Oxygen Transport and Delivery

Acknowledgment

This chapter is based on a previous contribution by Maria Delivoria-Papadopoulos and Jane E. McGowan.

Introduction

Because aerobic metabolism is critically dependent on a consistent and adequate supply of oxygen, oxygen is an essential fuel source for normal cellular metabolic function. Hence, control of oxygen uptake, transport, and release are essential functions. Although molecular oxygen participates in numerous oxidative reactions necessary for cellular metabolism (e.g., production of prostaglandins mediated by cyclooxygenase), its primary role is as the final electron acceptor in the mitochondrial respiratory chain—the process by which energy produced by the citric acid cycle is stored in high-energy phosphate bonds as adenosine triphosphate. Oxygen transport depends on many interrelated factors, including the fractional concentration or partial pressure of oxygen in inspired air, the adequacy of alveolar ventilation, the relation of ventilation to perfusion within the lungs, arterial blood pH and temperature, cardiac output, blood volume, hemoglobin concentration, and the affinity of hemoglobin for oxygen. The ability of this complex system to respond varies according to metabolic needs and maturation, and it may be confounded by coexisting disease processes, yet humans in good health have a reasonable reserve capacity and can respond rapidly to changes in oxygen needs. Birth and the immediate postnatal period represent situations that make special demands upon the oxygen transport system. In this chapter, we review the principal determinants of oxygen transport, with emphasis on the modulator role of the cardiovascular system.

Oxygen Delivery: Overview of Biologic Contributors

Oxygen delivery ( DO ₂ ), defined as the quantity of oxygen entering a tissue, organ, or the entire body in arterial blood each minute, is the product of the concentration (or content) of oxygen in arterial blood ( C _a O ₂ ) and the rate of blood flow to the region of interest. For the whole body, oxygen delivery is determined by the equation:

D O_{2} = C_{a} O_{2} \times C O ̙ 100

$D O_{2} = C_{a} O_{2} \times C O ̙ 100$

where C _a O ₂ is the oxygen content of arterial blood (in mL/dL) and CO is the cardiac output (in L/min); the 100 is a unit reconciliation factor (100 mL/L). The oxygen content of arterial blood includes both oxygen carried by hemoglobin and oxygen in solution. Oxygen delivery therefore is determined by function of the lungs, heart, and hemoglobin.

This term may be somewhat of a misnomer, since not all the oxygen “delivered” to tissues in arterial blood remains there. It is important to distinguish DO ₂ as so defined from oxygen uptake or utilization ( $\dot{V} O_{2}$ $\dot{V} O_{2}$ ), which for the entire body is:

\dot{V} O_{2} (C_{a} O_{2} - C_{\bar{v}} O_{2}) \times C O ̙ 100

$\dot{V} O_{2} (C_{a} O_{2} - C_{\bar{v}} O_{2}) \times C O ̙ 100$

where $C_{\bar{v}} O_{2}$ $C_{\bar{v}} O_{2}$ is the oxygen content of mixed venous blood. At the tissue or organ level, oxygen utilization is often expressed in terms of fractional tissue oxygen extraction (FTOE, often referred to simply as oxygen extraction):

F T O E = (C_{a} O_{2} - C_{\bar{v}} O_{2}) / C_{a} O_{2}

$F T O E = (C_{a} O_{2} - C_{\bar{v}} O_{2}) / C_{a} O_{2}$

Cardiopulmonary Factors

Under basal conditions, the lungs of a newborn infant load approximately 6 to 8 mL/kg/min onto hemoglobin (compared to 3 to 4 mL/kg/min typically for adults). This can be increased up to 15-fold in response to input from the carotid and aortic bodies (which sense arterial oxygen content) and brain stem chemoreceptors. The effectiveness of oxygen uptake from the lungs may be compromised by parenchymal lung disease, pulmonary vasoconstriction, or diseases leading to ventilation-perfusion mismatch. Arterial blood flow transports oxygen from the pulmonary capillaries to systemic tissues. The oxygen content of the arterial blood usually is high enough to readily meet cellular oxygen demands. When the oxygen content is decreased, however, local perfusion or hemoglobin oxygen affinity may change to compensate for the lower oxygen content.

