Tissue Hypoxia: Implications for the Respiratory Clinician Neil R MacIntyre MD FAARC Introduction Causes of Hypoxia Hypoxemia Oxygen Delivery Oxygen Extraction/Utilization Compensatory Mechanisms for Hypoxia Current and Future Clinical Implications Summary Oxygen is essential for normal aerobic metabolism in mammals. 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 up- take/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. As we move into the future, the clinical focus needs to change to assessing and managing mission-critical regional hypoxia 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. Key words: hypoxia; hypoxemia; alveolar ventila- tion; ventilation/perfusion matching; diffusion; hemoglobin binding; hemoglobin-oxygen binding; re- gional oxygenation; oxygen extraction; oxygen utilization; hypoxia-inducible factors. [Respir Care 2014;59(10):1590–1596. © 2014 Daedalus Enterprises] Introduction with oxygen to produce energy (converting adenosine 5Ј- Ј diphosphate to adenosine 5 -triphosphate) along with CO2 Oxygen is essential for normal aerobic metabolism in and H2O. Hypoxia is a state of low oxygen content and mammals.1-3 The key reaction occurs in the mitochondria partial pressure in the cell. Depending upon the cell of cells and involves combining a fuel (eg, sugars, fats) type, its metabolic demands, and its ability to adapt to hypoxia, the response to various levels of hypoxia can range from substantial adaptation to cell death.4,5 The dis- cussion below will focus on 3 areas: (1) causes of hypoxia, Dr MacIntyre is affiliated with the Division of Pulmonary and Critical (2) physiologic responses/adaptations to hypoxia (global, Care Medicine, Duke University Medical Center, Durham, North Carolina. regional, and cellular), and (3) current and future clinical Dr MacIntyre presented a version of this paper at the 29th New Horizons implications. Symposium at the AARC Congress 2013, held November 16–19, 2013, in Anaheim, California. Causes of Hypoxia The author has disclosed no conflict of interest. Tissue hypoxia can be caused by one of 3 general ab- Correspondence: Neil R MacIntyre MD FAARC, E-mail: neil.macintyre @duke.edu. normalities: hypoxemia, impaired oxygen delivery to tis- sues, and impaired tissue oxygen extraction/utilization. DOI: 10.4187/respcare.03357 Each will be addressed separately. 1590 RESPIRATORY CARE • OCTOBER 2014 VOL 59 NO 10 TISSUE HYPOXIA:IMPLICATIONS FOR THE RESPIRATORY CLINICIAN Fig. 2. Depiction of the various barriers oxygen must traverse as it moves from the alveolar space to ultimately combine with hemo- globin (Hb) in the red blood cell. Adapted from Reference 6. Fig. 1. Plots of alveolar P , hemoglobin saturation, and alveolar O2 P as a function of alveolar ventilation in a normal subject at sea CO2 level (inspired oxygen pressure of 150 mm Hg). The dashed line in high V˙ /Q˙ units cannot make up for the unsaturated Hb indicates normal values. Adapted from Reference 2. coming from underventilated low V˙ /Q˙ units. This is not ˙ ˙ the case for CO2, where high V/Q units can compensate for low V˙ /Q˙ units. V˙ /Q˙ inhomogeneities thus have less Hypoxemia effect on P . CO2 Regardless of V˙ /Q˙ matching, the next step in blood Hypoxemia refers to low oxygen content in arterial oxygenation is the diffusion of oxygen through the alve- blood, and there are several factors that impact this state.1-3 olar-capillary interface and plasma and then into the red The first is the oxygen content of inspired gas. At sea blood cell cytoplasm, where it can bind with the Hb ϳ 6 level, the inspired PO is 150 mm Hg. Inspired PO falls molecule (Fig. 2). This can be expressed by the determi- 2 2 ϭ ϩ progressively with altitude and nadirs at 43 mm Hg at the nants for lung diffusing capacity (DL): 1/DL 1/(DM) ϫ ␪ summit of Mt Everest (29,028 feet). (1/Vc ), where DM is the membrane diffusing capacity Alveolar ventilation is the next step in oxygenating blood. reflecting the properties and surface areas of the alveolar- As alveolar ventilation increases, alveolar P (P ) rises capillary interface, V is the capillary Hb volume, and ␪ is O2 AO2 c logarithmically and assymptotes on the inspired P the binding rate of Hb to oxygen.1-3,6 O2 (Fig. 1).2 From Figure 1, it can be seen that in a normal In normal humans, the diffusion and Hb-binding pro- human at rest with an inspired P of 150 mm Hg, an cess is time-dependent, and equilibration generally occurs O2 alveolar ventilation near normal (eg, 5 L/min) provides a over