Therapeutic Gases: Oxygen, Carbon Dioxide, Nitric Oxide, and Helium

Oxygen is a fundamental requirement for animal existence. Hypoxia is a life-threatening condition in which oxygen delivery is inadequate to meet the metabolic demands of the tissues. Since oxygen delivery is the product of blood flow and oxygen content, hypoxia may result from alterations in tissue perfusion, decreased oxygen tension in the blood, or decreased oxygen carrying capacity. In addition, hypoxia may result from a problem in oxygen transport from the microvasculature to the cells or in utilization within the cell. Irrespective of cause, an inadequate supply of oxygen ultimately results in the cessation of aerobic metabolism and oxidative phosphorylation, depletion of high-energy compounds, cellular dysfunction, and death.

History

Soon after Priestley's discovery of oxygen in 1772 and Lavoisier's elucidation of its role in respiration, oxygen therapy was introduced in England by Beddoes. His publication in 1794, entitled 'Considerations on the Medicinal Use and Production of Factitious Airs,' can be considered the beginning of inhalational therapy. Beddoes, overcome with enthusiasm for his project, treated all kinds of diseases with oxygen, including such diverse conditions as scrofula, leprosy, and paralysis. Such indiscriminate therapeutic applications naturally led to many failures, and Beddoes died a disconsolate man. Beddoes' assistant Sir Humphrey Davy went on to make significant contributions to our knowledge of the anesthetic gas nitrous oxide. It was as a result of pioneer investigations such as those of Haldane, Hill, Barcroft, Krogh, L. J. Henderson, and Y. Henderson that oxygen therapy achieved a sound physiological basis (Sackner, 1974). Although Paul Bert had studied therapeutic aspects of hyperbaric oxygen in 1870 and identified oxygen toxicity (Bert, 1873), the use of oxygen at pressures above 1 atmosphere for therapeutic purposes did not begin until the 1950s (Lambertsen et al., 1953; Boerema et al., 1960).

Normal Oxygenation

Oxygen makes up 21% of air, which at sea level (1 atmosphere, 101 kPa) represents a partial pressure of 21 kPa (158 mmHg). While the fraction (percentage) of oxygen remains constant regardless of atmospheric pressure and altitude, the partial pressure of oxygen (PO ) decreases with lower atmospheric pressure. Since it is this partial pressure that drives the diffusion of oxygen, ascent to elevated altitude reduces the uptake and delivery of oxygen to the tissues. Conversely, increases in atmospheric pressure (hyperbaric therapy, or breathing at depth) increase the PO in inspired air and result in increased gas uptake. As the air is delivered to the distal airways and alveoli, the PO decreases by dilution with carbon dioxide and water vapor and by uptake into the blood. Under ideal conditions, when ventilation and perfusion are uniformly distributed, the alveolar PO will be approximately 14.6 kPa (110 mmHg). The corresponding alveolar partial pressures of water and carbon dioxide are 6.2 kPa (47 mmHg) and 5.3 kPa (40 mmHg), respectively. Under normal conditions, there is complete equilibration of alveolar gas and capillary blood, and the PO in end capillary blood is typically within a fraction of a kPa of that in the alveoli. Under conditions of disease, when the diffusion barrier for gas transport may be increased, or exercise, when high cardiac output reduces capillary transit time, full equilibration may not occur, and the alveolarend capillary PO gradient may be increased.

The PO in arterial blood, however, is further reduced by venous admixture (shunt), the addition of mixed venous blood, which has a PO of approximately 5.3 kPa (40 mmHg). Together, the diffusional barrier, inhomogeneities of ventilation and perfusion, and the shunt fraction are the major causes of the alveolar-to-arterial oxygen gradient, which is normally 1.3 to 1.6 kPa (10 to 12 mmHg) when air is breathed and 4.0 to 6.6 kPa (30 to 50 mmHg) when 100% oxygen is breathed (Clark and Lambertsen, 1971).

Oxygen is delivered to the tissue capillary beds by the circulation and again follows a gradient out of the blood and into cells. Tissue extraction of oxygen typically reduces the PO of venous blood by an additional 7.3 kPa (55 mmHg). The mean tissue PO is much lower than the value in the mixed venous blood because of substantial diffusional barriers and the consumption of oxygen in the tissues. Although the PO at the site of oxygen utilizationthe mitochondriais not known, oxidative phosphorylation can continue at a PO of only a few mm Hg (Robiolio et al., 1989).

