Oxygen Delivery

Metabolizing tissues require an adequate supply of oxygen to efficiently produce the energy needed for cellular function. The quantity of oxygen loaded onto the arterial bloodstream per unit time (O₂ delivery) is the product of the cardiac output and the oxygen contained within each milliliter of blood. Therefore, a deficiency of either cofactor can be partially offset by a compensatory increase of the other. Conversely, sluggish blood flow, whether caused by low cardiac output or high resistance through the tissues, can limit the O₂ actually delivered to the cell. Increased blood viscosity impedes the transit of erythrocytes through the capillary bed, tending to limit oxygen consumption (VO₂).³ For this reason, paraproteinemia, extreme leukocytosis, and polycythemia can pose life-threatening challenges to O₂ consumption that are independent of any impact on cardiac output.³ Studies performed in animal models demonstrate that hematocrit (Hct), a primary determinant of viscosity, bears a nonlinear relationship to oxygen delivery that varies somewhat with circulating blood volume.⁴ At low values of Hct, a rising Hb concentration predictably adds to O₂ content and delivery. Above a Hct of 30% to 34%, however, it is difficult to demonstrate in critically ill patients an increase in oxygen consumption or an outcome benefit that derive from increases of O₂ content arising from further increments of Hb.⁵ At an Hct of around 55% to 57%, O₂ delivery reaches its maximum in normal subjects, falling sharply with each further rise in Hct (Figure 44-1). Above an Hct of approximately 65%, phlebotomy may be required to avert a hemodynamic crisis, as vital tissues may be deprived of delivered oxygen. Viscosity, and therefore tolerance for higher Hct, is partially determined by the circulating blood volume; the polycythemia associated with intravascular volume contraction is much less well tolerated than that of polycythemia vera, a condition in which circulating blood volume is expanded.³ As might be expected, patients with vascular disease are less tolerant to the adverse rheologic effects of high Hct.

Figure 44-1 Effect of hematocrit on viscosity and oxygen delivery.

Raising hematocrit simultaneously increases oxygen content and viscosity, which adversely affects blood rheology. Consequently, oxygen delivery reaches a maximum at hematocrit values in the upper midrange.

At the mitochondrial level, oxygen acts as the terminal acceptor in a chain of organic electron donors known as cytochromes. The PO₂ within the mitochondrion needed to sustain this process is very low—estimated to be much less than 1 mm Hg.⁶ To provide that needed level of mitochondrial oxygen tension, an appropriate oxygen diffusion gradient must be established from the arterial blood, across tissue and cellular boundaries, and into the cellular organelles. At sea level, normal levels of mitochondrial O₂ are achieved at a PaO₂ of about 95 mm Hg. The actual PO₂ within the mitochondrion, however, is affected by many factors other than arterial PO₂: tissue metabolic rate, microvascular control, tissue properties, and blood flow. Over time, varying degrees of accommodation to subnormal PaO₂ occur by adjustments of the cardiovascular system, Hb concentration, capillary system, and mitochondrial density.⁷ Although this adaptive phenomenon is commonly observed in patients with chronic lung diseases, the extent to which gradual accommodation to hypoxemia can occur and should be encouraged in patients who are critically ill is a provocative and largely unexplored question.

Oxygen Transfer Across the Lung

Oxygen is driven from the airspace to the pulmonary capillary by a diffusion gradient determined by the PO₂ difference between them and the resistance to diffusion presented by the intervening tissues and fluids. To keep the alveolar O₂ tension adequate, the oxygen supplied to the alveolus must be replaced at a rate equal to or greater than that at which the oxygen is removed by the passing capillary blood. Classically, six mechanisms can account for hypoxemia:

Low FIO₂ is an important mechanism of hypoxemia occurring at altitude and in fires that occur in confined spaces. Although the relationship is not a strictly linear function, as a rough estimate, inspired O₂ declines approximately 15 mm Hg for each 1000 meters of altitude above sea level.⁸ For practical purposes, however, a reduced concentration of inspired oxygen does not account for hypoxemia that occurs in the setting of critical illness. Hypoventilation alters the alveolar oxygen tension (PAO₂) in proportion to the rise of PaCO₂ (and PACO₂) and becomes an important factor when it occurs during breathing of room air (as in narcotic overdose) or of relatively low inspired concentrations of supplemental oxygen (e.g., via nasal cannulae). The importance of impaired diffusion as a hypoxemic mechanism is sometimes debated, since the transfer of O₂ from alveolus to Hb usually requires only a brief time for completion—somewhat less than the normal transit time of the erythrocyte through the capillary.⁹ Yet under many conditions that are commonly encountered, fewer capillaries are available to accept the cardiac output, so the rate at which blood flows through the lung is accelerated. Simultaneously, diffusion distances are lengthened, and the driving gradient is reduced by disease. For this reason, impaired diffusion is likely to contribute to hypoxemia occurring in the stressed patient with critical illness who receives near-normal FIO₂.

