Oxygen transport

Energy generation in the cell

The process of glucose breakdown to CO ₂ , water, and energy comprises the metabolic backbone of the energy production of the cell, although other molecules such as amino acids and fatty acids can also enter at different steps of this process.

Glycolysis (the first step in the process of glucose metabolism) requires the division of glucose into two molecules of pyruvate. This first step occurs universally in the cytoplasm of all mammalian cells, yielding two molecules of ATP. This constitutes only 5.2% of the total potential energy that can be released from glucose.

With insufficient oxygen to support oxidative metabolism, pyruvate is metabolized by lactic dehydrogenase to lactate. Under anaerobic conditions, such as those that occur with intense physical activity or during shock states that can accompany heart failure or bleeding, lactate rapidly accumulates in the circulation. The delivery of this lactic acid to the liver, where it is converted back to glucose, is known as the Cori cycle. Lactate concentration in blood of less than 2 mmol/L is considered normal. Increased lactate production and accumulation in plasma may reflect increased anaerobic metabolism and a state of shock. Lactate levels, rate of rise in lactate, and lactate clearance have all been identified as reliable prognostic indicators in both adults and children. Lactate clearance, defined as a decrease in lactate level after treatment/resuscitation indicative of adequate tissue perfusion, has been utilized as an endpoint of resuscitation in shock. Lactate half-life is approximately 20 minutes; therefore, a persistently high level of lactate reflects continuous production and/or lack of elimination. In most circumstances, successful treatment of shock should be followed by normalization of lactate in plasma. Importantly, lactate clearance can be confounded by causes other than persistent hypoperfusion, including hepatic dysfunction, sepsis, and malignancy.

In the presence of oxygen, pyruvate is oxidized to and ultimately metabolized to CO ₂ and water. This aerobic phase of glucose metabolism is termed respiration and occurs entirely within the mitochondria. The generation of energy from pyruvate involves three stages. The first stage generates acetyl-coenzyme A (acetyl CoA), an irreversible process. In the second stage, acetyl-CoA is metabolized in an eight-step process (the citric acid cycle) through enzymatic oxidation generating CO ₂ and energy that is conserved in NADH and FADH ₂ . In the final stage (the electron transfer chain), NADH and FADH ₂ are oxidized through an electron-carrying process that uses oxygen as the final electron acceptor.

In the aerobic portion of glucose metabolism, 36 molecules of ATP are generated per each molecule of glucose. Thus, cellular respiration yields 18 times more energy than anaerobic glycolysis. Most of the cells in our body are dependent on cellular respiration for the generation of energy and ultimate survival. Organic molecules that generate pyruvate are not limited to glucose since other molecules, such as certain amino acids and fatty acids, can be utilized. It is therefore oxygen, not pyruvate, which becomes the rate-limiting step in the generation of energy.

Pathologic states that involve abnormal mitochondrial utilization of oxygen are observed in various clinical processes. For example, cyanide poisoning impairs oxidative phosphorylation, primarily through the inhibition of the mitochondrial enzyme cytochrome a ₃ oxidase; this results in the rapid development of a severe energy deficit, accumulation of lactate, and death. More commonly, states of septic shock are thought to cause “mitochondrial disease” that renders these organelles incapable of efficiently utilizing oxygen for the generation of energy.

Microcirculation and oxygen delivery

The diffusion of oxygen into the cell is limited by the distance between the cell itself and the circulating source of oxygen, which typically is approximately 100 to 200 μm. A highly complex capillary network (microcirculation) distributes the oxygen to cells and tissues. The surface area in the microcirculation far exceeds the circulating blood volume. Thus, a hypovolemic state would occur if all capillary beds were open at any given time. To avoid this, blood flow is selectively distributed to various vascular beds as needed to meet their oxygen demands.

A breakdown in the regulation of oxygen distribution (dysoxia) across the microcirculation occurs in septic shock; thus, septic shock is a form of distributive shock. Nitric oxide, a potent vasodilator, is thought to play a central role in sepsis dysoxia and has been proposed as a potential treatment target. Both oxygen diffusion and tissue extraction contribute to sepsis dysoxia. Tissue edema increases the distance between the cells and the capillaries, which contributes to poor oxygen diffusion. Maldistribution of capillary flow is also a major component of sepsis, which limits oxygen extraction.

Hemoglobin, the ultimate oxygen carrier

Oxygen is carried in the blood in two forms: dissolved (2%) and bound to hemoglobin (Hb) (98%). Hemoglobin serves as a unique oxygen carrier by capturing oxygen in the capillaries abutting the alveoli of the lung, distributing it through the microcirculation, and ultimately releasing it in the pericellular environment. Adult human Hb consists of two α and two β polypeptide chains, each bound to a heme group capable of binding one molecule of O ₂ . Each gram of hemoglobin binds 1.34 mL of O ₂ . Since Hb concentration is easily measured, the content of O ₂ carried per 100 mL of blood can be calculated as follows:

1.34(mL/g) × Hb (g/dL) × O ₂ saturation (SaO ₂ , fraction of 1) = Hb oxygen content/100 mL

Example:

1.34 × 15 × 0.98 = 19.7 mL/100 mL

The degree of oxygen saturation in Hb through spectrophotometric absorption of light (pulse oximeter) is a widely used tool in intensive care. Hemoglobin saturation is highly nonlinear, roughly following a sigmoidal S curve ( Fig. 1 ), allowing Hb to easily bind or release O ₂ under physiologic conditions. Minor drops in SaO ₂ at saturations of less than 90% reflect greater change in partial pressures of O ₂ (PO ₂ ) compared with drops at a lower SaO ₂ as the curve is linear beneath this upper asymptotic limit; 90% SaO ₂ reflects a PaO ₂ of approximately 60 mm Hg. Pathologic alterations of the Hb-oxygen dissociation curve are observed with alterations in pH, temperature, and concentration of 2-3 diphosphoglycerate (2-3 DPG).

A small percentage of O ₂ is also dissolved in and transported by the plasma and is a function of the PO ₂ . This concentration is approximately

0.003 mL/100 mL (of plasma)/(PO ₂ ) mm Hg

Thus, the total amount of O ₂ contained in a given amount of blood, “arterial oxygen content” (CaO ₂ ), is calculated as:

(1.34 [Hb] × SaO ₂ ) × 0.003 (PO ₂ ) = CaO ₂

Based on this formula, one might predict that increasing levels of serum hemoglobin through blood transfusion will increase CaO ₂ and therefore oxygen delivery, which will improve outcomes. However, attempts to achieve normal levels of serum Hb in critically ill patients are not uniformly beneficial and may in fact be harmful. The landmark Transfusion Requirements in Critical Care trial by Hebert et al showed increased mortality in patients who were treated with a liberal transfusion strategy (transfused when Hb falls below 10.0 g/dL) versus those with a restrictive transfusion therapy (Hb maintained at 7.0–9.0 g/dL). In a subsequent meta-analysis of 31 trials, there was no benefit to a liberal transfusion strategy in terms of mortality, morbidity, or myocardial infarction. Importantly, these trials did not directly measure oxygen consumption or delivery. In other cohorts, however, data suggest that while red blood cell transfusion in septic patients may increase oxygen delivery, higher Hb does not correspond to an increase in oxygen consumption.