bloodstream is dependent upon cardiac output and the content of oxygen in arterial blood. Use
Assistant Professor, University of Maryland School of Nursing, Baltimore. Reprint requests to University of Maryland School of Nursing, 655 W Lombard St, Baltimore, MD 21201 (kjohnson@son.umaryland.edu).

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Figure 1. Johnsons conceptual model of oxygenation. CaO2, content of oxygen in arterial blood; CvO2, content of oxygen in venous blood; O2, oxygen; ATP, adenosine triphosphate. Adapted with permission from Taylor CR, Weibel ER. Design of the mammalian respiratory system. Respiration Physiology. 1981;41(p2). Copyright 1981 by Elsevier Science.

of oxygen for energy metabolism requires extraction and consumption of oxygen through aerobic metabolism. Each of these three physiologic processes must function properly to ensure adequate oxygenation. Each of these components may vary independently in response to pathophysiologic conditions and therapeutic interventions. Therefore, an assessment of oxygenation must include assessments of pulmonary gas exchange, oxygen delivery, and oxygen consumption. There are two goals in the assessment of oxygenation: (1) to determine overall adequacy of oxygenation and (2) to determine which element of oxygenation dysfunction should be manipulated to improve patient outcome.
Assessment

ternal environment to the alveoli, diffusion across the alveolar-capillary membrane, and the combination of oxygen with hemoglobin (Hb) in the pulmonary capillaries. Pulmonary gas exchange is dependent upon the physiologic processes of alveolar ventilation, diffusion of gases across the alveolar-capillary membrane, pulmonary perfusion, and ventilation perfusion matching (V/Q) (see Figure 1). Therefore, an assessment of pulmonary gas exchange should ideally include an evaluation of these physiologic processes.
Assessment of Ventilation

of Pulmonary

Gas Exchange
Pulmonary gas exchange involves the inspiration and delivery of oxygen from the ex-

Alveolar ventilation depends on respiratory rate and tidal volume. An average tidal volume of 600 mL results in an alveolar ventilation of 450 mL, with 150 mL required to overcome normal physiologic dead space of the conducting airways. At very low tidal volumes, the dead space alone may be ventilated even though the minute volume (rate

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times tidal volume) is normal due to a high respiratory rate. Assessment of the adequacy of ventilation begins with a focused physical examination that can provide some of the most useful clues about ventilation. Lethargy and somnolence may indicate hypercapnea. Evaluation of rate, rhythm, and depth of respirations can provide an insight into the work of breathing and adequacy of alveolar ventilation which are important factors to analyze when considering initiation of mechanical ventilation, alteration of ventilator settings, weaning a patient from the ventilator, or advancing a patients activity level. A normal respiratory rate and absence of the use of accessory muscles may reflect a manageable work of breathing. Conversely, tachypnea and the use of accessory muscles of inspiration (sternocleomastoid or external intercostals) or expiration (internal intercostals, abdominal muscles) may indicate the patient has insufficient muscle strength to maintain the work of breathing necessary to overcome increased resistance or decreased compliance. Resistance and compliance can be directly measured in patients receiving mechanical ventilation (See Assessment of the Patient Receiving Mechanical Ventilation in this issue). Auscultation of the lungs can be used to evaluate the effectiveness of ventilation. Bronchial sounds may be indicative of extensive consolidation, and bronchovesicular sounds may indicate early pulmonary disease. Wheezing, produced by airflow through narrow airways, may be heard on expiration. Inspiratory wheezes may indicate bronchial constriction. Crackles may indicate fluid in the lung or weakened airway wall strength. Cardiac disease is more likely to produce excessive fluid type crackles that respond to fluid removal, while pulmonary disease is more likely to produce crackles that are nonresponsive to fluid removal. The major route of elimination of carbon dioxide (CO2) is through the lungs. Therefore, a quantitative assessment of ventilation is made through CO2 evaluation. The higher the serum CO2, the more significant the ventilatory failure. CO2 can be measured through arterial blood gas analysis (PaCO2) or end-tidal CO2 monitoring (PetCO2). PetCO2 monitoring is a noninvasive mea-

surement of exhaled CO2. It ideally represents an assessment of alveolar ventilation as PetCO2 should correlate with PaC02. In healthy individuals under normal conditions of V/Q matching, the difference between PetCO2 and PaCO2 is minimal (5 mm Hg); as exhaled CO2 is always slightly lower than PaCO2. In these situations, PetCO2 can be used as a substitute for PaCO2.1-4 Several patient conditions inhibit the use of PetCO2 to reflect PaCO2. PetCO2 does not accurately reflect PaCO2 under conditions of respiratory failure, hemodynamic instability, or extremes in temperature.5 For example, if perfusion to the lungs is decreased (cardiac arrest, pulmonary embolism), then less CO2 is carried to the lungs from the tissues and PetCO2 will be lower than PaCO2. There must be adequate perfusion to the lungs to bring CO2 to the alveolar capillary membrane so that gas exchange can occur and CO2 is exhaled. Increased peripheral CO2 production, such as that which occurs in a febrile state, can increase PetCO2. Isolated PetCO2 values must be evaluated cautiously in critically ill patients. Multiple measurements of PetCO2 or monitoring the PaCO2-PetCO2 gradient over time may provide important clues related to either improved or worsening patient clinical status.5 A large PaCO2-PaC02 gradient (20 mm Hg) may reflect a large V/Q mismatch. A gradual improvement in the gradient (a narrowing of the gradient) may represent improved V/Q matching and ventilatory function. Physiologic processes of the respiratory system can be evaluated by different pulmonary function tests (PFTs). PFTs evaluate lung mechanics by measuring the volume of air the patient is able to move in and out during ventilation and estimating several lung capacities (Table 1). Potential uses of PFTs in critically ill patients include: evaluation of known or suspected lung disease; evaluation of symptoms such as chronic cough, dyspnea, or chest tightness; monitoring the effects of exposure to pulmonary toxic drugs; risk stratification prior to surgery; and monitoring the effectiveness of therapeutic interventions.6 Physiologic abnormalities that may be measured by PFTs include obstruction to airflow, restriction of lung size, and a decrease in transfer of gases across the alveolar-capillary membrane.

