In this issue of A & A Case Reports, 2 reports describe patients in whom extremely low hemoglobin (Hgb) levels were reached without critical end-organ failure.1,2 Both patients survived what would otherwise seem to be lethally decreased Hgb oxygen (O2)-carrying capacity. In fact, the patient described by Kariya et al.2 may be a survivor of the lowest Hgb ever recorded. When these rare, freakish cases occur, we need to pause and reconsider conventional teaching regarding hemodilution and critical O2 delivery (DO2) as well as the limits of human physiology. Cellular DO2 in the end (plasma and cytosol) is via dissolved O2, and the take-home point is that we need to appreciate the importance of dissolved O2, especially in cases of extreme anemia.
Anesthesiologists know that compensatory mechanisms for bleeding and hemodilution include increased cardiac output (CO), improved ventricular emptying, tachycardia, decreased viscosity, and vasodilation.3 These relatively easily measured macrovascular changes occur in large capacitance/resistance vascular beds. The capillary network/microcirculation may not be affected by the changes of anemia until perfusion pressure/CO is very low or there is intercedent vascular disease.4
Anesthesiologists are conversant with the concepts of supply-dependent or supply-independent DO2. The inflection point at which cells no longer receive adequate O2 to meet cellular demand is critical DO2 (DO2crit). DO2crit defines shock.3 The O2 content equation (CaO2 = 1.36 × Hgb × SaO2/100 + 0.0031 × PaO2) gives an estimate of total blood O2. Standard critical care teaching minimizes the contribution of dissolved O2 (0.0031 × PaO2) as being negligible compared with Hgb-carried O2.5
The complex physiology of DO2/utilization, however, is not governed by any one equation and is dependent on O2 movement in the microcirculation.6–8 An emerging understanding of the microcirculation emphasizes O2 movement due to a driving O2 pressure, from erythrocytes to plasma, then across cell membranes into cytosol, and finally to the mitochondria.6–8
Most physicians consider cellular O2 supply to be completely dependent on Hgb. However, a focus on Hgb must be tempered with the fact that metabolically used O2 is exclusively dissolved O2. Hgb serves as a bank or O2 reserve to supercharge the plasma with dissolved O2. The largest O2 diffusion difference occurs between the arterioles and tissues.6 Capillary O2 partial pressure is at equilibrium with tissue O2—5 to 25 mm Hg O2.6 Lymphatics (without Hgb) have the same O2 tension as intracellular cytosol—15 to 25 mm Hg. The plasma, cell membranes, and cytosol all represent impediments to O2 movement.6–8
Changes in calculated blood O2 content due to anemia versus hypoxia can point out the importance of dissolved O2. An example is useful. If one calculates O2 content in a patient with PaO2 of 90 mm Hg having 15 g/dL Hgb, and then recalculates it at an Hgb of 7.5 g/dL (e.g., a normal Hgb decreases during cardiopulmonary bypass), the reduction in O2-carrying capacity is 49.5%; however, if one calculates O2 content at 15 g/dL, but the PaO2 decreases 50% to 45 mm Hg (the level at Everest base camp 5300 m elevation), the reduction in O2-carrying capacity is only 18.9%. Thus, although the patient with the Hgb loss is fine, the patient with that 50% reduction in PaO2 (dissolved O2) is in distress, even though he does not undergo nearly as much loss of total O2-carrying capacity as the patient with the Hgb loss. Thus, calculated O2 content shifts alone do not explain clinical DO2; dissolved O2 is critical clinically.
Decreased Hgb alone does not cause tissue hypoxia until it becomes severe, that is, until the Hgb level is reduced to less than DO2crit.9–13 In small studies in humans with young volunteers undergoing progressive hemodilution, anemia <5 g/dL created a subjective feeling of energy loss, a decrease in cerebral processing (P300 latency), and tachycardia, although lactate did not increase and DO2crit was not reached.14–17 These changes were taken as evidence of an O2 deficit. Although these studies showed that subjective and objective changes did occur, DO2 remained adequate for cellular metabolism (no lactate shift). Resolution of the cerebral slowing occurred with an increase of inspired O2 to 100% (which increased dissolved O2 dramatically but increased total O2 by only 8%).1 Tachycardia was relieved equally well by the subject breathing an increased inspired O2 concentration or by increasing Hgb.16
Hgb is, at best, a surrogate for O2-carrying capacity and is not an estimator for tissue DO2/utilization or metabolic demand. An underappreciated fact is that decreased circulating Hgb/hematocrit (Hct) does not affect the microcirculation until the Hct reaches a level at which DO2crit occurs. The Hct of the capillaries is relatively fixed at 15% ± 5% (for all mammalian species),4 but Hct in the microcirculation is highly regulated by capillary guard cells along with fluid dynamics.3,12 Also, O2 flux in the microcirculation is very complex and is regulated by localized cellular biochemistry (adenosine, adenosine triphosphate, nitric oxide, and O2 partial pressure). In addition, the functional capillary density (number of capillaries per gram of tissue) can change rapidly depending on tissue O2 demand and other complex signaling (e.g., nitric oxide and adenosine diphosphate).
