(Chest. 2005;128:547S-553S.)
© 2005
American College of Chest Physicians
Pathophysiology of Oxygen Delivery in Respiratory Failure*
Mitchell M. Levy, MD, FCCP
* From the Division of Pulmonary and Critical Care Medicine, Rhode Island Hospital Brown University School of Medicine, Providence, RI.
Correspondence to: Mitchell M. Levy, MD, Division of Pulmonary and Critical Care Medicine, Rhode Island Hospital Brown University School of Medicine, 593 Eddy St, Main 7, Providence, RI 02903; e-mail: mitchell_levy{at}brown.edu
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Abstract
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Complex physiologic interactions exist between oxygenation, hemoglobin, and cardiac output (Qt) in critically ill patients with respiratory failure. When any or all of these three critical factors fail, clinicians are challenged to support oxygen delivery (DO2) in order to avoid tissue hypoxia, end-organ damage, and high mortality rates. Many of the interventions performed to improve DO2, including mechanical ventilation, blood transfusions, fluid management, and invasive monitoring of cardiac function, are accompanied by serious risks that can exacerbate the pathology of DO2. This article provides an overview of oxygenation, hemoglobin, and Qt in patients with respiratory failure and highlights some of the current research that seeks safe and effective ways to improve DO2 in these patients.
Key Words: organ damage • oxygen delivery • oxygenation • respiratory failure • tissue hypoxia
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Introduction
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Respiratory failure is a condition that leads to inadequate oxygen delivery (DO2) and requires immediate clinical intervention to avoid tissue hypoxia and subsequent organ damage. Global DO2 is the product of cardiac output (Qt) and arterial oxygen content (CaO2). CaO2 is, in turn, the product of arterial oxygen saturation (SaO2), hemoglobin concentration, and a constant, reflecting the hemoglobin-oxygen binding capacity.1 A concise review of these basic equations appears elsewhere in this Supplement (see Huang YCT; Monitoring Oxygen Delivery in the Critically Ill).
Despite years of study, the relationship between DO2 and oxygen consumption (
O2) is still incompletely understood.23 The theory of pathologic oxygen supply dependency in critically ill patients—when tissue oxygen extraction falls short of demand over a wide range of DO2—is now believed to be an artifact of mathematical coupling, which occurs because DO2 and O2 are calculated with equations that share common variables.34 The critical DO2 threshold, known as the point at which DO2 fails to meet the metabolic demand and anaerobic metabolism begins, is currently a more clinically relevant and widely accepted concept. In humans, healthy or otherwise, the critical DO2 value remains unknown,5 and determination of "adequate" tissue oxygenation has long been an elusive goal for clinicians.6 Although identification of oxygen utilization at the tissue level would help clinicians decide how much oxygen is enough, the options are limited for assessing changes in global or individual organ oxygen requirements (usually as a change in O2) and tissue perfusion.7 Of the relationships that are known, three major, interdependent components must be monitored and supported in the critically ill patient with respiratory failure in order to preserve DO2: oxygenation, hemoglobin-related parameters, and Qt.
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Determinants of Oxygen Exchange
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Respiration is a process that involves the exchange of oxygen and carbon dioxide between a living organism and its environment. Figure 1
contains a schematic diagram of normal gas transport in a healthy adult, demonstrating the interplay of lung alveoli, heart, blood, capillaries, and intracellular mitochondria in the respiratory process.1 Following oxygen uptake in the lung via inspiration and then passive oxygen diffusion into arterial blood, DO2 next depends on the oxygen-carrying capacity of blood, ie, its hemoglobin content and dissociation kinetics. Global and regional DO2 to tissues also relies on adequate Qt and local control of blood flow to end organs. Oxygen diffuses from capillaries to cells, where it is utilized at the tissue level. Simultaneous exchange of oxygen and carbon dioxide is followed by removal of carbon dioxide from the blood into the alveoli, where this waste gas is ultimately exhaled, completing the normal respiratory cycle. Respiratory failure and inadequate DO2 can result from malfunction of any aspect of the "ventilatory apparatus." A decrease in convective oxygen transport and increased oxygen extraction by tissues can lead to progressive decreases in venous oxygen saturation (SvO2), rapid arterial desaturation, and an insufficient oxygen supply to the tissues.8
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Figure 1. Gas transport in a healthy 70-kg adult breathing room air (FIO2 of 0.21) at standard barometric pressure (101 kPa).1 Values in parentheses are for the normal 70-kg adult. The oxygen partial pressures of dry, humidified, and alveolar air are assumed to be 21.3 kPa, 20 kPa, and 14.7 kPa, respectively. Hb = hemoglobin; CvO2 = mixed venous oxygen content; PeCO2 = mixed expired PCO2; PeO2 = mixed inspired PO2; PIO2 = inspired PO2; P50 = PO2 at which 50% of the hemoglobin is saturated. Used with permission from Treacher et al.1