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TABLE 1 Pulmonary Function Test Parameters

Measurement of Pulmonary Function
Tidal volume: Amount of air inhaled or exhaled during normal tidal breathing (normal 3-7 mL/L). Minute volume: Total amount of gas breathed per minute (normal 5-10 L/min). (Tidal volume multiplied by respiratory rate.) Forced Expiratory Reserve Volume (FEV): Measures how rapidly a person can forcefully exhale air after a maximal inhalation. Also expressed as the amount of air exhaled in the first, second, and third second of forced exhaled maneuver (FEV1, FEV2, FEV3). Inspiratory capacity: Maximal volume of air that can be inhaled from the resting expiratory level.

Implications
Decreases may indicate patient fatigue, alveolar ventilation, or onset of parenchymal process. May indicate work of breathing onset of metabolic rate changes, or changes in dead space. Normal with restrictive airway disease. Reduced rate of expiratory flow with obstructive airway diseases. The ratio of FEV1/FEV is a specific measure of airway obstruction with or without restrictive disorder. Normally the ratio is 75%; values 75% suggest obstruction. Decreased value may indicate restrictive lung disease; one of the parameters used to determine patients possibility of being weaned from mechanical ventilation. Decreased value is the hallmark of Acute Respiratory Distress Syndrome. Increased value reflects overdistension of the lungs, which may result from obstructive disease or excessive use of positive end expiratory pressure. Decreased value indicates resistance to expiratory flow as in obstructive disease.

Functional residual capacity: Volume of air in the lungs at resting end expiration.

Forced Vital Capacity: The total volume of air that can be exhaled during a maximal forced expiration effort.

PFTs can detect these abnormalities early in the course of a disease when the physical examination and radiographic studies still appear normal.7 A major limitation of PFTs is that they require considerable patient effort and cooperation which limits their use in the intensive care unit (ICU) patient population. Inadequate patient effort can lead to misdiagnoses and inappropriate treatment.8 However, in critically ill mechanically ventilated patients, it is important to monitor some of the components of PFTs including vital capacity, tidal volume, and minute ventilation (See Assessment of the Patient Receiving Mechanical Ventilation elsewhere in this issue). These parameters can help measure the effects of a disease process on ventilation. Decreased tidal volume results in alveolar hypoventilation and acute respiratory failure. Tidal volume and vital capacity monitor respiratory muscle strength. Therefore, as the patient experiences respiratory muscle fatigue, these values decrease. Increased minute ventilation is associated with in-

creased work of breathing. Decreased minute ventilation is associated with hypoventilation.

Assessment of Intrapulmonary Shunt

Intrapulmonary shunt is the proportion of blood that flows past alveoli without participating in gas exchange. An elevated intrapulmonary shunt indicates a large percent of venous blood has bypassed alveoli and entered arterial blood without being oxygenated. Increased intrapulmonary shunt can be attributed to: (1) diffusion impairment produced by a thickened alveolar capillary membrane, (2) ventilation to perfusion (V/Q) abnormalities, or (3) atelectasis, consolidation, and pulmonary edema. Normal intrapulmonary shunt is relatively low; 5% of the blood flow fails to make contact with functioning alveoli. A mild intrapulmonary shunt is 5 to 15%, a major intrapulmonary shunt is 15 to 30%, and a severe intrapulmonary shunt is greater than 30%. There are several methods to assess intrapulmonary

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shunt, each with advantages and limitations. The value of assessing intrapulmonary shunt is to identify alterations in pulmonary gas exchange, determine the degree to which the lung deviates from ideal as an oxygenator of blood, and to evaluate patient response to interventions.
PHYSIOLOGIC SHUNT. The physiologic shunt equation (Qs/Qt) is identified as the gold standard for assessing impairment of pulmonary gas exchange in critically ill patients.9 Qs/Qt can be measured by calculating the difference between the content of fully oxygenated pulmonary capillary (CcO2) and arterial blood (CaO2) divided by a difference between full CcO2 blood and mixed venous blood (CvO2) according to the formula in Table 2. It is the most accurate indicator of pulmonary gas exchange that is clinically available.9,10 However, it is time consuming to obtain, complex to calculate, and costly. Data needed to calculate oxygen content in the Qs/Qt formula are available only from patients who have pulmonary and peripheral artery catheters in place. These data are obtained by drawing simultaneous mixed venous and arterial blood gases from these catheters. It is a complex formula to calculate, although most bedside monitoring systems in the ICU have the capability to calculate Qs/Qt once mixed venous and arterial blood gas data are available (Hb, arterial oxygen saturation [SaO2], PaO2, partial pressure of venous oxygen [PvO2], and venous oxygen

saturation [SvO2]) and are entered into the bedside monitoring system. Several indices to estimate Qs/Qt were developed because of the complexity of the classic shunt equation calculation, necessity for frequent sampling of arterial and mixed venous blood, and the need for a pulmonary artery catheter.10-12 The indices are collectively referred to as oxygen tension derived indices of pulmonary gas exchange, and include: alveolar-arterial gradient, ratio of arterial-toalveolar oxygen tension, and ratio of arterial oxygen tension to fraction of inspired oxygen (Table 3). All relate the driving pressure (fraction of inspired oxygen [FiO2] or partial pressure of alveolar oxygen [PAO2]) for diffusion into the pulmonary capillary blood, which is the mean determinant of PaO2. There has been some debate on the use of PAO2 versus FiO2 in a hypoxemia index. Some argue that PAO2 is more advantageous because it includes the effect of CO2.13 Others contend that this addition has little value, adds further assumptions, and may vary somewhat with permissive hypercapnea.14 Alveolar-Arterial Gradient. The alveolar-arterial gradient (A-a) gradient was developed based on the relationship between alveolar and arterial oxygen tension: PAO2 equals PaO2 when ventilation and perfusion are perfectly matched. The gradient describes the overall efficiency of oxygen uptake from alveolar gas to pulmonary capillary blood. In healthy
OXYGEN TENSION DERIVED INDICIES.