In the blood, oxygen is carried primarily in chemical combination with hemoglobin and to a small extent dissolved in solution. The quantity of oxygen combined with hemoglobin depends on the PO , as illustrated by the sigmoid-shaped oxyhemoglobin dissociation curve (Figure 161). Hemoglobin is about 98% saturated with oxygen when air is breathed under normal circumstances, and it binds 1.3 ml of oxygen per gram when fully saturated. The steep slope of this curve with falling PO facilitates unloading of oxygen from hemoglobin at the tissue level and reloading when desaturated, mixed venous blood arrives at the lung. Shifting of the curve to the right with increasing temperature, increasing PCO , and decreasing pH, as is found in metabolically active tissues, lowers the oxygen saturation for the same PO and thus delivers additional oxygen where and when it is most needed. However, the flattening of the curve with higher PO indicates that increasing blood PO by inspiring oxygen-enriched mixtures only minimally can increase the amount of oxygen carried by hemoglobin. Further increases in blood oxygen content can occur only by increasing the amount of oxygen dissolved in plasma. Because of the low solubility of oxygen (0.226 ml/liter per kPa or 0.03ml/liter per mm Hg at 37C), breathing 100% oxygen can increase the amount of oxygen in blood by only 15 ml per liter, less than one third of normal metabolic demands. However, if the inspired PO is increased to 3 atmospheres (304 kPa) in a hyperbaric chamber, the amount of dissolved oxygen is sufficient to meet normal metabolic demands even in the absence of hemoglobin (Table 161).

Oxygen Deprivation

An understanding of the causes and effects of oxygen deficiency is necessary for the rational therapeutic use of the gas. Hypoxia is the term used to denote insufficient oxygenation of the tissues. Hypoxemia generally implies a failure of the respiratory system to oxygenate arterial blood.

Pulmonary Mechanisms of Hypoxemia

Classically there are five causes of hypoxemia: low inspired oxygen fraction (FI_O2), increased diffusion barrier, hypoventilation, ventilation/perfusion ( ) mismatch, and shunt or venous admixture.

Low FI_O2 is a cause of hypoxemia only at high altitude or in the event of equipment failure, such as a gas blender malfunction or a mislabeled compressed-gas tank. An increase in the barrier to diffusion of oxygen within the lung is rarely a cause of hypoxemia in a resting subject, except in end-stage parenchymal lung disease. Both of these problems may be alleviated with administration of supplemental oxygen, the former by definition and the latter by increasing the gradient driving diffusion.

Hypoventilation causes hypoxemia by reducing the alveolar PO in proportion to the build-up of CO₂ in the alveoli. In essence, during hypoventilation there is decreased delivery of oxygen to the alveoli while its removal by the blood remains the same, causing its alveolar concentration to fall. The opposite occurs with carbon dioxide. This is described by the alveolar gas equation: PA_O2= PI_O2(PA_CO2/R), where PA_O2 and PA_CO2 are the alveolar partial pressures of O₂ and CO₂, PI_O2 the partial pressure of O₂ in the inspired gas, and R the respiratory quotient. Under normal conditions, breathing room air at sea level (corrected for the partial pressure of water vapor), the PI_O2 is about 20 kPa (150 mmHg), the PA_CO2 about 5.3 kPa (40 mmHg), R is 0.8, and thus the PA_O2 is normally around 13.3 kPa (100 mmHg). It would require substantial hypoventilation, with the PA_CO2 rising to over 9.3 kPa (70 mmHg), to cause the PA_O2 to fall below 7.8 kPa (60 mmHg). This cause of hypoxemia is readily prevented by administration of even small amounts of supplemental oxygen.