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Oxygenation
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Under normal conditions, alveolar oxygen pressure drives the diffusion of oxygen into arterial blood, measured clinically as PaO2. The transfer of inspired oxygen and removal of waste carbon dioxide will be limited if there is alveolar damage or injury to respiratory muscles, carotid bodies, or the central respiratory center. Acute lung injury and ARDS commonly lead to hypoxemic respiratory failure.9
Arterial hypoxemia may be initiated by alveolar hypoventilation (respiratory depression, respiratory muscle weakness, or obstructive airway disease) but also can result from development of a diffusion barrier such as occurs in pulmonary edema or from ventilation-perfusion (/
) mismatch.1 This results either from inadequate ventilation of perfused alveoli or reduced perfusion of well-ventilated alveoli,10 and is the most frequent contributor to clinically important oxygen desaturation.11
PaO2 and SaO2 are the main determinants of arterial hypoxemia; in addition, clinical assessment, pH, lactate, DO2/O2, changes in PCO2, gastric mucosal pH, and SvO2 have all been used to monitor tissue oxygen status.12 There are, however, examples in which these measures are inadequate. Although frequently used to monitor oxygen exchange, PaO2 may not provide sufficient information about the adequacy of DO2. A below-normal PaO2 generally indicates / mismatch, but a normal PaO2 does not necessarily mean that there is / homogeneity in the lung. The alveolar PO2/PaO2 gradient reflects the efficiency of oxygen uptake from the alveoli to blood11 and may be a more sensitive indicator of / abnormalities. When severe / mismatch is suspected as the cause of hypoxemia, the PaO2/fraction of inspired oxygen (FIO2) ratio is a good index of oxygenation that is easily calculated.13 Values of PaO2 and SaO2 can also be normal in a critically ill patient who is anemic or has low Qt, and thus these parameters will fail to detect the presence of tissue hypoxia. In these situations, mixed SvO2, when very low, may be a better indicator of tissue oxygenation than PaO2 or SaO2.6 The measurement of SvO2 requires the presence of a pulmonary arterial catheter, which is not without risk.1415
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Strategies for Improving Oxygenation
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Oxygen may be supplemented directly with invasive or noninvasive ventilatory support. While attempting to improve oxygenation by mechanical means, the potential for oxygen toxicity should be considered. In the critically ill patient, excess FIO2 has the potential to decrease vital capacity and increase alveolar-capillary permeability.16 The least amount of FIO2 to achieve effective oxygenation should be used, typically < 0.60.17 If / mismatch is present, there will be a positive response of PaO2 to administered oxygen, but if there is a "true shunt"—if the amount of mixed venous blood that completely bypasses the pulmonary capillaries exceeds 30%—increasing the FIO2 will not improve the PaO2.1
Ventilatory management is shifting from a strategy that prioritized oxygen exchange and DO2 optimization to a new strategy that attempts to ensure that the lung is protected.17 The goals of the old vs new strategies are not mutually exclusive, since functional lung density and oxygen exchange efficiency are correlated.18 Mainstream lung protective approaches to mechanical ventilation include the use of lower tidal volumes and optimized pressure settings for positive end-expiratory pressure (PEEP). Noninvasive ventilation may be appropriate in some patients. Less conventional but potentially promising strategies involve prone positioning, permissive hypercapnia, and high-frequency ventilation that allows lower tidal volumes while maintaining minute ventilation.
Reduced Tidal Volumes and PEEP
Conclusive evidence that a lung protective strategy improves mortality was provided by the ARDS Network.19 In a study of 861 patients with ARDS, ventilation with low tidal volumes (6 mL/kg) combined with an airway plateau pressure of 
30 cm H2O reduced the relative risk of mortality by 22% compared to traditional ventilation volume (12 mL/kg) with 50 cm H2O. The number of ventilator-free days and percentage of patients breathing without assistance by day 28 were also significantly higher in the group with low tidal volumes (p = 0.007 and p < 0.001, respectively). Largely because of the ARDS Network study and another investigation by Amato et al,20 which coupled higher PEEP settings with low tidal volumes and achieved a 47% reduction in mortality, there is general agreement that low tidal volume ventilation should be the standard of care against which other interventions and supportive techniques are measured.21
The primary rationale for using PEEP in patients with ARDS is to prevent end-expiratory alveolar collapse and the hypoxemia that results from this increased shunt in patients with ARDS. This occurs for several reasons, including a qualitative and quantitative surfactant defect as well as the increased weight on dependent lung regions due to increased lung density.18 There is also evidence that repetitive recruitment and derecruitment during tidal ventilation may result in shear stress injury, which may contribute to ventilator-associated lung injury. The exact method for determining "optimal PEEP" in ARDS remains uncertain.