Not only is ventilation perfusion (V/Q) imbalance the most common contributor to clinical hypoxemia but it is also the mechanism least well understood among practitioners. It is the relative distribution of ventilation and perfusion that is critical to effective oxygenation. Ventilation must take place where perfusion does, or else the same levels of each that normally allow oxygenation and alveolar ventilation may produce both hypoxemia and wasted ventilation (ventilatory dead space). With respect to impaired oxygenation, this concept is perhaps best understood by considering the fall in alveolar oxygen tension that occurs as a result of regional alveolar hypoventilation. Owing to the sigmoidal shape of the oxyhemoglobin dissociation curve, excess ventilation of normal alveoli cannot fully compensate for regional desaturation elsewhere, so the net PaO₂ declines after blood from these two types of unit admix in the pulmonary veins. Like hypoxemia due to low FIO₂, hypoventilation, and diffusion impairment, hypoxemia resulting from V/Q imbalance responds to supplementation of inspired oxygen. Poor ventilation of a given lung unit can be compensated by raising the O₂ concentration of the inspired gas it receives.

Whereas the relationship of FIO₂ to PaO₂ is more or less linear for the first three oxygen-responsive mechanisms already covered, the response to oxygen supplementation for V/Q imbalance depends on the distribution of abnormal V/Q units contributing to the problem.¹⁰ Hypoxemia due to a relatively small number of lung units with very low V/Q characteristics may not respond noticeably to supplemental oxygen unless a very high FIO₂ is employed. Conversely, a lung comprised predominantly of lung units with mild V/Q impairment tends to respond in more linear fashion (Figure 44-2). It is also possible to convert very poorly ventilated lung units into airless, unventilated units with inspired gas having a very high FIO₂, owing to replacement of unabsorbable nitrogen with diffusible oxygen, leading to the unit’s contraction and eventual collapse as this process continues below the closing volume of the compromised region (absorption atelectasis).¹¹ Unless compensation by hypoxic vasoconstriction is complete, raising FIO₂ can paradoxically increase shunt even as it improves O₂ transfer in units that remain patent.

Figure 44-2 Influence of severity of ventilation/perfusion inequality on the FIO₂/arterial PO₂ relationship.

Arterial PO₂ rises linearly in normal and mildly affected lungs, whereas very high inspired oxygen fractions may be necessary to raise arterial PO₂ when the V/Q abnormality is severe.

Given the importance of matching blood flow to ventilation, it is not surprising that several mechanisms have developed to effect pulmonary microvascular regulation. Autonomic control, although less prominent and less precise than in the peripheral vasculature, is important nonetheless. Severe head injury, for example, can cause dysregulation and hypoxemia via this mechanism.¹² Local acidosis, such as that existing in poorly ventilated areas, tends to vasoconstrict the pulmonary arterial microvessels. The strength of this reflex, however, pales before that of hypoxic pulmonary vasoconstriction, which for most individuals is a well-developed protection against the consequences of perfusing underventilated areas.¹³ These mechanisms may be overpowered by pathologic processes or by pharmacologic interventions. For example, local release of inflammatory mediators or use of certain vasoactive drugs (e.g., nitroprusside) may counter these protective reflexes,¹⁴ and an abrupt rise of pulmonary artery pressure may overwhelm them.

Shunting occurs when systemic venous blood is not brought into close proximity with the inspired gas. Shunt can originate in the heart (e.g., through a patent communication at the atrial or ventricular level). Rarely, direct venous-to-arterial transfer occurs through micro- or macrovascular defects known as pulmonary arteriovenous fistulae. Such communications are encountered in relatively common diseases such as hepatic cirrhosis as well as in other settings, exemplified by the heritable Osler-Weber-Rendu abnormality. Diseases that affect the lung parenchyma are much more common causes of shunt than these cardiovascular disorders. Filling of the airspaces with fluid (e.g., edema) or cellular infiltrate (e.g., pneumonia) prevents effective gas-blood interchange. Inflammatory conditions may inhibit hypoxic vasoconstriction, worsening arterial hypoxemia, as does hypocapnic alkalosis.¹⁵ Collapse of lung units may occur on any anatomic scale, resulting in shunt through the affected regions. Causes for collapse vary from compression (e.g., by a pleural effusion), to disease-induced surfactant depletion or inactivation, to airway plugging, such as by retained secretions or a misplaced endotracheal tube. Sustained reversal of atelectasis requires attention to the inciting cause as well as recruitment of the problem area by deep lung expansion. Pure oxygen breathing will not improve hypoxemia due to shunting. Conversely, reduction of FIO₂ will not cause shunt-related hypoxemia to worsen and may spare ventilated areas the exposure to potentially toxic concentrations of inspired O₂ (Figure 44-3).