Shunt and mismatch are related causes of hypoxemia, but with an important distinction in their responses to supplemental oxygen. Optimal gas exchange occurs when blood flow () and ventilation () are quantitatively matched. However, regional variations in matching typically exist within the lung, particularly in the presence of lung disease. As ventilation increases relative to blood flow, the alveolar PO (PA_O2) increases; but because of the flat shape of the oxyhemoglobin dissociation curve at high PO (Figure 161), this increased PA_O2 does not contribute much to the oxygen content of the blood. In addition, high ratio lung regions have a relatively reduced blood flow, eventually becoming pure dead space regions at the extremecontributing nothing to the oxygenation of the blood while decreasing the efficiency of CO₂ removal. Conversely, as the ratio falls and perfusion increases relative to ventilation, the PA_O2 of the blood leaving these regions falls relative to regions with better matched ventilation and perfusion. Since the oxyhemoglobin dissociation curve is steep at these lower PO values, the oxygen saturation and content of the pulmonary venous blood falls significantly. At the extreme of low ratios, there is no ventilation to a perfused region and pure shunt results, and the blood leaving the region has the same low PO and high PCO as mixed venous blood.

The deleterious effect of mismatch on arterial oxygenation is thus a direct result of the asymmetry of the oxyhemoglobin dissociation curve. Adding supplemental oxygen will generally make up for the fall in PA_O2 in low units and thus improve arterial oxygenation. However, since there is no ventilation to units with pure shunt, supplemental oxygen will not be effective in reversing the hypoxemia from this cause. Because of the steep oxyhemoglobin dissociation curve at low PO , even moderate amounts of pure shunt will cause significant hypoxemia despite oxygen therapy (Figure 162). For the same reason, factors that decrease mixed venous PO , such as decreased cardiac output or increased oxygen consumption, enhance the effects of mismatch and shunt in causing hypoxemia.

Nonpulmonary Causes of Hypoxia

In addition to failure of the respiratory system to adequately oxygenate the blood, there are a number of other factors that can contribute to hypoxia at the tissue level. These may be divided into categories of oxygen delivery and oxygen utilization. Oxygen delivery decreases globally when cardiac output falls or locally when regional blood flow is compromised, as from a vascular occlusion (stenosis, thrombosis, microvascular occlusion) or increased downstream pressure to flow (compartment syndrome, venous stasis, or venous hypertension). Decreased oxygen-carrying capacity of the blood will likewise decrease oxygen delivery, as occurs with anemia, carbon monoxide poisoning, or hemoglobinopathy. Finally, hypoxia may occur when transport of oxygen from the capillaries to the tissues is decreased (edema) or utilization of the oxygen by the cells impaired (cyanide toxicity).

Multiple causes of hypoxia often coexist. A victim of smoke inhalation may have an airway obstruction as a result of thermal injury and reduced oxygen carrying capacity because of carbon monoxide poisoning and anemia. An organ with a marginal blood supply because of atherosclerosis may be seriously damaged if the PO of its arterial supply is decreased only slightly.

Effects of Hypoxia

Regardless of the cause, hypoxia ultimately results in the cessation of aerobic metabolism, exhaustion of high-energy intracellular stores, cellular dysfunction, and death. The time course of cellular demise depends upon the tissue's relative metabolic requirements, oxygen and energy stores, and anaerobic capacity. Survival times (the time from the onset of circulatory arrest to significant organ dysfunction) range from 1 minute in the cerebral cortex to around 5 minutes in the heart and 10 minutes in the kidneys and liver, with the potential for some degree of recovery if reperfused. Revival times (the duration of hypoxia beyond which recovery is no longer possible) are approximately 4 to 5 times longer. Less severe degrees of hypoxia have progressive physiological effects on different organ systems (Nunn, 1993b).

Respiratory System

Hypoxia stimulates the carotid and aortic baroreceptors to cause increases in both the rate and depth of ventilation. Minute volume almost doubles when normal individuals inspire gas with a PO of 6.6 kPa (50 mm Hg). Dyspnea is not always experienced with simple hypoxia but occurs when the respiratory minute volume approaches half the maximal breathing capacity; this may occur with minimum exertion in patients in whom maximal breathing capacity is reduced by lung disease. In general, little warning precedes the loss of consciousness resulting from hypoxia.