TABLE 2 Physiologic Shunt Equation

Qs/Qt CcO2 CaO2 CcO2 CvO2 where CcO2 (1.34 x ScO2 x Hb) (0.0031 PAO2); CaO2 (1.34 x SaO2 x Hb) (0.0031 PaO2); and CvO2 (1.34 x SvO2 Hb) + (0.0031 PvO2). Making these substitutions, Qs/Qt = (1.34 ScO2 x Hb 0.0031 PAO2) (1.34 SaO2 Hb 0.0031 PaO2) x100 (1.34 x ScO2 Hb + 0.0031 PAO2) (1.34 SvO2 Hb + 0.0031 PvO2)

ScO2, pulmonary capillary oxygen saturation (100%); Hb, hemoglobin; PAO2, alveolar oxygen tension, calculated as: (FiO2 [Pb PH20] PaCO2/R), where FiO2 Fraction of inspired oxygen; Pb barometric pressure; PH20=Pressure of water vapor (47 mm Hg); PaCO2 partial pressure of carbon dioxide; R respiratory quotient (CO2 production/O2 consumption in a steady state 0.8); SaO2, saturation of oxygen in arterial blood; PaO2, partial pressure of oxygen in arterial blood; PvO2, partial pressure of oxygen in venous blood; SvO2, mixed venous oxygen saturation.

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TABLE 3 Oxygen Tension Based Indices of Pulmonary Gas Exchange

Index
Alveolar-Arterial Gradient PAO2-PaO2 Ratio of arterial to alveolar PaO2/PAO2 oxygen tension Ratio of arterial oxygen tension to fraction of inspired oxygen PaO2/FiO2

Interpretation
As the gradient between PAO2 and PaO2 increases, intrapulmonary shunt increases As PaO2 decreases relative to PAO2, the ratio decreases, reflecting increasing intrapulmonary shunt As the ratio decreases, greater levels of FiO2 are required to maintain a given PaO2, reflecting intrapulmonary shunt is increasing

Normal Values
10-15 mmHg 0.75

300-500

PAO2, partial pressure of oxygen in alveoli; PaO2, partial pressure of oxygen in arterial blood; FiO2, fraction of inspired oxygen.

conditions, there is generally a small difference between PAO2 and PaO2 because PAO2 is approximately 100 mmHg and PaO2 is about 95 mmHg. As the gradient between PAO2 and PaO2 increases, intrapulmonary shunt increases. Table 4 illustrates the use of the A-a gradient in different clinical situations. Patient A reflects a normal healthy person breathing room air. The A-a gradient is 1.7, which represents a near-perfect match between ventilation and perfusion. Patient B reflects respiratory failure in a patient breathing room air. In this example, the A-a gradient is 31, which is a large gradient and, therefore, a large ventilation perfusion disturbance. Several studies have compared the A-a gradient and Qs/Qt and have demonstrated the two measures moderately correlate in evaluating ventilation perfusion imbalance in critically ill patients (r = 0.58-0.68).15-18 How-

ever, one study reported that 51% of the A-a gradients did not accurately reflect Qs/Qt 16; another found that in 25% of the measurements, Qs/Qt and A-a gradient varied in opposite directions.15 Thus, while it appears A-a gradient is useful in situations where the patient is breathing room air, its use in critically ill patients is limited because it cannot differentiate the severity of different clinical situations.15-19 Patients C and D in Table 4 illustrate this point. Patient C is receiving FiO2 1.0 and is in respiratory failure; a large A-a gradient is noted. Patient D is receiving FiO2 0.4, but has a normal PaCO2 and PaO2, yet the Aa gradient is still large. Another limitation of the A-a gradient is that varying FiO2 concentrations affect the measurement.20,21 Patients E and F in Table 4 reflect that with varying FiO2, A-a gradient increases markedly. Patient E is receiving FiO2 0.7 with a PaCO2 40 mmHg and a PaO2 of 70 mmHg that results

TABLE 4 Clinical Application of Oxygen Tension Derived Indices

Patient
A B C D E F

FiO2
0.21 0.21 1.00 0.40 0.70 0.90

PaO2 mmHg
98 50 50 98 70 200

PaCO2 mmHg
40 55 55 40 40 40

PAO2
99.7 80.9 644 643 449 592

A-a Gradient
1.7 30.9 594.3 545 379 392

a/A Ratio
0.98 0.61 0.08 0.15 0.16 0.34

PaO2/FiO2
467 238 50 98 101 222

PAO2, partial pressure of oxygen in alveoli; PaO2, partial pressure of oxygen in arterial blood; FiO2, fraction of inspired oxygen; PaCO2, partial pressure of carbon dioxide in arterial blood; A-a gradient, PAO2-PaO2; a/A Ratio, PaO2/PAO2; mmHg, mm mercury.