The cardiovascular system regulates oxygen supply through variation in cardiac output and distribution of blood flow. Alterations in the metabolic rate of peripheral tissues activate local regulatory mechanisms that modulate arterial blood flow and venous return and, consequently, cardiac output. Accordingly, different controls exist in different tissues. Coronary blood flow, for example, reflects the metabolic activity of heart muscle; because the oxygen extraction of cardiac muscle is normally high, changes in cardiac work must be matched closely by concomitant changes in coronary blood flow. In moderate or severe hypoxic-ischemic brain injury, cerebral oxygen extraction may be markedly reduced because of decreased oxygen utilization by injured brain cells. When oxygen supply is limited, flow is reduced to tissues with low oxygen extraction (such as kidney and gut) in favor of tissues with high extraction (such as heart and brain). The high flow–low extraction areas of the circulation constitute an oxygen reserve capacity that may be deployed in times of oxygen deprivation. By contrast, total cardiac output does not appear to be directly responsive to moderate changes in either arterial partial pressure of oxygen or blood oxygen content (presumably because other mechanisms provide an adequate adjustment) and is virtually unaffected by increased arterial partial pressure of carbon dioxide up to 50 mm Hg. Blood viscosity and volume are additional determinants of cardiac output.

Hemoglobin

Hemoglobin concentration is regulated by a renal sensing mechanism that operates to maintain a balance between oxygen supply and oxygen requirement of renal tissues. A decrease in concentration or arterial oxygen saturation of hemoglobin or any increase in hemoglobin affinity for oxygen causes increased erythropoietin production through increased expression of hypoxia-inducible factor. The effect of erythropoietin on bone marrow is usually limited by available iron, so red blood cell production can only be stimulated to approximately double its basal value of 1% of the total red blood cell mass per day. Consequently, red blood cell mass increases slowly in response to hypoxia. Because it increases blood viscosity, a higher hemoglobin concentration at the same total blood volume reduces blood flow, offsetting the increase in oxygen delivery. Normal cardiac output is reestablished by a proportionate increase in plasma volume (i.e., by an increase in total blood volume). The affinity of hemoglobin for oxygen, in association with blood flow distribution, translates blood flow into oxygen availability. This characteristic of hemoglobin is classically depicted in the oxyhemoglobin dissociation curve (oxygen equilibrium curve). Because of its remarkable ability to combine reversibly with large quantities of oxygen, hemoglobin increases the oxygen transport capacity of blood approximately 70-fold over that of oxygen transported dissolved in plasma.

Cellular Factors

Diffusion of oxygen from capillaries to mitochondria within cells, the last step in oxygen transport, depends on several factors, including the oxygen pressure gradient between the capillary and the cell, the distance between the closest perfusing capillary and the cell, and impedance to diffusion within the tissue. The pressure gradient, which directly affects mitochondrial oxygen uptake, varies with regional oxygen delivery, tissue oxygen consumption, and the hemoglobin-oxygen affinity. In vitro, mitochondrial function remains at maximal levels at oxygen partial pressures ( P o ₂ ) as low as 0.5 mm Hg. In vivo, however, it is likely that mitochondrial respiration is compromised at oxygen tensions below a higher “critical” P o ₂ .