Cardiovascular System

Hypoxia causes reflex activation of the sympathetic nervous system via both autonomic and humoral mechanisms, resulting in tachycardia and increased cardiac output. Peripheral vascular resistance, however, decreases primarily via local autoregulatory mechanisms, with the net result that blood pressure is generally maintained unless hypoxia is prolonged or severe. In contrast to the systemic circulation, hypoxia causes pulmonary vasoconstriction and hypertension, an extension of the normal regional vascular response that matches perfusion with ventilation to optimize gas exchange in the lung (hypoxic pulmonary vasoconstriction).

Central Nervous System (CNS)

The CNS is least able to tolerate hypoxia. Hypoxia is manifest initially by decreased intellectual capacity and impaired judgment and psychomotor ability. This state progresses to confusion and restlessness and ultimately to stupor, coma, and death as the arterial PO decreases below 4 to 5.3 kPa (30 to 40 mm Hg). Victims often are unaware of this progression.

Cellular and Metabolic Effects

When the mitochondrial PO falls below about 0.13 kPa (1 mm Hg), anaerobic metabolism stops, and the less efficient anaerobic pathways of glycolysis become responsible for the production of cellular energy. End-products of anaerobic metabolism, such as lactic acid, may be released into the circulation in measurable quantities. Energy-dependent ion pumps slow and transmembrane ion gradients dissipate. Intracellular concentrations of Na⁺, Ca²⁺, and H⁺ increase, finally leading to cell death. The time course of cellular demise depends on the relative metabolic demands, O₂ storage capacity, and anaerobic capacity of the individual organs. Restoration of perfusion and oxygenation prior to hypoxic cell death paradoxically can result in an accelerated form of cell injury (ischemia-reperfusion syndrome), thought to result from the generation of highly reactive oxygen free radicals (McCord, 1985).

Adaptation to Hypoxia

Long-term hypoxia results in adaptive physiological changes; these have been studied most thoroughly in persons exposed to high altitude. Adaptations include increased numbers of pulmonary alveoli, increased concentrations of hemoglobin in blood and myoglobin in muscle, and a decreased ventilatory response to hypoxia (Cruz et al., 1980). Short-term exposure to altitude produces similar adaptive changes. In susceptible individuals, however, acute exposure to high altitude may produce 'acute mountain sickness,' a syndrome characterized by headache, nausea, dyspnea, sleep disturbances, and impaired judgment, progressing to pulmonary and cerebral edema (Johnson and Rock, 1988). Mountain sickness is treated with supplemental oxygen, descent to lower altitude, or an increase in ambient pressure. Diuretics (carbonic anhydrase inhibitors) and steroids also may be helpful. The syndrome usually can be avoided by a slow ascent to altitude, permitting time for adaptation to occur.

It has been noted that certain aspects of fetal and newborn physiology are strongly reminiscent of adaptation mechanisms found in hypoxia-tolerant animals (Mortola, 1999; Singer, 1999), including shifts in the oxyhemoglobin dissociation curve (fetal hemoglobin), reduction in metabolic rate and body temperature (hibernation-like mode), reduction in heart rate and circulatory redistribution (as in diving mammals), and redirection of energy utilization from growth to maintenance metabolism. These adaptations help account for the relative tolerance of the fetus and neonate to both chronic (uterine insufficiency) and short-term hypoxia.

Oxygen Inhalation

Physiological Effects of Oxygen Inhalation

The primary use for inhalation of oxygen is to reverse or prevent the development of hypoxia; other consequences usually are minor. However, when oxygen is breathed in excessive amounts or for prolonged periods, secondary physiological changes and toxic effects can occur.

Respiratory System

Inhalation of oxygen at 1 atmosphere or above causes a small degree of respiratory depression in normal subjects, presumably as a result of loss of tonic chemoreceptor activity. However, ventilation typically increases within a few minutes of oxygen inhalation because of a paradoxical increase in the tension of carbon dioxide in tissues. This increase results from the increased concentration of oxyhemoglobin in venous blood, which causes less efficient removal of carbon dioxide from the tissues (Lambertsen et al., 1953; Plewes and Farhi, 1983).

In a small number of patients whose respiratory center is depressed by long-term retention of carbon dioxide, injury, or drugs, ventilation is maintained largely by stimulation of carotid and aortic chemoreceptors, commonly referred to as the hypoxic drive. The provision of too much oxygen can depress this drive, resulting in respiratory acidosis. In these cases, supplemental oxygen should be titrated carefully to ensure adequate arterial saturation. If hypoventilation results, then mechanical ventilatory support with or without tracheal intubation should be provided.