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in an A-a gradient of 379. Patient F is receiving an FiO2 0.9 with PaCO2 40 mmHg and PaO2 200 mmHg and the A-a gradient is still high at 392. At increasing FiO2, A-a gradient increases markedly, causing this index to lose clinical utility in critically ill patients. Its clinical usefulness is limited to patients with a Qs/Qt 15% and FiO2 0.5.12 Arterial-Alveolar Oxygen Tension Ratio. The arterial alveolar oxygen tension ration (a/A ratio) was developed based on the relationship between alveolar and arterial oxygen tension. This index uses the same variables as the A-a gradient: PAO2 (PaCO2, FiO2) and PaO2. As PaO2 decreases relative to PAO2, the ratio decreases and intrapulmonary shunt increases. A normal value is 0.75 and a ratio 0.75 indicates pulmonary dysfunction due to ventilation perfusion abnormality, shunt, or a diffusion limitation.22 Table 4 illustrates the clinical use of a-A ratio. Patient A reflects a normal healthy person breathing room air with an a-A ratio of 0.98. This represents a near-perfect match between ventilation and perfusion. Patient B reflects respiratory failure in a patient breathing room air. Here, the a-A ratio is 0.61, which reflects a worsening intrapulmonary shunt. There are conflicting data on the accuracy with which this index reflects Qs/Qt. Cane and colleagues examined the relationship of Qs/Qt and a-A ratio in a heterogeneous group of 75 critically ill patients (50 medical and 25 surgical ICU patients) and reported a high correlation between Qs/Qt and a-A ratio (r = -0.78).18 Rasanen and colleagues examined the relationship between Qs/Qt and the a-A ratio in 17 critically ill patients with respiratory failure, but reported a poor correlation (r = 0.47).12 Like A-a gradient, a-A ratio appears to be vulnerable to changes in peripheral circulation and oxygen therapy as can be seen by analyzing the data in Table 4. Patient C in respiratory failure on FiO2 0.40 has a low a-A ratio that reflects a significant intrapulmonary shunt. Patient D on FiO2 1.0 has a normal PaCO2 and PaO2, yet the a-A ratio is only 0.15. Again, as was noted with the A-a gradient, the a-A ratio can also not differentiate the severity of two clinical situations as noted in Patients E and F in Table 4. PaO2/FiO2. The PaO2/FiO2 ratio was introduced in an attempt to overcome the limi-

tations of A-a gradient and a-A ratio and enable the evaluation of PaO2 at varying FiO2.23 A normal ratio is 300 to 500 and a value 250 reflects a clinically significant impairment of pulmonary gas exchange.23 Table 4 illustrates the clinical use of PaO2/FiO2. Patient A reflects a normal healthy person breathing room air with a normal PaO2/FiO2. Patient B, in respiratory failure, appears to have an intrapulmonary shunt as reflected by a PaO2/FiO2 of 238. PaO2 /FiO2 and Qs/Qt are moderately to highly correlated (r -0.51 to -0.90).10,17,18,24 Covelli and colleagues found that a PaO2/ FiO2 200 correlated with a Qs/Qt 20% in critically ill patients with acute respiratory distress syndrome (ARDS).17 In a retrospective analysis of previously published data of 16 patients with ARDS, PaO2/FiO2 in patients with moderate shunts (30%) varied considerably with alteration in FiO2.14 When the use of the ratio was restricted to FiO2 values 0.5 and PaO2 values 100, there was little variation in the ratio for a given patient. With low values of true shunt or with substantial perfusion of alveolar units with low ventilation/perfusion ratios, PaO2 increased to 100 and diminished the value of PaO2/FiO2 as an index of hypoxemia. The American-European consensus conference definition of acute lung injury and ARDS is partially based on the PaO2/FiO2. A PaO2/FiO2 of less than 300 defines acute lung injury and PaO2/FiO2 200 defines ARDS.25 PaO2/FiO2 has been shown to be higher in patients with ARDS who survive26 and significantly lower in nonsurvivors.27 However, several studies26,28 and a metaanalysis29 suggest that it is an inconsistent predictor of outcome in patients with ARDS. Doyle and colleagues found no difference in mortality between patients with a PaO2/FiO2 ratio of 150 to 300 and those whose ratio was 150.28 The Prostaglandin E1 Study Group found that an improvement in the PaO2/FiO2 ratio after day 1 of conventional therapy predicted a favorable prognosis in their control patients.26 This improvement in oxygenation among survivors was maintained over a 7-day period. Thus, monitoring trends over time may provide more useful information than any single measurement. Despite these reports, PaO2/ FiO2 remains the most important clinical

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physiologic variable used in the diagnosis and assessment of ARDS.30-32 In a survey of 448 ICU medical directors in the United States, respondents considered the PaO2/ FiO2 ratio to be the physiologic variable most important to determine the respiratory status of a patient with ARDS.31
Assessment

tions. Maintenance of DO2 to the most hypoxia-sensitive organs is crucial. Measurement of DO2 to individual organs is an important goal for the future, but is not currently possible in the clinical setting. At present, only near infrared spectroscopy and gastric tonometry are used clinically to detect organ hypoxia.
Physical Assessment of DO2

of Oxygen Delivery
Direct physical assessment of oxygen delivery is difficult for a variety of reasons including that oxygen is a colorless, odorless gas. Indirect assessments of DO2 can be made using parameters such as level of consciousness, skin color, capillary refill, and skin temperature. A diminished level of consciousness, confusion, or agitation may be manifestations of hypoxemia. Capillary refill as a marker of DO2 is controversial. It may be useful as a marker of hypovolemia and poor myocardial function during early resuscitation in children34; however, in elderly patients it does not correlate with objective measures of hypovolemia.35 The poor sensitivity of capillary refill to blood loss (6% sensitivity and 93% specificity)36 leads to the conclusion that capillary refill has no proven diagnostic value in the adult.37 In a more recent investigation of the usefulness of the physical examination of subjective extremity skin temperature in a population of critically ill adult patients with a variety of disease processes, cool distal extremities correlated with other markers of hypoperfusion (base deficit, high lactate levels, and low mixed venous oxygen saturation).38 Other clinical indices used in the assessment of DO2 (such as heart rate, skin temperature, and urine output) are unreliable and slow to change, particularly in compensatory shock states, and abnormal values may only occur in the late stages of severe