Determinants of Cardiac Output

Fetal and Transitional Cardiovascular Physiology

The integrity of oxygen transport in the newborn period is dependent on adequacy of the cardiac output, which must be maintained through the transition from fetal to neonatal life. Therefore, a thorough understanding of the fetal, transitional, and neonatal circulations is essential. Similarly, an understanding of the terms used when one is defining the components determining cardiac output is necessary. Cardiac output is determined by heart rate (chronotropy), preload (amount of blood present in the ventricle at the end of diastole, which is dependent on hydration status, pulmonary and systemic venous return, and diastolic compliance of the ventricle [lusitropy]), myocardial performance (the intrinsic ability of the myocardium to contract [inotropy]), and afterload (force generation necessary to overcome the resistance against which the ventricle muscle must contract, which depends on vascular resistance and compliance, blood viscosity, ventricular muscle wall thickness, and ventricular outflow tract obstructions). Intrauterine, transitional, and postnatal changes in each of these determinants of cardiac output have significant impacts on oxygen delivery before, during, and after birth.

Characteristics of Fetal and Early Neonatal Myocardium

Adult myocardium is more efficient at contraction than its neonatal and fetal counterparts. In adults, surface L-type calcium channels allow a small amount of extracellular calcium to enter the myocytes after depolarization. These in turn lead to further intracellular calcium release from intrinsic stores called the sarcoplasmic reticulum, leading to effective myofibril shortening and muscle contraction. The process is facilitated by the proximity of the sarcoplasmic reticulum to the L-type calcium channels and the presence of transverse tubules. Conversely, the immature fetal heart muscle relies on L-type calcium channels as a source of calcium to facilitate contraction, because of the lack of transverse tubules and the physical separation of the sarcoplasmic reticulum from the L-type calcium channels. Furthermore, the immature myocytes have a higher surface area–to–volume ratio to compensate for the lack of the T-tubule system necessary for effective calcium entry into the cell. The arrangement of the myofibrils within the myocardium is also less organized during fetal life, with only 30% consisting of contractile tissue, compared with 60% in the adult myocardium. The ability of the fetal myocardium to relax (accommodate preload) is compromised with less compliant elastic tissue present. These developmental differences drastically reduce the functional reserve of the fetal heart in the face of postnatal stresses. In the early neonatal period, failure of a normal postnatal transition may place the infant in a vulnerable hemodynamic situation, which may lead to compromised cardiac output and tissue oxygenation. This problem may be further compounded by any potential stressors, such as hypoxia, anemia, asphyxia, and mechanical ventilation, all of which can alter cardiac loading conditions and affect contractility.

Fetal Physiology of the Cardiovascular System

Fetal cardiac output rises from 50 mL/min at 18 weeks’ gestation to 1200 mL/min at term, reflecting the growing demand placed on the myocardium to supply vital organs in the developing fetus. In utero, the left ventricle (LV) is subject to low afterload owing to sustained exposure to a low-resistance circuit that includes the highly compliant placental circulation; therefore, the LV, in particular, is subjected to less wall stress during the fetal period. This low-pressure system is suitable for the immature myocardium to ensure effective transplacental perfusion but also makes it vulnerable in the face of additional stresses. The major source of preload to the LV during fetal life is derived from the placenta through the umbilical circulation. Oxygenated blood returning from the placenta into the right atrium is directed through the foramen ovale into the left atrium, thus determining LV preload and LV output (LVO). Because of the low afterload to which the LV is subjected by the systemic circulation, most of the LVO, constituted of oxygenated blood, is directed to vital organs such as the brain. The right ventricle (RV) receives most of the blood draining from the superior vena cava, and a proportionately lower amount of oxygenated blood from the umbilical venous system. Ninety percent of the RV output flows from the pulmonary artery to the descending aorta across the ductus arteriosus (DA). This is a consequence of the high pulmonary vascular resistance (PVR) during fetal life. Pulmonary venous return into the left atrium is low, and as mentioned above, LV preload depends primarily on umbilical venous supply through the foramen ovale. Because the DA diverts the RV output to the low resistance systemic and placental circulation, the RV also is subjected to a low afterload in utero.