Expansion of poorly ventilated alveoli is maintained in part by the nitrogen content of alveolar gas; nitrogen is poorly soluble and thus remains in the airspaces while oxygen is absorbed. High oxygen concentrations delivered to poorly ventilated lung regions can promote absorption atelectasis, occasionally resulting in an increase in shunt and a paradoxical worsening of hypoxemia after a period of oxygen administration.

Cardiovascular System

Aside from reversing the effects of hypoxia, the physiological consequences of oxygen inhalation on the cardiovascular system are of little significance. Heart rate and cardiac output are slightly reduced when 100% oxygen is breathed; blood pressure changes little. While pulmonary arterial pressure changes little in normal subjects with oxygen inhalation, elevated pulmonary artery pressures in patients living at altitude who have chronic hypoxic pulmonary hypertension may reverse with oxygen therapy or return to sea level (Grover et al., 1966; Spievogel et al., 1969). In particular, in neonates with congenital heart disease and left-to-right shunting of cardiac output, oxygen supplementation must be carefully regulated because of the risk of further reducing pulmonary vascular resistance and increasing pulmonary blood flow.

Metabolism

Inhalation of 100% oxygen does not produce detectable changes in oxygen consumption, carbon dioxide production, respiratory quotient, or glucose utilization.

Oxygen Administration

Oxygen is supplied as a compressed gas in steel cylinders, and a purity of 99% is referred to as 'medical grade.' Most hospitals have oxygen piped from insulated liquid oxygen containers to areas of frequent use. For safety, oxygen cylinders and piping are color-coded (green in the United States), and some form of mechanical indexing of valve connections is used to prevent the connection of other gases to oxygen systems. Oxygen concentrators, which employ molecular sieve, membrane, or electrochemical technologies, are available for low-flow home use. Such systems produce 30% to 95% oxygen, depending on the flow rate. These devices reduce the resupply problem inherent in the use of compressed or liquid gas systems.

Oxygen is delivered by inhalation except during extracorporeal circulation, when it is dissolved directly into the circulating blood. Only a closed delivery system, with an airtight seal to the patient's airway and complete separation of inspired from expired gases, can precisely control FI_O2. In all other systems, the actual delivered FI_O2 will depend upon the ventilatory pattern (rate, tidal volume, inspiratory:expiratory time ratio, and inspiratory flow) and delivery system characteristics.

Low-Flow Systems

Low-flow systems, in which the oxygen flow is lower than the inspiratory flow rate, have a limited ability to raise the FI_O2 because they depend upon entrained room air to make up the balance of the inspired gas. The FI_O2 of these systems is extremely sensitive to small changes in the ventilatory pattern. Devices such as face tents are used primarily for delivering humidified gases to patients and cannot be relied upon to provide predictable amounts of supplemental oxygen. Nasal cannulaesmall, flexible prongs that sit just inside each narisdeliver oxygen at 1 to 6 liters/minute. The nasopharynx acts as a reservoir for storing the oxygen, and patients may breathe through either the mouth or nose as long as the nasal passages remain patent. These devices typically deliver 24% to 28% FI_O2 at 2 to 3 liters/minute. Up to 40% FI_O2 is possible at higher flow rates, although this is poorly tolerated for more than brief periods because of mucosal drying. The simple face-mask, a clear plastic mask with side holes for clearance of expiratory gas and inspiratory air entrainment, is used when higher concentrations of oxygen delivered without tight control are desired. The maximum FI_O2 of a facemask can be increased from around 60% at 6 to 15 liters/minute to greater than 85% by adding a 600- to 1000-ml reservoir bag. With this partial rebreathing mask, most of the inspired volume is drawn from the reservoir, avoiding dilution of the FI_O2 by entrainment of room air.