The second component in the assessment of oxygenation is oxygen delivery (DO2) which involves the process of transporting oxygen to cells. The major function of the cardiovascular system is to transport oxygen from the lungs to the tissues at a rate to meet cellular oxygen demands. The concept of a failure of DO2 to meet metabolic demand requirements commonly defines shock. Under normal resting conditions, DO2 is more than adequate to meet tissue oxygen requirements for aerobic metabolism. DO2 is dependent on cardiac output (CO) and the oxygen content in arterial blood (CaO2) as expressed in the Fick Formula (Table 5). The overall transport of oxygen to cells is dependent on the quantity of blood being pumped (CO) and the quality of the blood (CaO2). DO2 is approximately 1000 mL/min and when indexed to body surface area, is approximately 600 mL/min/m2. DO2 may be compromised by anemia, oxygen desaturation, and a low CO, either singularly, or in combination. Individual cells and organs vary in their sensitivity to impaired DO2. Cardiomyocytes, neurons, and renal tubular cells are particularly sensitive to an acute reduction in DO2. The kidneys and liver can tolerate 15 to 20 minutes of hypoxia, skeletal muscle 60 to 90 minutes; however, in contrast, hair and nails can continue to grow for several days after death.33 This variation in tissue tolerance to impaired DO2 has important clinical implica-

TABLE 5 Fick Formula for Oxygen Delivery

DO2 CO CaO2 10 where CaO2 ( Hb 1.34 SaO2 ) (PaO2 0.003) where CaO2 content of oxygen in arterial blood; 1.34 mL of O2/g of Hb; SaO2 hemoglobin saturation with oxygen; PaO2 is the amount of O2 dissolved in blood; 0.003 is the solubility coefficient for O2 , and 10 is a constant to express CaO2 in mL/min

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DO2 impairment.39 Even though urine output is used as an index of kidney perfusion (based on the presumed sensitivity of the kidney to intravascular volume and pressure changes), it is now widely accepted that even in the face of adequate urine output, other crucial tissue beds may be underperfused.40 In addition, polyuria may be observed in the course of some altered perfusion states including sepsis.41 Using these traditional clinical signs is more problematic in the aging patient population because of chronic disease states and the use of concurrent medications. Examples include the inability of some patients using cardioactive medications to mount an appropriate tachycardia from volume loss, hypertensive patients presenting with normal blood pressure as a manifestation of hypovolemia, and patients with limited cardiac reserve in shock states from relatively minor blood loss or whose cardiac function deteriorates as the result of pain and stress.42 The presence of peripheral edema should alert the clinician about the potential for impaired DO2 to individual cells. Tissue edema due to increased vascular permeability or excessive intravascular volume expansion may result in impaired oxygen diffusion from capillary blood to individual cells, particularly in clinical situations associated with arterial hypoxemia. In these situations, avoiding tissue edema may improve DO2 to cells.33
Assessment of Cardiac Output

tions, bias, precision, and risks of the method used to determine CO to avoid treatment decisions based on spurious data. An even greater challenge lies in understanding the number once its generated. Tibby and Murdock suggest an approach that may assist clinicians in interpreting CO data.44 They recommend CO should ideally be interpreted from four aspects: (1) a quantitative element, (2) a qualitative element, (3) a temporal element, and (4) as part of a global assessment of metabolic well-being. In other words, adequacy of CO should be determined by answering the following question: Is the CO (x L/min.) adequate for this patient at this time? Integration of CO into a global metabolic assessment requires an appreciation of the contribution of CO to DO2 and an understanding of the balance between DO2 and oxygen consumption (VO2 ). This global assessment can be made by considering the following questions: (1) Is the DO2 adequate to meet metabolic needs of the patient (both globally and regionally)? (2) Is DO2 occurring with adequate perfusion pressure? (3) Is the patient able to use oxygen delivered? (4) If the answer is no to any of the above, why is this so?44
Measurement of Oxygen Content in Arterial Blood

Cardiac output (CO) is a product of stroke volume and heart rate. The role of hemodynamic monitoring is to evaluate the three components of stroke volume (preload, afterload, and contractibility) and optimize components to ensure adequate CO (See Hemodynamic Assessment elsewhere in this issue). The two most commonly used techniques to measure CO are bolus thermodilution and continuous CO. The choice of method depends on the patient and the clinical situation. A detailed description of these and other techniques to measure CO is beyond the scope of this article, but has been reviewed elsewhere.43 ICU clinicians must have a thorough understanding of the limita-

As Table 5 demonstrates, many measurements are required to calculate DO2. If all measurements had zero error, the Fick method would be accurate and reproducible. However, all clinical measurements, particularly in critically ill patients, have associated systematic measurement errors (bias) and random measurement errors (precision). In the Fick equation these measurement errors are not simply added in the equation, but they are multiplied in the final equation. Even with modest individual measurement errors, large overall errors occur in the calculation of DO2. CaO2 is calculated according to the formula in Table 5. Normal CaO2 is 20 mL O2/dL. PaO2 contributes minimally to overall DO2 and is frequently omitted from the calculation. Global DO2 depends more on SaO2 than PaO2. Therefore, there is little extra benefit from increasing PaO2 above 90 mmHg due to the shape of the oxyhemoglo-

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bin dissociation curve when over 90% of Hb is already saturated with oxygen. Increasing Hb through blood transfusion may seem to be an appropriate intervention to optimize CaO2. However, blood viscosity increases with Hb 10 g/dL33 and can impair blood flow. Recent evidence suggests that traditionally accepted Hb concentrations for critically ill patients of 10 g/dL may be too high since an impaired outcome was observed if Hb was maintained between 7 to 9 g/dL (with the exception of patients with coronary artery disease in whom a level of 10 g/dL may be appropriate).45 Pulse oximetry is used for continuous measurement of SaO2 and when measured this way it is designated as SpO2. Because desaturation is detected earlier by pulse oximetry than by clinical observation, the use of pulse oximetry is recommended for any patient at risk for hypoxemia.46 Pulse oximetry has become a standard monitoring device in the ICU upon which therapeutic interventions are frequently made. Its uses include detection of hypoxemia,47 reduction in the frequency of arterial blood gases,48 titration of FiO2,49 and weaning from mechanical ventilation.50 A full review of research related to pulse oximetry can be found in research-based clinical protocols on pulse oximetry.46,51 Comparison of pulse oximetry with direct CO-oximeter measurements is reported in terms of bias (mean difference between two techniques) and precision (standard deviation between two techniques). In healthy volunteers, oximeters have a bias of 2% and a precision of 3% when Sa02 90%.52,53 Comparable results have been reported in critically ill patients with good arterial perfusion.54,55 However, decreased bias and precision have been reported in hemodynamically compromised patients and patients with hypoxemia, in whom accurate and reliable monitoring is of major importance. In low perfusion states with decreased CO, the bias and precision reach unacceptable limits of agreement (4%).56-58 Accuracy of pulse oximeters appears to deteriorate when SaO2 falls below 80%. In healthy individuals under hypoxemic conditions, bias of pulse oximetry ranges from 15% to 13%, while the precision ranges from 1 to 16%.52,59-