ϳ250 ms.1-3,6 This is important because the normal P of 100 mm Hg, a pressure adequate to fully saturate transit time at rest for a red blood cell in the alveolar AO2 hemoglobin (Hb). Importantly, because oxygen is poorly capillary is 500–750 ms, a time adequate for complete O2 soluble in plasma, once Hb is fully saturated, increasing transfer. However, with extreme exercise and high pul- alveolar ventilation further adds little to blood oxygen con- monary capillary blood flow, transit times may be shorter tent (Fig. 1). This is in contrast to P , which continues to than 250 ms and produce hypoxemia. In disease states CO2 decrease in both blood and alveolar gas as alveolar venti- with abnormal alveolar-capillary structures and reduced lation is progressively increased (Fig. 1). P , reduced membrane diffusing capacity and shorter AO2 Once oxygen is in the alveolar spaces, the matching of transit times may both contribute to hypoxemia. blood and alveolar gas is the next step in determining The final determinant of blood oxygen content is the arterial oxygen content.1-3 In normal humans at both rest amount of Hb in blood and its binding properties.7 In and exercise, smooth muscles in both the airways and normal humans, Hb approaches full saturation at a P of O2 blood vessels ensure that ventilation/perfusion (V˙ /Q˙ )is Ͼ 60–70 mm Hg. Tighter Hb binding to oxygen (a shift to matched nearly 1:1 in all alveolar-capillary units. In disease the left in the oxyhemoglobin dissociation curve) means states, V˙ /Q˙ relationships become deranged, and oxygen that lower levels of P are associated with near-complete O2 transport into blood is impaired. Similar to the phenome- saturation of Hb, and thus, tissue unloading is more diffi- non described in Figure 1, because of poor O2 solubility in cult. Severe left shifting and functional loss of Hb can plasma, relative hyperventilation and 100% Hb saturation occur when oxygen-binding sites are impaired or blocked RESPIRATORY CARE • OCTOBER 2014 VOL 59 NO 10 1591 TISSUE HYPOXIA:IMPLICATIONS FOR THE RESPIRATORY CLINICIAN Table 1. Differences in Blood Flow, O2 Used, and Venous PO2 of Selected Organs and Tissues Blood Flow O2 Used Arteriovenous Oxygen Difference Venous Blood P Tissue/Organ O2 ˙ (mL of O2/100 of mL Blood) (mm Hg) mL/min % of QT mL/min % of Total Heart 250 4 26.4 11 11.4 23 Skeletal muscle 1,200 21 72.0 30 8.4 34 Brain 750 13 48.0 20 6.3 33 Splanchnic (liver) 1,400 24 60.0 25 4.1 43 Kidneys 1,100 19 16.8 7 1.3 56 Skin 500 9 4.8 2 1.0 60 Other 600 10 12.0 5 Total 5,800 100 240.0 100 4.1 (average) 46 (average) Modified from Reference 3. ˙ QT ϭ cardiac output (eg, methemoglobin, sulfhemoglobin, carboxyhemoglo- Importantly, oxygen delivery is regulated by region. bin). On the other hand, a shift to the right of the curve This facilitates oxygen delivery to regions that need it means that at a given P less oxygen is bound to Hb, and most.1-3,6,7 Table 1 gives regional distributions of blood O2 this facilitates delivery of oxygen into the tissues. Normal flow (and thus O2 delivery) at rest. Under exercise condi- values for oxygen content in blood with 150 g/L Hb are tions, blood flow to skeletal muscle can increase signifi- ϳ200 mL/L of blood. cantly, whereas blood flow to skin and intestines may Hypoxemia can be expressed in several ways. Typi- decrease. Governing this distribution of oxygen delivery cally, a P of 60–80 mm Hg is considered mildly are both global factors (eg, adrenergic tone, systemic in- aO2 hypoxemic, whereas a P of Ͻ 60 mm Hg is consid- flammatory mediators) and local factors, including local aO2 ered hypoxemia generally sufficient to warrant an inter- hypoxia, local cytokine production, local nitric oxide, vas- vention. These values can be referenced to the estimated cular factors, and Hb properties.8-11 P (inspired oxygen pressure Ϫ P /respiratory quo- AO2 aCO2 tient) and expressed as an alveolar-arterial oxygen differ- Oxygen Extraction/Utilization ence (P ). This separates the effects of inspired oxy- (A-a)O2 gen pressure and alveolar ventilation (P ) from the AO2 effects of alveolar-capillary gas transport (P )onhy- Oxygen extraction/utilization is the process of moving (A-a)O2 poxemia. A normal P is a value less than one half oxygen from the Hb molecule into the cytoplasm of cells (A-a)O2 your age, with a maximum of 25 mm Hg. Hypoxemia can and ultimately into the mitochondria, where it is used for also be expressed using arterial oxygen content, which oxidative metabolism.