Extravascular spaces

It has the ability to cross the placenta and therefore provides a major line of defence against infection for the newborn. This can be reinforced by transfer ofcolostral IgG across the gut mucosa of the neonate. It diffuses readily into the extravascular spaces where it can act in the neutralization of bacterial toxins and can bind to microorganisms enhancing the process of phagocytosis (opsonization). This is due to the presence on the phagocytic cell surface of a receptor for Fc. 

These reaetions are due to the presence of immune eomplexes either in the eireulation or extravascular space. The complexes may localize in capillary networks (lungs, kidney, joints) where, together with complement and polymorphs, they may produce extensive tissue damage. Two main types of reactions fall into this group. 

As previously discussed, increased portal pressure triggers the release of nitric oxide to directly vasodilate the splanchnic arterial bed and decrease portal pressure. Unfortunately, nitric oxide also dilates the systemic arterial system, causing a decrease in blood pressure and a decrease in renal perfusion by lowering the effective intravascular volume. The kidney reacts by activating the renin-angiotensin-aldosterone system, which increases plasma renin activity, aldosterone production, and sodium retention. This increase in intravascular volume furthers the imbalance of intravascular oncotic pressure, allowing even more fluid to escape to the extravascular spaces. 

Because it is a small protein, the factor IX molecule passes into the intravascular and the extravascular spaces. Therefore, the volume of distribution of recombinant factor IX is twice that of factor VIII. Consequently, 1 unit of factor IX administered per kilogram of body weight yields a 1% rise in the plasma factor IX level (0.01 unit/mL, or 1 IU/dL). Thus 1750 units of factor IX provides an incremental increase of 50% of normal (0.5 unit/mL, or 50 IU/dL), that is, 1750 units/70 kg x 0.01 unit/mL (1 IU/dL).12 Additionally, the recovery rate with recombinant factor IX is 20% lower than that with the plasma-derived products. Therefore, initial and subsequent maintenance doses should be adjusted accordingly. 

Because of their low molecular weight (<2000 Da), the standard NS-CA are extravasated to a massive extent on first pass in noncerebral areas. Thus, Canty et al. reported that first-pass extraction of a conventional nonionic CA averaged 33 % in normally perfused myocardial areas and 50% in stenotic areas (where coronary blood flow was reduced by 50%) [15]. These data may even have underestimated first-pass myocardial extraction of CA because of back diffusion of the molecule. In another model, approximately 80% of the myocardial content of I-iothalamate was found in the extravascular space 1 minute after intravenous injection in rats [16]. 

The quinolones are rapidly and almost completely absorbed after oral administration and are widely distributed in body tissues. Levels in extravascular spaces can often exceed serum levels. Levels lower than those found in serum occur in CSF, bone, and prostatic fluids. Ciprofloxacin and ofloxacin have been detected in breast milk and ofloxacin levels in ascites fluid are close to serum levels. Food ingestion does not affect bioavailability, which ranges from 50 to 95%. The half-life for most quinolones is 3 to 4 hours. 

Figure 10.4. Schematic representation of antibody distribution into extravascular space across endothelial cells lining blood capillaries and into the tumor mass. Some of these antibody molecules may be further distributed into lymphatic capillaries.

IgG molecules found outside the extravascular space can accumulate and penetrate into a tumor mass within a tissue by several mechanisms. The rate of IgG accumulation in tissue and subsequent penetration into the tumor mass depends on the affinity and avidity of the antibody for a tumor-associated antigen. According to one model, based on computer simulations, penetration of the tumor mass is influenced by diffusion and convection, while binding affinity determines residence time of the antibody molecule bound to antigen expressed on tumor cells [23-25]. 

The most frequent adverse reactions associated with the administration of proleukin include fever, chills, fatigue, malaise, nausea and vomiting. It has also been associated with capillary leak syndrome (CLS). CLS is defined as a loss of vascular tone and effusion of plasma proteins and fluids into the extravascular space. This leads to hypotension and decreased organ perfusion, which may cause sudden death. Other side effects include anaphylaxis, injection site necrosis and possible autoimmune and inflammatory disorders. 

Neutrophils are also rapidly attracted to the site of a foreign body reaction, but likely persist in large numbers for only a few days. They generally reside within blood vessels, but in response to signals such as histamine, which increases vascular permeability, neutrophils enter the extravascular space through a process known as diapedesis. A recent study by Wozniak found that nitric oxide produced by neutrophils plays an important role in loosening of total joint implants.11... 

