The Microcirculation as a Therapeutic Target in the Treatment of Sepsis and Shock

Vanina S. Kanoore Edul, M.D.; Arnaldo Dubin, M.D., Ph.D.; Can Ince, Ph.D.

Disclosures

Semin Respir Crit Care Med. 2011;32(5):558-568. 

In This Article

The Relationship Between Global Oxygen Delivery and Oxygen Consumption

Oxygen delivery (DO2) and oxygen's utilization by tissues require the integration of the respiratory, hematopoietic, and cardiovascular systems. Oxygen uptake (VO2) is normally determined by tissue O2 demand;[7] consequently, VO2 and DO2 are tightly coupled to maintain cellular energy balance. In times of health, and during rest, VO2 remains relatively constant and independent over a wide range of O2 delivery values. Indeed, under resting conditions, VO2 represents ~25% of DO2, leaving a large reserve of O2 to be extracted under conditions of decreased DO2 by increasing the O2 extraction ratio (O2ER). This situation is called the O2 supply independent phase (Fig. 1) and is characterized by the preservation of aerobic metabolism. Below a critical level, a "supply dependent phase" ensues because subsequent increases in the O2ER can no longer maintain VO2, which can result in anaerobic metabolism (Fig. 1), a dangerous condition that, if left uncorrected, may eventually produce MOF and ultimately death. Cain studied this issue extensively and showed that this critical oxygen transport point (DO2crit) was the same regardless of whether DO2 was decreased by progressive anemia or by hypoxemia.[8] In experimental models of sepsis, however, the ability to increase O2ER is disturbed, and the DO2crit is typically higher and the O2ER is lower in septic shock than in hemorrhagic shock.[9] VO2 varies as a function of DO2 in critically ill patients,[10] suggesting a lack of the ability to augment the tissue O2ER. This phenomenon was called pathological oxygen supply dependency to distinguish it from the physiological oxygen supply dependency described in models of hypoxic, anemic, and stagnant hypoxia (Fig. 1). The mechanisms that underlie this situation have been an issue of intense debate, and two theories have been developed: (1) that the alteration and loss of regulation of the microcirculation leads to heterogeneous perfusion, causing areas of hypoxic pockets and resulting in enhanced shunting pathways;[11] and (2) that despite adequate oxygen delivery sepsis-induced mitochondrial dysfunction causes an inability of the mitochondria to utilize oxygen, a condition that was termed cytopathic hypoxia.[12]

Figure 1.

Physiological and pathological oxygen supply dependency.

Recently, it has been proposed that regional tissue dysoxia caused by microcirculatory dysfunction leads to mitochondrial depression and that attention should be focused not only on sepsis but also on sepsis that is not responsive to therapy, in which there are relatively normal global systemic hemodynamic variables but clear signs of tissue and microcirculatory factors known to be associated with a bad outcome. This condition has been termed microcirculatory and mitochondrial distress syndrome (MMDS) to identify the compartments in which the failure occurs, and it could explain the inadequacy of therapeutic strategies in sepsis and shock in which therapy is aimed at correcting systemic hemodynamic and oxygen-derived variables and not at the compartments perpetuating cellular distress leading to organ dysfunction, namely that of the microcirculation and the mitochondria. Current evidence has shown that the origin of circulatory failure in such patients is not found in alterations in systemic variables but rather in microcirculatory failure.[13] In fact, the VO2/DO2 dependency may be occurring regionally while whole body relationships are relatively normal. Therefore, global hemodynamics and O2 transport parameters may fail to show regional and microcirculatory blood flow derangements.

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