Transitional Circulation After Birth

The cardiovascular system undergoes significant changes after birth. Important changes in both preload and afterload occur in quick succession after the loss of the uteroplacental circulation and the onset of reliance on the lungs as the organ of gas exchange. After birth, the loss of the low-resistance circulation of the placenta results in a sudden increase in systemic vascular resistance (SVR). This in turn leads to an increase in LV afterload. Another important transition faced by the neonate after birth is enhanced aeration of the lungs, the fall in PVR, and the increase in pulmonary blood flow, with commencement of gas exchange. During fetal life, the lungs are fluid filled. This liquid is necessary for fetal lung development. After birth a combination of mechanisms, including pressure gradients generated during inspiration and through sodium exchange channels, result in lung fluid clearance and enhanced lung compliance. The subsequent fall in PVR is promoted by increased alveolar oxygen content and lung recruitment. However, recent data demonstrate that oxygen is not the only contributor to the increase in pulmonary blood flow. Other active substances such as prostaglandins, bradykinins, and histamine may play a role in inducing pulmonary vasodilation after birth. This is supported by rabbit experimental models, where an increase in pulmonary blood flow independent of lung aeration was noted in nonventilated lungs. The fall in PVR results in preferential flow of RV output through the pulmonary vascular bed, and not through the DA. The changes described above lead to a change in the circulation from a circuit in series to one in parallel. LV preload now becomes solely dependent on pulmonary venous return. Adequate LV preload is essential to maintain the necessary LVO in the face of increasing LV afterload. Therefore, the changes occurring in the lungs are essential for maintaining postnatal life. RV preload is now dependent on adequate systemic venous return from the upper and lower body. The fall in PVR occurring soon after birth ensures that the RV continues to be exposed to low afterload. Recent data shows a relative difference between the RV and LV performance immediately after birth. The RV improved in both systolic and diastolic function, whereas the LV showed no change in systolic performance and a small improvement in diastolic performance during the transitional period. The authors demonstrated an increase in RVO and no change in LVO during the first day after birth.

Regulation of Vascular Tone During Transition

The sudden increase in SVR immediately after birth can compromise organ blood flow by reducing cardiac output. After the transitional period, vascular tone is regulated by a balance between vasoconstrictors and vasodilators. Nitric oxide (NO), vasopressin, and prostaglandins all play vital roles. Immaturity of the autonomic nervous system may also have an impact on transitional vascular changes. NO is produced by actions of NO synthase, present in abundance in smooth muscle tissue. NO acts via cyclic guanosine monophosphate on calcium-sensitive potassium channels and myosin light chain phosphatases to cause smooth muscle relaxation. Endotoxins and cytokines, such as tumor necrosis factor (TNF)α and a variety of interleukins, can induce NO synthase synthesis of NO, leading to profound dilatation and a reduced systemic blood flow in the presence of sepsis. In addition, excess NO leads to formation of free oxygen radicals, leading to vascular wall damage. Vasopressin plays an important role in regulating vascular tone during the postnatal period. Vasopressin increases vascular tone via specific vasopressin receptors that increase calcium release from the sarcoplasmic reticulum, up-regulate adrenergic receptors on smooth muscle walls, and reduce NO synthesis. In adults, augmentation of vasopressin levels occurs in the early phase of shock to maintain vascular tone. As the degree of shock and hemodynamic compromise progresses, however, vasopressin stores are depleted and vascular tone is therefore compromised. Vasopressin is a useful adjunctive pressor that spares epinephrine and norepinephrine requirements in patients with shock, but its use is not without risk, particularly when it is combined with sustained moderate to high infusions of norepinephrine. ^, Prostaglandins are eicosanoids derived from cell membrane arachidonic acid by the actions of cyclooxygenases and play an important role in regulation of vascular tone. An imbalance between prostaglandin I ₂ , a potent vasodilator, and thromboxane A ₂ , a vasoconstrictor, is implicated in the early regulation of vascular tone and may have a role in the pathogenesis of hypovolemia associated with shock.

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