At diagnosis, new patients with type 1 diabetes may exhibit ketoacidosis with resultant acid-base and electrolyte disturbances. The most common abnormality is hyponatremia, which is often due to the movement of water to the extravascular space. Volume contraction may lead to elevations in blood urea nitrogen (BUN) and creatinine, as well as mild erythrocytosis. Leukocytosis may also exist in the absence of infection, and serum triglycerides and urine glucose are almost universally elevated. 

The interaction of the various aP integrin complexes with ICAMs results in firm attachment and spreading. Subsequent VCAM-1-integrin and PECAM-1-integrin interactions are involved in leucocyte transmigration through endothelial cell junctions into the extravascular space. Leucocytes can thence proceed to interact with target cells and initiate inflammatory processes. 

An uneven distribution between the intravascular and the (combined) extravascular spaces implies that we cannot use the plasma concentration of a drug as an immediate measure of the total amount in the body. To correct for uneven distribution, a coefficient named volume of distribution (Vj) has been invented (Figure 2.1 la). This is not a real volume but an experimentally determined number (with the dimension of a volume, hence the fancy name). 

The rate of disappearance of radiothyroxine from the plasma has been reported as raised after operation. Oppenheimer and Bernstein (01), on the other hand, found a decrease in the fractional removal of T4 from plasma in the absence of a diminished degradative clearance. It has been suggested that H T< may be redistributed either in the extravascular spaces or even in the gut. A significant increase in radioiodinated thyroxine in the urine has been found after injury and it is suggested that there is an increase in the peripheral degradation of thyroxine after injury (B5). 

A wide range of aldesleukin-induced adverse effects is associated with the capillary leak syndrome, which is characterized by an increase in vascular permeability with subsequent leakage of fluids and proteins into the extravascular space (4). This results in a third-space clinical syndrome, generalized or peripheral edema, weight gain, cardiovascular and pulmonary comphcations with hypotension, pericardial, and pleural effusions, ascites, oliguria, and prerenal azotemia. Symptoms usually resolve in a few days after aldesleukin withdrawal. Studies on the mechanism have raised a number of hypotheses, such as damage to the endothehal cells, release of secondary cytokines, and activation of the complement cascade (15). 

The unbound fractions are averaged values in the respective volumes. Because the apparent volumes of distribution, Vi and Vss, are much larger than the real physiological volumes, the ratios (ap/ ) and ( p/ap) must be larger than unity, that is, an appreciably higher binding of ascorbic acid to structures in the extravascular space compared with binding to plasma proteins is derived. 

Within a few minutes of an infant s birth, fluid passes from the blood vessels into the extravascular spaces. This fluid is similar to plasma except that the fluid lost from the intravascular space contains no protein. Consequently the plasma protein concentration increases. The serum activities of several eu2ymes, including CK, GGT, and AST, are high at birth, but the increase of alanine aminotransferase (ALT) activity is less than that of other enzymes. 

Immediately after an injury, there is loss of fluid to extravascular tissue with a resulting decrease in plasma volume. If the decrease is enough to impair circulation, glomerular filtration is diminished. Diminished renal function leads to the accumulation of urea and other end products of protein metabolism in the circulation. In burned patients, serum total protein concentration falls by as much as 0.8g/dL became of both loss to extravascular spaces and catabolism of protein. Serum aj-, tt2-, and y-globulin concentrations increase, but not enough to compensate for the reduced albumin concentration. The plasma fibrinogen concentration responds dramatically to trauma and may double in 2 to 8 days after surgery. The concentration of C-reactive protein rises at the same time. 

The primary function of albumin is generally considered to be the maintenance of COP in both the vascular and extravascular spaces. This is supported teleologically by the fact that its synthesis is regulated primarily by COP. If the plasma albumin level rises or falls, the concentration in extravascular spaces rapidly equilibrates with plasma to compensate for this. As discussed later, most analbuminemic individuals have little or no edema, in part because of this equflibration and in part by increased synthesis of other proteins. 

The binding of albumin to endothelial membrane-associated glycoproteins increases capillary permeability to small protems that are important for metabolism in the extravascular space. 

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