Figure 44-3 Effect of shunt percentage on arterial PO₂ for a range of FIO_2.

When shunt percentage exceeds 35% to 40%, variations of FIO₂ only modestly affect arterial PO₂. Moreover, because the risk of oxygen toxicity rises hyperbolically with inspired oxygen concentration, reductions of FIO₂ from 1.0 to 0.8 may yield benefit with only marginal impact on arterial oxygenation.

In the clinical setting, shunting due to collapse of unstable alveolar units can be addressed by increasing transpulmonary pressure after they are reopened. Raising mean alveolar pressure by elevating end-expiratory airway pressure (positive end-expiratory pressure [PEEP]), extending the inspiratory time fraction or changing body position can be effective once the collapsible alveoli are reopened (recruited) to become part of the communicating airspace. Available evidence does not clearly indicate the best method to select PEEP in patients with hypoxemic respiratory failure. If recruitment potential is low, an increase in PEEP will have marginal effects on shunt and arterial oxygen tension. Simultaneously, higher PEEP may contribute to overdistention of open alveoli, increasing the risk of ventilator-induced lung injury (VILI) and dead-space formation as pulmonary blood flow is redirected to less well-ventilated regions. PEEP may adversely affect arterial oxygen tension in the presence of unilateral or asymmetric lung disease or when PEEP impairs venous return, limits oxygen delivery, and obligates oxygen extraction.

While the benefit of PEEP in patients with refractory hypoxemia depends on the potential for alveolar recruitment, not providing PEEP to a recumbent patient is usually inappropriate because of the associated positional loss of resting lung volume. In the early stage of hypoxemic respiratory failure, a PEEP setting of 8 to 15 cm H₂O is suitable for most patients. Higher levels of PEEP should be used when a greater potential for recruitment can be demonstrated to be effective in improving oxygen delivery and/or compliance of the respiratory system; however, PEEP above 24 cm H₂O is seldom required.

Modification of body position may dramatically affect shunting and blood oxygenation when the lungs are injured, especially when disease is asymmetrically distributed. Prone positioning routinely improves oxygen exchange by altering the distribution of transpulmonary pressure as it modifies chest wall compliance and allows the heart to sink to a dependent position that does not compress the lungs. The dorsal lung zones, which are generally the best perfused, tend to reopen when prone. Drainage of secretions and lymphatic efficiency may also improve (Figure 44-4).

Figure 44-4 Lung volumes in various body positions.

Compression by the abdominal viscera compresses the dependent (dorsal) lung in the supine position, decreasing the functional residual capacity (FRC). Changing body position modifies both chest wall compliance and resting lung volume. RV, residual volume; TLC, total lung capacity.

With healthy lungs, variations in mixed venous oxygen content do not influence PaO₂ perceptibly; recharging of desaturated Hb with oxygen takes place at the alveolar-capillary junction, even during exercise. In the presence of shunt or very low V/Q units, however, the influence of mixed venous oxygen content may be profound because of its admixture with well-oxygenated pulmonary venous blood. Because mixed venous O₂ content is influenced primarily by the ratio of oxygen consumption to oxygen delivery, hypoxemia may be at least partially alleviated by reducing O₂ demand or improving O₂ delivery. The equation relating these variables, which is derived by rearrangement of the Fick equation for oxygen, is:

On-line measurements of with a fiberoptic Swan-Ganz catheter enable venous desaturation to be detected and monitored.

Venous oxygen saturation is a clinical tool to evaluate the relationship between oxygen uptake and delivery for the whole body. In the absence of pulmonary artery catheter–derived mixed venous oxygen saturation (), the central venous oxygen saturation (ScvO₂) is increasingly being used as an imprecise but convenient surrogate measure. Central venous catheters are simpler to insert, less expensive, and associated with fewer complications than pulmonary artery catheters. Blood sampling through central venous catheters allows measurement of ScvO₂ or even continuous monitoring if a fiberoptic oximetric catheter is used. The normal range for is 68% to 77%, and ScvO₂ is considered to be approximately 5% above these values.^16,17

A decrease in Hb is associated with a decrease in oxygen delivery when cardiac output remains unchanged, since oxygen delivery is the product of cardiac output and arterial oxygen content. A decrease in Hb is one of four determinants responsible for a decrease in (or ScvO₂). Anemia can act alone or in combination with hypoxemia, increased oxygen consumption, or reduced cardiac output. When oxygen delivery decreases, oxygen consumption is maintained (at least initially) by an increase in oxygen extraction (O₂ER). O₂ER and are linked by a simple equation:

In human studies, dysoxia is usually present when falls below 45%. Tissue oxygen privation may occur at higher levels of when oxygen extraction is impaired. Ideally, efforts to boost cardiac output (by intravenous fluids or inotropes), Hb, and/or arterial oxygen saturation return to levels above 65% (or ScvO₂ to ≥70%).^16,18