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Sepsis and Blood Flow

Decreased Erythrocyte Deformability:  the Crucial Abnormality in Multiple Organ Dysfunction Syndrome

The February 14, 2013 edition of the New York Times tells the story of an “Athlete’s Near-Death from Sepsis, and His Mysterious Recovery,” where a college basketball star with an apparently ordinary case of pneumonia found himself battling sepsis, multiple organ dysfunction, and death.  Only with the administration of the anticoagulant, activated protein C, did he manage to survive.  

In the intensive care setting, multiple organ dysfunction syndrome (MODS) is one of the most important factors contributing to mortality and morbidity.  Infection, trauma, burns and the like, that develop into sepsis, are the most common insults that can trigger the uncontrolled inflammation leading to MODS.  As a syndrome, MODS is widely accepted to be a form of organ dysfunction that results from a systemic inflammatory response and decreased tissue perfusion.

Sepsis and MODS sometimes have an aura of mystery surrounding them, in part because of the large amount of research done in the field which has implicated a bewildering number of cytokines, bacterial toxins, complement, apoptosis, and mitochondrial dysfunction. Mitochondrial dysfunction in particular is an intriguing concept, but the available data cannot distinguish the putative effects of mitochondrial dysfunction from decreased tissue perfusion caused by impaired erythrocyte deformability. 

In this month’s commentary, I zero in on the role of red blood cell stiffness, or erythrocyte deformability, in MODS and make the case that MODS is a prototypical syndrome caused by impaired erythrocyte deformability.  I hope that this commentary may stimulate deeper thinking on the role of hemodynamic forces not only in sepsis and MODS but also in a broader range of inflammatory conditions, both acute and chronic.

Numerous clinical studies have demonstrated that red blood cell deformability is impaired in sepsis.  In a 2009 study of 196 intensive care unit patients (36 with sepsis and 160 without) and 20 healthy controls, erythrocyte deformability was shown to be significantly impaired in septic patients vs. nonseptic patients and controls (p<0.05), [1].  Plugging of capillaries by stiff erythrocytes decreases blood flow, allowing erythrocytes to aggregate.  Red blood cell aggregation, a separate hemodynamic parameter, was associated with the degree of organ failure in this study as determined by the Sequential Organ Failure Assessment.  

A 2001 animal study on erythrocyte deformability, nitric oxide (NO), and capillary density in sepsis provides an insight on the underlying mechanism.  Functional capillary density, a measure of capillary blood flow distribution, was used to gauge tissue perfusion.  With sepsis induced in rats, red blood cell deformability decreased by 13%, NO levels increased by 254%, and number of blocked capillary vessels increased 149% (all p values < 0.05), [2].

Physiologically, NO serves as a local mediator, affecting the immediate area in which it is produced.  Nitric oxide has a very short half-life, on the order of seconds.  In endothelial cells, NO is produced by the enzyme inducible nitric oxide synthase (iNOS), which, in vitro, is upregulated by endotoxin.  When NO accumulates to the extent that it appears in the systemic circulation, the onset of MODS is more likely. 

In the animal model of sepsis, NO was detectable in the systemic circulation three hours after induced peritonitis.  The appearance of NO was associated with decreased erythrocyte deformability and a significant increase in the number of capillaries in which no blood flow could be seen microscopically.   However, treatment with aminoguanidine, an inhibitor of iNOS, reduced the number of capillaries with no flow to levels seen in controls [2].  

In a separate human clinical study, serum nitrate levels, an indirect measure of NO production in vivo, was shown to be correlated with scores for MODS and renal insufficiency [3].     

At the cellular level, the exchange of gases and nutrients occurs by diffusion.  Diffusion is more efficient over shorter distances, so the human body contains an estimated 60,000 miles of capillaries to minimize the distance of blood to each cell.  All cells are estimated to be at most 100 to 200 microns from the nearest capillary.   

The diameter of capillaries can be as small as 3 microns, so red blood cells, with diameters of 7 to 8 microns, must reversibly deform to traverse them.  To accomplish this, the erythrocytes must elongate, which not only permits capillary perfusion but also increases the red blood cell surface area in contact with the endothelium, maximizing diffusion (see Figure 1).  

 

Figure 1.  Hosseini SM, Feng JJ. A particle-based model for the transport of erythrocytes in capillaries. Chemical Engineering Science 2009; 64:4488-97.

Any increases in the stiffness of the red blood cell directly decreases perfusion on a systemic basis.  Reduced red blood cell deformability and tissue perfusion both decrease tissue oxygen utilization and ATP production.

One can easily see that a decrease in the ability of erythrocytes to deform has a negative effect on the function of the tissue they supply.  Decreased perfusion of the brain causes decreased consciousness, whereas decreased perfusion of the heart contributes to hypotension.  Decreased perfusion of the intestines causes damage which allows escape of more bacterial toxins into the circulation.  With additional research, greater attention to perfusion may have benefits not only in the acute inflammation found in sepsis but also in chronic inflammatory illnesses.


References:

1. Early alterations of red blood cell rheology in critically ill patients.  Giulia R, Occhpinti G, De Gasperi A, Vencent J-L, Piagnerelli M.  Crit Care Med 2009; 37: 3041-6.  

2. Erythrocyte deformability is a nitric oxide-mediated factor in decreased capillary density during sepsis.  Bateman RM, Jagger JE, Sharpe MD, Ellsworth ML, Mehta S, Ellis CG.  Am J Physiol Heart Circ Physiol 2001; 28o:H2848-56.

3. Nitric oxide (NO) production correlates with renal insufficiency and multiple organ dysfunction syndrome in severe sepsis.  Groeneveld PH, Kwappenberg KM, Lanermans JA, Nibbering PH, Curtis L.  Intensive Care Medicine 1996; 22: 1197-202.    

 

Last Updated: 2014-12-30

 

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