High-Flow Systems

The most commonly used high-flow oxygen delivery device is the Venturi mask, which utilizes a specially designed mask insert to reliably entrain room air in a fixed ratio and thus provides a relatively constant FI_O2 at relatively high flow rates. Typically, each insert is designed to operate at a specific oxygen flow rate, and different inserts are required to change the FI_O2. Lower delivered FI_O2 values use greater entrainment ratios, resulting in higher total (oxygen plus entrained air) flows to the patient, ranging from 80 liters/minute for 24% FI_O2 to 40 liters/minute at 50% FI_O2. While these flow rates are much higher than those obtained with low-flow devices, they still may be lower than the peak inspiratory flows for patients in respiratory distress, and thus the actual delivered oxygen concentration may be lower than the nominal value. Oxygen nebulizers, another type of Venturi device, provide patients with humidified oxygen at 35% to 100% FI_O2 at high flow rates. Finally, oxygen blenders provide high inspired oxygen concentrations at very high flow rates. These devices mix high-pressure, compressed air and oxygen to achieve any concentration of oxygen from 21% to 100% at flow rates up to 100 liters/minute. These same blenders are used to provide control of FI_O2 for ventilators, CPAP/BiPAP machines, oxygenators, and other devices with similar requirements. Again, despite the high flows, the delivery of high FI_O2 to an individual patient also depends on maintaining a tight-fitting seal to the airway and/or the use of reservoirs to minimize entrainment of diluting room air.

Monitoring of Oxygenation

Monitoring and titration are required to meet the therapeutic goal of oxygen therapy and to avoid complications and side effects. Although cyanosis is a physical finding of substantial clinical importance, it is not an early, sensitive, or reliable index of oxygenation. Cyanosis appears when about 5 g/dl of deoxyhemoglobin is present in arterial blood (Lundsgaard and Van Slyke, 1923), representing an oxygen saturation of about 67% when a normal amount of hemoglobin (15 g/dl) is present. However, when anemia lowers the hemoglobin to 10 g/dl, then cyanosis does not appear until the arterial blood saturation has decreased to 50%. Invasive approaches for monitoring oxygenation include intermittent laboratory analysis of arterial or mixed venous blood gases and placement of intravascular cannulae capable of continuous measurement of oxygen tension. The latter method, which relies on fiberoptic oximetry, is used frequently for the continuous measurement of mixed venous hemoglobin saturation as an index of tissue extraction of oxygen, usually in critically ill patients.

Noninvasive monitoring of arterial oxygen saturation now is widely available from transcutaneous pulse oximetry, in which oxygen saturation is measured from the differential absorption of light by oxyhemoglobin and deoxyhemoglobin and the arterial saturation determined from the pulsatile component of this signal. Application is simple and calibration not required. Because pulse oximetry measures hemoglobin saturation and not PO , it is not sensitive to increases in PO that exceed levels required to fully saturate the blood. However, pulse oximetry is very useful for monitoring the adequacy of oxygenation during procedures requiring sedation or anesthesia, rapid evaluation and monitoring of potentially compromised patients, and titrating oxygen therapy in situations where toxicity from oxygen or side effects of excess oxygen are of concern.

Complications of Oxygen Therapy

Administration of supplemental oxygen is not without potential complications. In addition to the potential to promote absorption atelectasis and depress ventilation, discussed above, high flows of dry oxygen can dry out and irritate mucosal surfaces of the airway and the eyes, as well as decrease mucociliary transport and clearance of secretions. Humidified oxygen thus should be used when therapy of greater than an hour's duration is required. Finally, any oxygen-enriched atmosphere constitutes a fire hazard, and appropriate precautions must be taken both in the operating room and for patients on oxygen at home.

It is important to realize that hypoxemia still can occur despite the administration of supplemental oxygen. Furthermore, when supplemental oxygen is administered, desaturation occurs at a later time after airway obstruction or hypoventilation, potentially delaying the detection of these critical events. Therefore, whether or not oxygen is administered to a patient at risk for these problems, it is essential that both oxygen saturation and adequacy of ventilation be frequently assessed.

