Tissue Hypoxia: Implications for the Respiratory Clinician

Causes of Hypoxia

Tissue hypoxia can be caused by one of 3 general abnormalities: hypoxemia, impaired oxygen delivery to tissues, and impaired tissue oxygen extraction/utilization. Each will be addressed separately.

Hypoxemia

Hypoxemia refers to low oxygen content in arterial blood, and there are several factors that impact this state.^1–3 The first is the oxygen content of inspired gas. At sea level, the inspired P_O2 is ∼150 mm Hg. Inspired P_O2 falls progressively with altitude and nadirs at 43 mm Hg at the summit of Mt Everest (29,028 feet).

Alveolar ventilation is the next step in oxygenating blood. As alveolar ventilation increases, alveolar P_O2 (P_AO2) rises logarithmically and assymptotes on the inspired P_O2 (Fig. 1).² From Figure 1, it can be seen that in a normal human at rest with an inspired P_O2 of 150 mm Hg, an alveolar ventilation near normal (eg, 5 L/min) provides a P_AO2 of 100 mm Hg, a pressure adequate to fully saturate hemoglobin (Hb). Importantly, because oxygen is poorly soluble in plasma, once Hb is fully saturated, increasing alveolar ventilation further adds little to blood oxygen content (Fig. 1). This is in contrast to P_CO2, which continues to decrease in both blood and alveolar gas as alveolar ventilation is progressively increased (Fig. 1).

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Fig. 1.

Plots of alveolar P_O2, hemoglobin saturation, and alveolar P_CO2 as a function of alveolar ventilation in a normal subject at sea level (inspired oxygen pressure of 150 mm Hg). The dashed line indicates normal values. Adapted from Reference 2.

Once oxygen is in the alveolar spaces, the matching of blood and alveolar gas is the next step in determining arterial oxygen content.^1–3 In normal humans at both rest and exercise, smooth muscles in both the airways and blood vessels ensure that ventilation/perfusion (V̇/Q̇) is matched nearly 1:1 in all alveolar-capillary units. In disease states, V̇/Q̇ relationships become deranged, and oxygen transport into blood is impaired. Similar to the phenomenon described in Figure 1, because of poor O₂ solubility in plasma, relative hyperventilation and 100% Hb saturation in high V̇/Q̇ units cannot make up for the unsaturated Hb coming from underventilated low V̇/Q̇ units. This is not the case for CO₂, where high V̇/Q̇ units can compensate for low V̇/Q̇ units. V̇/Q̇ inhomogeneities thus have less effect on P_CO2.

Regardless of V̇/Q̇ matching, the next step in blood oxygenation is the diffusion of oxygen through the alveolar-capillary interface and plasma and then into the red blood cell cytoplasm, where it can bind with the Hb molecule (Fig. 2).⁶ This can be expressed by the determinants for lung diffusing capacity (D_L): 1/D_L = 1/(D_M) + (1/V_c × θ), where DM is the membrane diffusing capacity reflecting the properties and surface areas of the alveolar-capillary interface, V_c is the capillary Hb volume, and θ is the binding rate of Hb to oxygen.^1–3,6

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Fig. 2.

Depiction of the various barriers oxygen must traverse as it moves from the alveolar space to ultimately combine with hemoglobin (Hb) in the red blood cell. Adapted from Reference 6.

In normal humans, the diffusion and Hb-binding process is time-dependent, and equilibration generally occurs over ∼250 ms.^1–3,6 This is important because the normal transit time at rest for a red blood cell in the alveolar capillary is 500–750 ms, a time adequate for complete O₂ transfer. However, with extreme exercise and high pulmonary capillary blood flow, transit times may be shorter than 250 ms and produce hypoxemia. In disease states with abnormal alveolar-capillary structures and reduced P_AO2, reduced membrane diffusing capacity and shorter transit times may both contribute to hypoxemia.

The final determinant of blood oxygen content is the amount of Hb in blood and its binding properties.⁷ In normal humans, Hb approaches full saturation at a P_O2 of > 60–70 mm Hg. Tighter Hb binding to oxygen (a shift to the left in the oxyhemoglobin dissociation curve) means that lower levels of P_O2 are associated with near-complete saturation of Hb, and thus, tissue unloading is more difficult. Severe left shifting and functional loss of Hb can occur when oxygen-binding sites are impaired or blocked (eg, methemoglobin, sulfhemoglobin, carboxyhemoglobin). On the other hand, a shift to the right of the curve means that at a given P_O2 less oxygen is bound to Hb, and this facilitates delivery of oxygen into the tissues. Normal values for oxygen content in blood with 150 g/L Hb are ∼200 mL/L of blood.

Hypoxemia can be expressed in several ways. Typically, a P_aO2 of 60–80 mm Hg is considered mildly hypoxemic, whereas a P_aO2 of < 60 mm Hg is considered hypoxemia generally sufficient to warrant an intervention. These values can be referenced to the estimated P_AO2 (inspired oxygen pressure − P_aCO2/respiratory quotient) and expressed as an alveolar-arterial oxygen difference (P_(A-a)O2). This separates the effects of inspired oxygen pressure and alveolar ventilation (P_AO2) from the effects of alveolar-capillary gas transport (P_(A-a)O2) on hypoxemia. A normal P_(A-a)O2 is a value less than one half your age, with a maximum of 25 mm Hg. Hypoxemia can also be expressed using arterial oxygen content, which incorporates both P_aO2 and Hb properties.