In a study of 54 mechanically ventilated patients with SaO2 90%, the bias and precision of pulse oximetry was 1.7% and 1.2%, respectively, but when the SaO2 was 90%, the bias and precision of pulse oximetry was 5.1 and 2.7%, respectively.49 Elevated carboxyhemoglobin or methemoglobin levels cause inaccurate oximetry readings.62-64 In patients with sickle cell anemia in acute crisis, the mean bias of pulse oximetry was 4.5%.65 More recently, Sequin and colleagues66 found that SpO2 consistently overestimated SaO2 and concluded that a minimum threshold SpO2 value of 96% is more reliable to ensure an SaO2 value 90%. Pulse oximeters have several technical limitations that may lead to inaccurate readings. Accuracy decreases during states of diminished blood flow through the point of attachment.67-69 as a result of vasoactive drugs, hypotension, or hypothermia. Accuracy of finger probes is generally found to be better than performance at other sites.70 Because the earlobe is the least vasoactive site and is least susceptible to signal loss, it may show faster response and greater accuracy during periods of vasoconstriction and hypotension.46 Blue, green, or black nail polish causes inaccurate SpO2 readings.71 Motion of the probe continues to be a significant source of error and false alarms.72-74 Nearly one-half of all false alarms in the ICU have been attributed to SpO2 signals.75 Many clinicians fail to appreciate the physical and technical limitations of pulse oximetry.76 The pulse oximeter remains a valuable tool in the care of critically ill patients, but an awareness of its limitations is an important component of enhancing the quality of care. The major challenge facing pulse oximetry is whether this technology can be incorporated into diagnostic and management algorithms that can improve the efficiency of clinical management in the ICU.77
Assessment

of Oxygen Consumption and Oxygen Extraction

The third component of oxygenation is oxygen consumption (VO2); the process by which cells use oxygen to generate energy. Ingested substrates are converted in the

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Krebs Cycle to form adenosine triphosphate (ATP) through aerobic metabolism and results in the creation of 38 molecules of ATP. As a back-up mechanism, cells can still produce ATP with a limited oxygen supply through the process of anaerobic metabolism where carbohydrates are broken down to generate two ATP molecules. However, in addition to ATP, the byproducts pyruvate and lactate are produced. The more time spent in anaerobic metabolism, the more lactate produced. Normal VO2 is approximately 250 mL/min. When indexed to body surface area, VO2 is approximately 130 mL/min/m2. Direct measures of cellular VO2 are in various developmental phases but are not yet available in the clinical setting. There are no physical assessment parameters that can be used to evaluate VO2. Current clinical techniques for measuring VO2 focus on global measurements that reflect the balance between DO2 and VO2.
Assessment of Oxygen Consumption

Indirect calorimetry is the gold standard for the determination of VO278 and is the recommended method to measure VO2 in critically ill adults.79 It uses a direct measure of VO2 and CO2 production. Although the use of indirect calorimetry is considered to be the most accurate method, it is time consuming, involves the use of expensive and specialized equipment, and requires trained personnel to perform it.80 These limitations prevent its widespread acceptance as a method to measure VO2 in critically ill patients. VO2 can also be measured using the Reverse Fick equation according to the formula in Table 6. Data needed to calculate VO2 using this equation are available from patients who have pulmonary artery and peripheral

arterial catheters in place to allow for obtaining simultaneous mixed venous and arterial blood gases. Like the Qs/Qt, it is time consuming to obtain, complex to calculate, and costly. Most bedside monitoring systems in the ICU have the capability to calculate it once mixed venous and arterial blood gas data are available (Hb, PaO2, SaO2, PvO2, SvO2) and entered into the bedside monitoring system. There are several methodological concerns about the accuracy and precision of the reverse Fick equation. It may underestimate whole body VO2 because it does not include the VO2 of the bronchial and thebesian circulations.81,82 Pulmonary VO2 is a physiologic variable of importance especially in pulmonary inflammatory conditions such as acute lung injury and pneumonia because it may be substantially increased.83 The Fick method is episodic and may not reflect actual trends in VO2.84 Investigators have demonstrated there can be large, apparently spontaneous, changes in VO2 in critically ill patients.85,86 Studies that have compared simultaneous measurements using indirect calorimetry have reported that indirect calorimetry measurements are 8 to 27% higher than measurements made using the Fick method.87-89 A more recent study reported a bias of 41 mL/min/m2, precision of 3.95 mL/min/ m2, and a 95% confidence interval of 20 to 63 mL/min/m2; which they considered to be far too wide and concluded that these two methods should not be considered to be interchangeable.90
Assessment

of Oxygen Extraction

With a normal resting DO2 of approximately 1000 mL/min and VO2 of 250 mL/min, rest-

TABLE 6 Reverse Fick Equation to Measure VO2

VO 2 ( CaO 2 - CvO 2) CO 10 where CaO 2 ( Hb 1.34 SaO 2 ) (PaO 2 0.003) and CvO 2 ( Hb 1.34 SvO 2) (PvO 2 0.003) where CaO2 content of oxygen in arterial blood; CvO2 content of oxygen in venous blood; 1.34 mL of O2/g of hemoglobin (Hb); SaO2 saturation of oxygen in arterial blood; SvO2 saturation of oxygen in mixed venous blood; PaO2 is the partial pressure of oxygen in arterial blood; PvO2 is the partial pressure of oxygen in venous blood; 0.003 is solubility coefficient for O2; 10 is a constant to express VO2 in mL/min.