Therapeutic Uses of Oxygen

Correction of Hypoxia

As stated above, the primary therapeutic use of oxygen is to correct hypoxia. However, hypoxia is most commonly a manifestation of an underlying disease, and administration of oxygen thus can be viewed as a symptomatic or temporizing therapy. Only rarely is hypoxia due to a primary deficiency in the inspired gas. Because of the many causes of hypoxia, supplementation of the inspired gas alone will not suffice to correct the problem. Efforts must be directed at correcting the cause of the hypoxia. For example, airway obstruction is unlikely to respond to an increase in inspired oxygen tension without relief of the obstruction. More importantly, while hypoxemia due to hypoventilation after a narcotic overdose can be improved with supplemental oxygen administration, the patient remains at risk for respiratory embarrassment if ventilation is not increased through stimulation, narcotic reversal, or mechanical ventilation. In general, the hypoxia that results from most pulmonary diseases can be alleviated at least partially by administration of oxygen, thereby allowing time for definitive therapy to reverse the primary process. Thus, administration of oxygen is a basic and important treatment to be used in all forms of hypoxia, with the understanding that the response will vary in a way that is generally predictable from knowledge of the underlying pathophysiological processes.

Reduction of Partial Pressure of an Inert Gas. Since nitrogen constitutes some 79% of ambient air, it also is the predominant gas in most gas-filled spaces in the body. In certain situations, such as bowel distension from obstruction or ileus, intravascular air embolism, or pneumothorax, it is desirable to reduce the volume of these air-filled spaces. Since nitrogen is relatively insoluble, inhalation of high concentrations of oxygen (and thus low concentrations of nitrogen) rapidly lowers total body partial pressure of nitrogen and provides a substantial gradient for the removal of nitrogen from gas spaces. Administration of oxygen for air embolism is additionally beneficial, because it also helps to relieve the localized hypoxia distal to the embolic vascular obstruction. In the case of decompression sickness or bends, lowering of inert gas tension in blood and tissues by oxygen inhalation prior to or during a barometric decompression can reduce the degree of supersaturation that occurs after decompression so that bubbles do not form. If bubbles do form in either tissues or the vasculature, administration of oxygen is based on the same rationale as that described for gas embolism.

Hyperbaric Oxygen Therapy

Oxygen is administered at greater than atmospheric pressure for a number of conditions when 100% oxygen at a single atmosphere is insufficient (Buras, 2000; Shank and Muth, 2000; Myers, 2000). To achieve concentrations of greater than 1 atmosphere, a hyperbaric chamber must be used. These chambers range from small, single-person affairs to multiroom establishments, which may include complex medical equipment. Smaller, one-person chambers typically are pressurized with oxygen, while larger ones are filled with air. In the latter case, a patient must wear a mask to receive the oxygen at the increased pressure. The larger chambers are more suitable for critically ill patients who require ventilation, monitoring, and constant attendance. Any chamber must be built to withstand pressures which may range from 200 to 600 kPa (2 to 6 atmospheres), though inhaled oxygen tension that exceeds 300 kPa (3 atmospheres) rarely is used (see Oxygen Toxicity, below).

Hyperbaric oxygen therapy has two components: increased hydrostatic pressure and increased oxygen pressure. Both factors are necessary for the treatment of decompression sickness and air embolism. The hydrostatic pressure reduces bubble volume, and the absence of inspired nitrogen increases the gradient for elimination of nitrogen and reduces hypoxia in downstream tissues. Increased oxygen pressure at the tissue level is the primary therapeutic goal for most of the other indications for hyperbaric oxygen. For example, even a small increase in PO in previously ischemic areas may enhance the bactericidal activity of leukocytes and increase angiogenesis. Thus, repetitive, brief exposure to hyperbaric oxygen is a useful adjunct in the treatment of chronic refractory osteomyelitis, osteoradionecrosis, or crush injury or for the recovery of compromised skin, tissue grafts, or flaps. Furthermore, increased oxygen tension can itself be bacteriostatic; the spread of infection with Clostridium perfringens and production of toxin by the bacteria are slowed when oxygen tensions exceed 33 kPa (250 mm Hg), justifying the early use of hyperbaric oxygen in clostridial myonecrosis (gas gangrene).