Compensatory Mechanisms for Hypoxia

If tissue hypoxia occurs, global compensatory respiratory and cardiac mechanisms similar to those seen with exercise occur to improve oxygen delivery. Acutely, these include regional pulmonary vasoconstriction to improve V̇/Q̇ matching, hyperventilation to improve P_AO2, acidosis-related right shifting of the oxyhemoglobin dissociation curve to facilitate O₂ unloading, and increases in cardiac output.^3–5 Over time, there is also an increase in red blood cell production, and this results in polycythemia in both subjects at altitude and in patients with chronic hypoxemia. Importantly, polycythemia can also increase blood viscosity and thus potentially impair blood flow and tissue oxygen delivery through capillaries. Indeed, subjects who adapt best to altitude dwelling have only a modest polycythemic response to hypoxemia.

Hypoxemia is also associated with an increase in red blood cell 2,3-diphosphoglycerate to facilitate O₂ unloading in the tissues.⁵ If regional hypoxia is present (eg, regional ischemia, exercise, or inflammation), regional blood flow distributional changes also occur to direct blood flow to where oxygen delivery is needed most and away from regions that are less mission-critical.⁵

Regardless of the cause of hypoxia, at the cellular level, important adaptive mechanisms also exist. Central to all of these are hypoxia-inducible factors (HIFs), a group of heterodimeric proteins that interact with hundreds of genes in response to hypoxia.^15–20 HIF activation results in up-regulation of erythropoietin, angiogenic factors, and vasoactive mediators; activation of glycolytic enzymes to produce anaerobic metabolism (with resulting lactate production); and even a mitochondrial hibernation-like phenomenon resulting in decreased oxygen demands.^15–24 HIFs can also down-regulate other processes in response to hypoxia.¹⁵ All of these actions are designed to enhance cellular tolerance to hypoxia.

Experimentally, HIFs have been implicated as protective in a number of ischemic models. Examples include the phenomenon of cardiac ischemia preconditioning (which reduces experimental myocardial infarct size),^25,26 protection from the systemic effects of ischemic colitis,^27,28 and protection from limb ischemia.^29,30 HIFs have also been demonstrated to be increased in high altitude dwelling Tibetans³¹ and to be crucial in fetal development.³² Ironically, the angiogenesis properties of HIFs have also been related to accelerated tumor growth.³³ Recent work has implicated other cellular factors, including endogenous carbon monoxide and hydrogen sulfide, as mediators of intracellular hypoxic protection.⁵

In healthy individuals in hypoxemic environments, these compensatory mechanisms can be quite effective. Classic examples include the ability of humans to live at very high altitudes with a P_aO2 of ≤ 50 mm Hg^5,34,35 and stories of stowaways surviving in airplane landing gear assemblies for many hours at an altitude of 35,000 feet (CNN website, April 21, 2014). Similarly, the near-term fetus has a P_aO2 of < 30 mm Hg.^5,36 It is clear that, with proper compensatory mechanisms, mammalian cells can thrive with a P_aO2 lower than the traditional clinical thresholds of 55–60 mm Hg.

In diseased individuals, many of these compensatory mechanisms may be blunted. Systemic inflammation and organ dysfunction may impair ventilation, create poor V̇/Q̇ mismatching, limit cardiac function, disrupt proper control of systemic perfusion distribution, impair tissue oxygen extraction, and limit the Hb response.^8,9 Tolerance to low levels of O₂ and P_aO2 in disease states is thus likely to be reduced compared with healthy individuals. For example, an otherwise healthy individual in the ICU with low oxygen demands (eg, a hypothermic drowning victim) might be expected to tolerate much lower oxygenation levels than an elderly septic patient with high oxygen demands.

Current and Future Clinical Implications

Managing hypoxia traditionally involves efforts to improve oxygen delivery and focuses on blood oxygenation (P_O2 and Hb) and cardiac output. The relative value of manipulating each of these parameters is given in Table 2.³⁷ Importantly, each of these interventions has consequences.³⁸ Improving P_O2 usually involves supplemental oxygen and positive-pressure ventilation, which expose patients to risks of oxygen toxicity and ventilator-induced lung injury. Transfusions expose patients to fluid overload, immunologic risks, and possible transfusion-related lung injuries. Increasing cardiac output exposes patients to risks of fluid overload and excessive adrenergic stimulation. Thus, like so many interventions employed in critical care, improving the physiology of oxygen delivery may not translate into improved outcomes and must always be implemented cautiously.