Furthermore, O2 transfer between arterioles, venules, and counter-current vessels is complex. There is a redundant 3D architecture of microcirculation that is different from the overly simplistic Krogh tissue cylinder models.7 In brief, in response to anemia, the microcirculation cannot increase red cell concentration due to physical fluid dynamic limits known as the Fahraeus-Lindqvist effect.4 Rather, it increases red cell transit time, rapidly increasing intracellular erythrocyte O2 extraction ratio, and opening nonflowing capillaries, etc. to increase O2 in the microcirculation. There is a DO2 (crit) of 184 mL/M2/min that is reached at 3 to 3.5 g/dL Hgb or 15% Hct (animal data) if preload is maintained and CO is maximized.4 This actually should be no surprise. Shock occurs at a DO2crit of 15% Hct (in mammals studied to date) if all other physiologic compensatory mechanisms are intact.
In trauma, O2 debt—calculated as the length of time a patient’s DO2 is less than DO2crit multiplied by the severity of degree below DO2crit—is a predictor of morbidity and mortality.18–21 O2 debt must be repaid, and the patient’s survival prospects are increased if this happens quickly. The longer it takes to repay O2 debt, the greater the risk of multisystem organ failure.18–21
The 2 case reports in this issue are unique in that the patients’ DO2 closely approached or exceeded DO2crit for a considerable period of time, yet both survived without multisystem organ failure or indolent courses leading to death. Why did they survive? Fortunately, it appears that both teams of physicians understood the importance of maintaining, indeed increasing, circulatory volume.
One of the patients discussed actually had a >50% reduction in O2 demand,2 which is fascinating and suggests that there are still many mysteries to unravel to determine the best ways to electively decrease O2 demand. What cellular signals trigger the patient’s body to reduce O2 demand? Are there ways to induce such a reduction, with either drugs or ischemic preconditioning? Cooling cells by just a few degrees promotes their survival during hypoxia or ischemia, whereas profound hypothermia to a degree approximating that achieved during complex congenital cardiac surgery or drowning in frigid water allows the “pump to be turned off” without causing cellular injury. Cold also increases dissolved O2. In other words, perhaps we should abandon the concept that a given transfusion trigger (or O2 demand level) is static and absolute. Although the DO2crit level of 3.5 g/dL (animal data) usually appears to be a threshold of cellular shock, the Hgb level was much lower in both of the cases reported, without apparent organ damage.
Historically, the 3.5 g/dL level is exactly what the transfusion trigger was in the early 1900s.22,23 Unlike transfusions today, early transfusions used fresh whole blood, with red cells having normal O2 function, normal cell deformability, and few or no storage lesions.23 Therefore, these early transfusion of cells were immediately effective.
Currently, treatment of Jehovah’s Witness (JW) patients with extremely low levels of Hgb occasionally gives scientists another glimpse into the world of extreme reductions in O2-carrying capacity. In a recent cohort matched series of JW patients undergoing cardiac surgery, the JW patients had better clinical outcomes at lower (sometimes shockingly low) Hgb levels than those patients treated with normal (transfusion based) cardiac care.24 There must be ways, yet to be discovered, that cells can signal themselves to down-regulate their O2 demand in response to anemia.
This brings the question full circle: “Is our understanding and teaching of physiology and clinical medicine (transfusion) and Hgb O2 content/DO2 correct?” Dissolved O2 is what actually keeps us alive, albeit supported by O2 content of the Hgb. It is dissolved O2 that must migrate from red cells across the plasma, cell membranes, and cytosol into the mitochondria. That physiology is very complex and occurs without Hgb. The relative contribution of dissolved O2 becomes even more important in severe anemia, perhaps necessitating the use of 100% inspired or hyperbaric O2 to maximize dissolved O2 content. Exactly how O2 moves in the microcirculation and even through the cell membrane/cytosol is fascinating.
Clearly, we still have a great deal to learn about the limits of human physiology!
Bruce Spiess, MD
Department of Anesthesiology
MCV/Virginia Commonwealth University
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