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ing oxygen extraction is approximately 25%. The amount of oxygen consumed as a fraction of oxygen delivered defines the oxygen extraction ratio (O2ER). The O2ER estimates the balance between oxygen delivery and oxygen consumption and is calculated as O2ER = VO2/DO2. As VO2 increases or DO2 decreases the O2ER rises to maintain aerobic metabolism. An O2ER greater than 0.35 implies an excessively high extraction of oxygen to meet metabolic demands and is often associated with shock states.9 Tissue hypoxia, either because DO2 is inadequate or cells do not extract and use oxygen normally, may be a contributor to organ failure in critical illness.83 One of the most important clinical questions about oxygenation that clinicians must evaluate is whether DO2 is adequate to meet the metabolic needs of the patient. There are no direct methods currently clinically available to assist clinicians in making this assessment. Instead, clinicians must rely on global and regional parameters. These parameters indirectly assess the balance between DO2 and VO2.
Global Parameters of DO2/VO2 Balance

in Figure 2, VO2 remains relatively constant over a wide range of DO2 because tissues can extract more oxygen when needed. When this occurs, venous oxygen saturation decreases. However, when DO2 reaches a critical threshold, tissue extraction of oxygen cannot be further increased to meet VO2. It is at this point that VO2 becomes directly dependent on DO2 (DO2[Crit]) and cells convert to anaerobic metabolism. This is manifested by an increase in lactate, a more significant base deficit, a decrease in mixed venous oxygen saturation (SvO2), and an increase in the O2 ER. The DO2(Crit) in humans has not been widely determined, but may be in the range of 180 to 330 mL/min/m2.91,92 As noted in Figure 2, a critical reduction in DO2 results in anaerobic metabolism, which, in turn, produces a significant elevation in serum lactate levels. Serum lactate levels are considered to be the clinical gold standard as a marker of inadequate cellular oxygenation.93-95 Normal serum lactate levels are 2 mMol/L. The magnitude and duration of elevated lactate levels maybe predictors of mortality and morbidity in some critically ill patient populations. In critically ill trauma, surgical, and burn patient populations, lactate normalization within 24 hours of admission is associated with increased survival.96-100 Initial and
SERUM LACTATE.

The relationship between whole body DO2 and VO2 is illustrated in Figure 2. (It should be noted that individual organ systems have their own DO2/VO2 relationship). As noted

Figure 2. Global indices of DO2/VO2 balance. L, lactate; SVO2, missed venous oxygen saturation; O2ER, oxygen extraction ratio; VO2, oxygen consumption; DO2, oxygen delivery; DO2(Crit), point at which VO2 becomes directly dependent on DO2.

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highest lactate levels appear to be higher in nonsurvivors than survivors, and significantly higher in patients with multiple organ failure than without organ failure.101 However, in a recent study102 blood lactate levels were not affected by worsening congestive heart failure severity in status I cardiac transplant candidates. Certain limitations and cautions must be considered when interpreting lactate levels. Serum lactate concentrations represent the balance of many complex factors that influence its production and clearance including cancer, acute alcohol intoxication, cocaine, and grand mal seizure.103-105 Exogenous catecholamine infusions can stimulate anaerobic metabolism in skeletal muscle resulting in increased production of lactate in the absence of tissue hypoxia.106 Use of large-volume lactated Ringers solution (28 mMol/L) may result in transiently elevated serum lactate levels because of the lag in lactate catabolism, particularly if hepatic and renal perfusion remain poor.107 Because the kidneys contribute to lactate removal, lactate can accumulate in the absence of tissue hypoxia in situations of impaired renal function.108 Evidence suggests that the lung can release lactate in the presence of acute lung injury.109 Despite these limitations, sequential use of lactate levels can establish and evaluate trends in cellular oxygenation. Any increase in lactate is a cause for concern and the etiology should be aggressively pursued. Base deficit is defined as the amount of base (mMol) required to titrate 1 L of arterial blood to a pH of 7.40 with the sample fully saturated with oxygen at 37C and partial pressure of CO2 at 40 mmHg. It is calculated from an arterial blood gas (ABG) analysis and is usually reported with the ABG results. A normal base deficit is 3 mMol to + 3mMol. Positive values reflect metabolic alkalosis and negative values reflect metabolic acidosis. Base deficit can result from an accumulation of lactate associated with anaerobic metabolism and has been classified in the trauma patient population as mild (-2 to -5 mMol), moderate (-6 to -14 mMol), or severe (> -15 mMol).110 Base deficit appears to be a sensitive measure of the degree and duration of inadequate DO2 in the critically ill trauma patient
BASE DEFICIT.

population. Rutherford and colleagues111 conducted a retrospective study of 3791 trauma patients and reported that a base deficit of -15 mMol within 24 hours postinjury was a significant marker of mortality in patients 55 years of age. However, in patients ages 55 and older, a base deficit of 8mMol was a significant marker of mortality. The use of a lower threshold of base deficit in elderly trauma patients is recommended because elderly patients with significant injuries and mortality risk may not manifest a base deficit out of the normal range.112 A more recent study found that trauma patients who had persistently high base deficit also had lower VO2 (126 40 mL/min/m2 versus 156 30 mL/min/m2) than with patients with a low base deficit.113 The investigators concluded that a persistently high arterial base deficit is associated with altered oxygen extraction and an increased risk of multiple organ failure and mortality. For these reasons, many trauma centers support the use of a normal base deficit as an appropriate endpoint of adequate DO2.94 The use of base deficit in other patient populations is unclear. In samples of critically ill surgical patients98 and burn patients,100 initial base deficit was a poor predictor of mortality and did not correlate with lactate levels. However, in a mixed sample of medical and surgical ICU patients, Smith and colleagues114 found that a base deficit more negative than -4 mMol/L and a lactate 1.5 mMol/L led to a sensitivity of 80.3% and a specificity of 58.7% for mortality. Limitations of base deficit exist and clinicians should consider this in the interpretation of these data. Administration of sodium bicarbonate, hypothermia, and hypocapnea can affect base deficit. Certain conditions that result in a metabolic acidosis, unrelated to lactic acidosis, can produce a base deficit that does not reflect DO2/VO2 balance. These include hyperchloremic acidosis as a result of infusions of large volumes of normal saline,115 preexisting renal failure, acute ingestion of certain substances (ie, alcohol, cocaine, aspirin), conditions associated with chronic CO2 retention (emphysema), and diabetic ketoacidosis.95,116
MIXED VENOUS OXYGEN SATURATION. Mixed venous oxygen saturation (SvO2) represents a