Other Lung Protective Strategies for Improving Oxygenation
Inhaled nitric oxide (NO) has the potential to improve / matching by dilating the pulmonary vasculature and has been suggested as a means to augment arterial and tissue oxygenation in patients receiving mechanical ventilation, with an added benefit of reduced inflammatory mediators and platelet aggregation.9 Although improved oxygenation with NO has been observed, outcomes in large multicenter studies have not improved,22 except in a small subgroup of patients who inhaled low doses (5 ppm) of NO.23
Prone positioning in patients with ARDS has been reported to improve oxygenation in 70 to 80% of patients.24 The mechanisms involved relate to increased / matching due to increased lung volume, redistribution of perfusion, and dorsal lung recruitment. The positive effects of prone positioning on oxygenation diminish after approximately 1 week of mechanical ventilation and are incompletely understood.24 In one study25 of patients with pulmonary aspiration, oxygenation was significantly improved in the patients who were subjected to prone positioning. The authors24 concluded that early prone positioning favorably altered / relationships, aided drainage of secretions, opened up alveoli, and prevented progression of pneumonitis. In a large, prospective, randomized, controlled study of prone positioning conducted by Gattinoni and colleagues,26 survival was unaffected despite improved oxygenation. However, a survival benefit was suggested in the subset of patients with the lowest PaO2/FIO2 ratio.
Largely investigated in pediatrics, permissive hypercapnia combined with high ventilation rates is another potentially beneficial lung protective strategy in patients receiving ventilation.27 The oxygen-hemoglobin dissociation curve shifts to the right when PaCO2 is elevated and favors peripheral tissue oxygen unloading.28 Hypocapnic alkalosis alters the balance between global DO2 and O2, decreasing supply and increasing demand for oxygen.29 In contrast, at the cellular level, lower PaCO2 increases the metabolic requirement for oxygen through increases in cell excitation or contraction, and contributes to cell death, the pathogenesis of acute lung injury, systemic inflammation, and the risk of permanent brain damage.2829 Data reporting a lower incidence of barotrauma during mechanical ventilation for near-fatal asthma30 and the ability of permissive hypercapnia to ameliorate stretch-induced lung injury in neonates31 have contributed to a growing acceptance of permissive hypercapnia in the ventilation strategy of adult patients with ARDS.32
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Hemoglobin
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The second component of DO2 apt to malfunction in the patient with respiratory failure is the oxygen-carrying capacity of blood. The concentration of circulating hemoglobin is the primary determinant of CaO2;33 therefore, all things being equal, an adequate hemoglobin concentration should delay the onset of anaerobic metabolism. For numerous reasons, including phlebotomy, hemorrhage secondary to trauma and/or surgery, inflammation, nutritional deficiencies, and decreased erythropoietin production,343536 anemia is prevalent in critically ill patients. During the course of an ICU stay, hemoglobin may fall from a baseline average of 11 g/dL to 8 to 10 g/dL.37
Optimal hemoglobin levels in critically ill patients and how they should be achieved has been a topic of interest and debate since the landmark work of Freudenberger and Carson38 and Hebert et al.39 One factor that complicates prediction of "optimal hemoglobin" is the dissociation profile of oxygen from hemoglobin, which is likely to be altered and/or changing throughout the course of critical illness. The kinetics of oxygen binding to hemoglobin are affected by temperature, pH, and inorganic phosphates in RBCs (eg, 2,3-diphosphoglycerate).6 Acidosis and increased temperature decrease the hemoglobin affinity for oxygen and tend to improve tissue oxygenation; however, the effects of hypophosphatemia on 2,3-diphosphoglycerate are opposing and tend to shift the hemoglobin dissociation curve back to the left.6
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Strategies for Improving Hemoglobin Parameters
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Theoretically, administration of RBC transfusions should supply hemoglobin and improve DO2 in critically ill patients, although studies40414243 have failed to show improvement in tissue oxygenation or outcomes following RBC transfusions. Raising hemoglobin concentration is a key factor for adequate tissue oxygenation, but the bulk of evidence seems to indicate that the DO2, O2, or survival benefits of using RBC transfusions as a vehicle to deliver hemoglobin do not outweigh their risks. Perhaps the most frequently cited evidence questioning the effectiveness of RBC transfusions was provided by Hebert et al,39 who demonstrated, in a well-designed, randomized clinical trial, that a liberal transfusion policy conferred no survival benefit over a restrictive transfusion policy, with the exception of a subset of patients with advanced cardiac disease. Spahn44 has recently acknowledged that there is no "magic number of hemoglobin" at which transfusions should be administered. The College of American Pathologists recommends RBC transfusions based on an oxygen extraction rate > 50%, PvO2 < 25 mm Hg (< 3.3 kPa), and a reduction in O2 to < 50% of baseline.45