Hyperbaric oxygen also is useful in selected instances of generalized hypoxia. In carbon monoxide poisoning, hemoglobin and myoglobin become unavailable for oxygen binding because of the high affinity of CO for these proteins. A high PO facilitates competition of oxygen with CO for binding sites, permitting the resumption of normal delivery of oxygen to the tissues. Hyperbaric oxygen decreases the incidence of neurological sequelae after CO intoxication; this effect may be independent of the ability of hyperbaric oxygen to speed the elimination of CO (Thom, 1989). However, a recent randomized study suggests that hyperbaric oxygen is not beneficial in carbon monoxide poisoning and might even be harmful (Scheinkestel et al., 1999). The occasional use of hyperbaric oxygen in cyanide poisoning has a similar rationale. Hyperbaric oxygen also may be useful in severe, short-term anemia, since sufficient oxygen can be dissolved in the plasma at 3 atmospheres to meet metabolic needs. However, such treatment must be limited, because oxygen toxicity is dependent on increased PO , not on the oxygen content of the blood.

Hyperbaric oxygen therapy also has been used in such diverse conditions as multiple sclerosis, traumatic spinal cord injury, cerebrovascular accidents, bone grafts and fractures, and leprosy. However, data from well-controlled clinical trials are not sufficient to justify these uses, and the costs of hyperbaric therapy remain very high.

Oxygen Toxicity

Oxygen is used in cellular energy production and is crucial for cellular metabolism. However, oxygen also may have deleterious actions at the cellular level. Oxygen toxicity probably results from increased production of reactive agents such as superoxide anion, singlet oxygen, hydroxyl radical, and hydrogen peroxide (Turrens et al., 1982). These agents attack and damage biological membranes, and thus eventually result in damage to most cellular components. A variety of factors limit the toxicity of oxygen-derived, reactive agents. These factors include enzymes such as superoxide dismutase, glutathione peroxidase, and catalase, which scavenge toxic byproducts. In addition, there are reducing agents including iron, glutathione, and ascorbate. These factors, however, are insufficient to limit the destructive actions of oxygen when patients are exposed to high concentrations over a period of time. Tissues show differential sensitivity to oxygen toxicity, which is likely the result of differences in both their production of reactive compounds and protective mechanisms. Oxygen toxicity recently was reviewed by Carraway and Piantadosi (1999).

Respiratory Tract

The pulmonary system is usually the first to exhibit toxicity, a function of its being continuously exposed to the highest oxygen tensions in the body. Subtle changes in pulmonary function can occur after as little as 8 to 12 hours of exposure to 100% oxygen (Sackner et al., 1975). Increases in capillary permeability, which will increase the alveolar/arterial O₂ gradient and ultimately lead to further hypoxemia, and decreased pulmonary function can be seen after only 18 hours of exposure (Davis et al., 1983; Clark, 1988). Serious injury and death, however, require much longer exposures. Pulmonary damage is directly related to the inspired oxygen tension, and concentrations of less than 0.5 atmosphere appear safe over long time periods. The capillary endothelium is the most sensitive tissue of the lung. Endothelial injury results in loss of surface area from interstitial edema and leaks into the alveoli (Crapo et al., 1980).

Decreases of inspired oxygen concentrations remain the cornerstone of therapy for oxygen toxicity. Modest decreases in toxicity have been observed in animals treated with antioxidant enzymes (White et al., 1989). Tolerance also may play a role in protection from oxygen toxicity; animals exposed briefly to high oxygen tension are subsequently more resistant to toxicity (Kravetz et al., 1980; Coursin et al., 1987). Sensitivity in human beings also can be altered by preexposure to both high and low oxygen concentrations (Hendricks et al., 1977; Clark, 1988). These studies strongly suggest that changes in alveolar surfactant and cellular levels of antioxidant enzymes play a role in protection from oxygen toxicity.

Retina

Retrolental fibroplasia can occur when neonates are exposed to increased oxygen tensions (Betts et al., 1977). These changes can go on to cause blindness and are likely caused by angiogenesis (Kushner et al., 1977; Ashton, 1979). Incidence of this disorder has decreased with an improved appreciation of the issues and avoidance of excessive inspired oxygen concentrations. Adults do not seem to develop the disease.

Central Nervous System

CNS problems are rare, and toxicity occurs only under hyperbaric conditions where exposure exceeds 200 kPa (2 atmospheres). Symptoms include seizures and visual changes, which resolve when oxygen tensions are returned to normal. These problems are a further reason to replace oxygen with helium under hyperbaric conditions (see Helium).