An alternative way to manipulate tissue oxygenation is to manipulate oxygen consumption. On a global level, this can be done through pain management, fever control, agitation control, neuromuscular blockade, or cooling (eg, therapeutic hypothermia after cardiac arrest).^39,40 Indeed, the ability to survive at 35,000 feet in the wheel wells of a commercial aircraft as noted above was likely associated with hypothermia-induced hibernation of tissues. Each of these, to varying degrees, can lower O₂ demands in specific tissue beds to improve regional tissue oxygenation. However, these manipulations can have their own toxicities. For example, narcotics and anxiolytics can prolong the need for mechanical ventilation,⁴¹ and neuromuscular blockade can lead to respiratory muscle disuse atrophy.⁴² Whether hypothermia produces long-term injury is unknown.

As we move into the future, focus is needed in 2 areas. First, more direct assessments of regional hypoxia and an understanding of threshold levels for hypoxic injury in different regions are required.⁴³ This will allow us to better balance tradeoffs associated with conventional therapies. Second, future therapies need to address both regional manipulations of oxygen delivery and the development of strategies building upon the powerful compensatory mechanisms already present in cells.

Regarding assessments, the traditional way to quantify tissue hypoxia is to simplify and measure only global hypoxemia, oxygen delivery, and oxygen extraction. Commonly recommended therapeutic targets are a P_aO2 of > 55 mm Hg, Hb levels of at least 70 g/L (but perhaps as high as 90–100 g/L in high O₂ demand states), and cardiac indices (cardiac output referenced to body surface area) of > 2 L/min/m².³⁸

However, oxygen utilization monitoring might offer more in-depth assessments of overall body oxygenation status than simple oxygen delivery. Using this approach, oxygen delivery could be deemed adequate if total body oxygen consumption was adequate (250 mL/min in a normal metabolic state: perhaps higher in sepsis, perhaps lower in the presence of paralytics). Indeed, a number of clinical studies in the last 2 decades argued that oxygen delivery should be increased until oxygen consumption is no longer increased.⁴⁴ However, because assessments of oxygen delivery and oxygen consumption utilize common variables (cardiac output and P_aO2 content), the use of simply the mixed venous P_O2 or mixed venous oxyhemoglobin saturation has been proposed as a more focused assessment of tissue oxygenation.^45,46 With this approach, a mixed venous P_O2 of > 40 mm Hg or mixed venous oxyhemoglobin saturation of > 70% (so-called goal-directed therapy)⁴⁷ might suggest the presence of adequate oxygen delivery. Importantly, these approaches assume that oxygen extraction capabilities are near normal, something that might not be present in a severe systemic inflammatory response state. Serum lactate has also been suggested as a monitor for global adequacy of oxygen delivery.⁴⁸

It is clear from the discussion above that these global parameters are insensitive and nonspecific indicators of safe oxygenation at the regional tissue level. Thus, efforts to normalize these global values may force excessive use of potentially harmful support strategies.³⁸ However, current attempts to assess regional hypoxia are largely indirect through monitoring of specific organ functions. Examples include monitoring heart function (contractility, dysrhythmias), renal function (creatinine), liver function (liver metabolic properties and enzymes), and central nervous system function (mental status or seizures). If we are ever going to be comfortable with global permissive hypoxemia (ie, allowing a P_aO2 of < 55 mm Hg), regional assessments are going to be critical to guide therapy.^49–53

Two organs for which direct venous or tissue P_O2 values are available are the brain and the intestine. The brain is a logical monitoring site, as it is the organ that is most sensitive to hypoxia.⁵ Both animal and human studies suggest that an intracellular P_O2 in brain tissue of < 10–15 mm Hg is injurious.⁵⁴ Brain injury is also associated with oxyhemoglobin saturation of < 50–54% in blood sampled in the jugular venous system.⁵⁵ External probes placed on the forehead to measure oxidative state using near-infrared technology are theoretically attractive but subject to artifacts from muscle metabolism on the scalp.⁵⁶

The intestine is also an attractive site to monitor, as regional hypoxia there results in translocation of intestinal bacteria into blood. This conceptually feeds systemic inflammation and multiple organ failure.⁵⁷ Moreover, if intestinal oxygenation is thought to be adequate, other organs such as the brain are also likely to be adequate. Currently available monitors utilize intestinal luminal pH (P_CO2) sensors to determine oxygenation adequacy.⁵⁷

In future therapies, we will need a better understanding of how regional blood flow is modulated and how oxygen is extracted and utilized both under normal conditions and in disease states. We also need a better understanding of the remarkable compensatory mechanisms for hypoxia that exist and develop ways to harness them. Examples of future therapies might include Hb manipulations for more targeted blood flow and exploitation of HIF properties to better protect the hypoxic cell. The next decade should provide exciting new ways to support hypoxic patients.

Summary

Hypoxia is the presence of lower than normal oxygen content and pressure in the cell. Causes of hypoxia include hypoxemia (low blood oxygen content and pressure), impaired oxygen delivery, and impaired cellular oxygen uptake/utilization. Many compensatory mechanisms exist at the global, regional, and cellular levels to allow cells to function in a hypoxic environment. Clinical management of tissue hypoxia usually focuses on global hypoxemia and oxygen delivery. In the future, the clinical focus needs to change to assessing and managing regional hypoxia in critical organs to avoid unnecessary and potential toxic global strategies. We also need to focus on understanding and better harnessing the body's own adaptive mechanisms to hypoxia.