An important consideration with regard to the oxygen-delivering capability of RBC transfusions is that allogeneic blood typically administered to ICU patients has been stored an average of 21 days.37 Older stored blood lacks 2,3-diphosphoglycerate, which increases the hemoglobin-oxygen binding affinity, as noted above, and impairs its ability to unload oxygen.6 The RBC membranes of older blood may also be less deformable and lead to microthromboses that could exacerbate tissue hypoxia.46 Despite these clinical and physiologic observations that ought to discourage the liberal transfusion of RBCs, a recent study of critically ill patients by Corwin et al37 (of whom 32% had a primary diagnosis of respiratory failure) showed that transfusions were still very commonly administered.
Transfusion practices were recently evaluated in a retrospective study47 of patients receiving mechanical ventilation from the study by Corwin et al.37 In that study,37 it was observed that patients receiving mechanical ventilation tended to receive transfusions more often than patients not receiving mechanical ventilation (49% vs 33%, p < 0.0001) [mean ± SD], and patients receiving mechanical ventilation had significantly higher pretransfusion hemoglobin levels (8.7 ± 1.7 g/dL) than patients not receiving mechanical ventilation (8.2 ± 1.7 g/dL, p < 0.0001). These data suggest an a priori assumption on the part of intensivists that maintaining hemoglobin at a higher level in patients receiving mechanical ventilation is beneficial. Among these patients, however, transfusions were not associated with better outcomes.
A few reports484950 have supported the notion that successful attempts to wean from mechanical ventilation are associated with higher hemoglobin levels. However, a post hoc analysis of the mechanical ventilation subset from the population investigated by Hebert et al51 revealed no difference between liberal and restrictive RBC transfusion groups with respect to the duration of mechanical ventilation or number of ventilator-free days. Given the present evidence, transfusing patients receiving mechanical ventilation with RBCs aggressively and at a higher hemoglobin threshold than in patients not receiving mechanical ventilation does not appear to be justified.
Administration of epoetin alfa (40,000 U/wk) significantly increased hemoglobin levels and reduced transfusion requirements in a randomized study of 1,302 critically ill patients, although no significant effects on ventilator outcomes, hospital or ICU length of stay, or 28-day mortality were detected.52 Further studies are necessary to investigate whether raising hemoglobin with epoetin alfa can improve DO2 and outcomes in the specific population of patients receiving mechanical ventilation.
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Qt
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Beyond optimizing oxygenation and hemoglobin, achieving adequate DO2 in the patient with respiratory failure also requires that Qt be maintained. For the heart to function properly, a constant replenishment of oxygen is needed, since the coronary circulation has limited oxygen reserve and extracts 60 to 75% of what is delivered.38 Cardiac dysfunction in the ICU population is one of the primary predictors of mortality,53 and in studies3754 of the critically ill, approximately 40% have significant cardiac disease as a comorbidity. Cardiac dysfunction may result from underlying organic heart disease; insufficient DO2 to the coronary circulation, which can be precipitated/exacerbated by anemia, subendocardial ischemia from left ventricular hypertrophy, compromised myocardial contractility from the effects of inflammatory cytokines, inappropriate intravascular fluid status, or a combination of factors.3855
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Strategies for Improving Qt
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During resuscitation maneuvers in shock patients, fluids, vasopressors, vasodilators, and inotropes are administered, often in combination, to augment Qt and overall DO2.56 Patients in respiratory failure supported with mechanical ventilation are frequently hemodynamically unstable, with low BP, tachycardia, and decreased Qt and urinary output.57 Clinical decisions must take into account the benefits vs risks of the type (colloid vs crystalloid) and volume of fluid chosen to increase circulating blood volume and venous return. With regard to fluid choice, the Saline vs Albumin Fluid Evaluation study investigators58 recently published results from a large, randomized study in which mortality and other outcomes were similar in patients administered 4% albumin or 0.9% saline solution, both overall and in the subgroup of patients with acute respiratory failure.