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global balance between DO2 and VO2. Normal SvO2 is 60 to 75%. If SvO2 decreases, one of two problems exist: (1) DO2 has decreased, or (2) VO2 has increased. To determine which of these situations is occurring, an assessment of DO2 must be made. If the components of DO2 have not changed, then the source for an increase in VO2 must be investigated. In order to circumvent the need for a pulmonary artery catheter, oxygen saturation of central venous blood (ScvO2) obtained from the lower superior vena cava or right atrium has been advocated as a surrogate. Studies evaluating the impact of this measure on the management of critically ill trauma patients have varied and its use is the subject of ongoing debate.122 A prospective study of 40 critically ill trauma patients found that ScvO2 did not correlate with base deficit or lactate concentration.123 Others have demonstrated that ScvO2 parallels elevations in lactate and that it can be of value in detecting tissue hypoxia not confirmed by vital signs in patients who are critically ill.124,125 Very few studies have examined the agreement between ScvO2 and SvO2 and the results are conflicting. Ladakis and colleagues126 examined the mean ScvO2 and SvO2 values in 61 mechanically ventilated patients and reported the mean values were similar (mean SvO2 68.2% and ScvO2 69.4%); however, comparing mean values between methods does not answer if the methods agree. They did report similar precision between the two methods (SvO2 1.2%; ScvO2 1.1%). In a more recent study in 32 critically ill medical surgical patients, ScvO2 averaged 7 4% higher than SvO2.127 More studies are needed to more fully understand the implications and limitations of the use of ScvO2 in the management of critically ill patients.
MIXED VENOUS OXYGEN SATURATION: LACTATE RA-

Global indices of DO2/VO2 balance lack the sensitivity necessary to be early warning signals, particularly in shock states when maldistribution of circulating volume occurs and not all organs become hypoxic all at once. The optimal tissue bed to monitor for DO2 impairment is unclear. Access to various tissues to make monitoring useful is an obvious consideration.
GASTRIC TONOMETRY. Splanchnic DO2 has been quantified using gastric tonometry which is based on the knowledge that when DO2 to the stomach decreases, anaerobic metabolism in gastric cells produces the byproducts of excess hydrogen ions, lactate, and CO2. As gastric CO2 levels increase, hypoperfusion may be present. Currently available methods of monitoring regional CO2 include gastric tonometry and sublingual capnography. An extensive review of these methods is beyond the scope of this article, but can be found elsewhere.129,130 Gastric tonometry is useful, particularly when used to monitor the difference between gastric and arterial CO2. In normal physiologic states, this difference is usually 10 mmHg. A widening gap indicates compromised blood flow to the splanchnic bed and a gap exceeding 20 mmHg requires aggressive treatment.129,131 Carbon dioxide is measurable in other tissue beds and using gastric tonometry principles, it has been extrapolated to other parts of the gastrointestinal system. Sublingual capnography was developed to overcome some of the limitations in gastric tonometry. Sublingual capnography is noninvasive and portable, and data are available within minutes. It correlates well with gastric PCO2.132 A full review of this technology can be found elsewhere.130

Preliminary data are available to indicate that using SvO2 (or ScvO2) lactate ratio may be valuable in recognizing DO2/VO2 imbalances.128 For example, when a high SvO2 or ScvO2 is coupled with an elevated lactate level, then inadequate cellular DO2 may be present. More information is needed to determine if this ratio is clinically relevant and meaningful.
TIO.

Summary

Oxygenation is dependent upon three physiologic processes: pulmonary gas exchange, oxygen delivery, and oxygen consumption. An accurate and thorough assessment of oxygenation must include an evaluation of each of these three processes. Diagnostic tools available to ICU clinicians to monitor pulmonary gas exchange, oxygen delivery,

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Figure 3. Clinical measures of pulmonary gas exchange, oxygen delivery, and oxygen consumption. Adapted with permission from Taylor CR, Weibel ER. Design of the mammalian respiratory system. Respiration Physiology. 1981;41(p2). Copyright 1981 by Elsevier Science. CO2, carbon dioxide; PaCO2, partial pressure of carbon dioxide in arterial blood; PetCO2, end-tidal carbon dioxide; PFTs, pulmonary function tests; Qs/Qt, intrapulmonary shunt; PAO2, partial pressure of oxygen in alveoli; PaO2, partial pressure of oxygen in arterial blood; FiO2, fraction of inspired oxygen; A-a gradient = PAO2 - PaO2; a/A Ratio = PaO2/PAO2; DO2, oxygen delivery; CO, cardiac output; CaO2, content of oxygen in arterial blood; Hb, hemoglobin; SaO2, arterial oxygen saturation; SvO2, mixed venous oxygen saturation; ScvO2, oxygen saturation of central venous blood; pHi, gastric pH; CvO2, content of oxygen in venous blood; O2,oxygen; ATP, adenosine triphosphate; PvO2, partial pressure of oxygen in venous blood.

and oxygen consumption presented in this review are summarized in Figure 3. It is imperative that ICU clinicians recognize and appreciate the implications and limitations of these diagnostic tools to avoid making treatment decisions based on spurious inaccurate data. Accurate assessment and treatment of disturbances in oxygenation are crucial to optimize patient outcomes.

4.

5. 6. 7. 8. 9. 10.

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