Ventricular end-diastolic pressure, measured indirectly as pulmonary artery occlusion pressure with a pulmonary artery catheter, can provide information about progressive increases in Qt resulting from fluid challenges. However, the benefit of the pulmonary artery catheter is somewhat controversial. Because permeability of the pulmonary capillary endothelium may be increased due to inflammation, the pressure corresponding to edema formation may be more accurately determined by bedside pulmonary capillary pressure measurements than by pulmonary artery occlusion pressure.56 Measurement of arterial pulse pressure or arterial pulse contour analysis has also been suggested as a means to predict which patients will respond favorably to a fluid challenge by increasing Qt.59
The inotropic agents dopamine and dobutamine (primarily ß1-agonists) are frequently employed in patients with respiratory failure when the response to fluid challenge is inadequate.60 Rivers et al61 examined the effects of early goal-directed therapy in patients with severe sepsis and shock, combining sequential protocol-driven (Fig 2
) administration of a crystalloid fluid bolus, vasopressors, and dobutamine with continuous monitoring of central venous pressure (CVP) and central SvO2 to achieve hemodynamic goals, which included a CVP of 8 to 12 mm Hg, mean arterial pressure of 65 to 90 mm Hg, and SvO2 of 70%. Patients randomly assigned to receive early goal-directed therapy for the first 6 h had significantly better outcomes (in-hospital mortality, organ failure, physiologic indicators of DO2) than those who received standard care during this time.61 Although this study61 was conducted in septic shock patients and not specifically in patients with respiratory failure, the marked reduction in mortality achieved with this aggressive approach is noteworthy and may also be relevant in the setting of respiratory failure.
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Critical Do2 Thresholds and Do2 Requirements
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In critically ill patients with and without sepsis in whom independent measurements of DO2 and O2 were made, Ronco and colleagues62 reported that the critical DO2 was approximately 4 mL of oxygen per kilogram per minute, noting that this was much lower than any values previously derived using nonindependent variables for anesthetized or critically ill patients. Although initially encouraging, prospective studies63 that have evaluated increasing DO2 have failed to consistently demonstrate benefit. In one study by Gattinoni and colleagues,63 achievement of supranormal hemodynamic values and patterns of increased oxygen transport in medical patients with ARDS produced no difference in mortality when compared to patients in whom normal DO2 was achieved. Several meta-analyses have confirmed this disappointing finding. The important findings of Rivers et al61 in septic patients suggest that the failure of these early trials may have been due to the timing of therapy. Most of the early studies did not increase DO2 until > 24 h after hospital admission.
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Conclusions
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Further study is needed to determine the optimal oxygenation requirements in respiratory failure, as well as to improve our understanding of the pathologies underlying oxygen deficits. More efficient and safer ways to deliver oxygen to tissues through manipulations of Qt and hemoglobin parameters are also needed. Although a source of hemoglobin, RBC transfusions may not be effective in improving oxygenation or outcomes in critically ill patients with respiratory failure. Further studies are needed to evaluate the appropriate levels of DO2 during respiratory failure and the best methods for restoring adequate tissue perfusion.
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Footnotes
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Abbreviations: CaO2 = arterial oxygen content; CVP = central venous pressure; DO2 = oxygen delivery; FIO2 = fraction of inspired oxygen; NO = nitric oxide; PEEP = positive end-expiratory pressure; PIO2 = inspired PO2; Qt = cardiac output; SaO2 = arterial oxygen saturation; SvO2 = venous oxygen saturation; O2 = oxygen consumption; / = ventilation/perfusion
Learning Objectives: 1. To review important considerations for managing patients in respiratory failure, ie, oxygenation, hemoglobin, and cardiac output. 2. To discuss several strategies for each aspect of care, with attention to controversies and/or new trends in treatment of respiratory failure.
Dr. Levy has disclosed financial relationships with a commercial party. Grant information and company names appear as provided by the author. Grant monies (from industry-related sources): Involved in EPO II trial, as principal investigator at Rhode Island
This publication was supported by an educational grant from Ortho Biotech Products, L.P.
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Abstract
Introduction
