Quantitative Approach to Peritoneal Exchange

Distributed Model of Peritoneal Transport

Because of the complex relationships between the various parts of the peritoneal transport system, an integrative approach needs to be taken in order to quantify the system. The distributed model was devised as a simplification of the actual system. In this concept, the blood capillaries are distributed uniformly throughout the tissue space, surrounded by parenchymal cells and the interstitium, which is also assumed to have uniform concentrations of interstitial matrix molecules. A layer of mesothelial cells and the underlying connective tissue of the peritoneum overly the tissue space. These principles are portrayed in a simplified fashion in Figure 1. Lymphatic vessels, which are typically at the tissue planes in the parietal tissue or distributed within the multiple layers of smooth muscle of the visceral tissues, are modeled as a separate flow from each tissue compartment (see Figure 3). Within this system, diffusion of small molecules (MW less than 6,000Da) between the blood and the peritoneal cavity is a symmetrical process, that is, small molecules from blood to the peritoneal cavity or from the peritoneal cavity to the blood follow an equivalent path. An asymmetry in transport exists in the case of larger molecules, which can transfer across capillary walls from the lumen to the interstitium via "large pores" but can only return to the blood via the lymphatics.

An engineering approach to the transfer of small solutes across the peritoneum is illustrated in the following equation:

rate of mass transfer =

where Cpc, Cplasma are concentrations in the peritoneal cavity and the plasma respectively. Vpc is the volume in the peritoneal cavity and in this version is assumed to remain constant. The terms MTQ and Ai are, respectively, the mass transfer coefficient and the contact surface area of each tissue element "i" of the transport system. In this equation, the peritoneal volume is assumed to be well mixed with a uniform concentration, and the total transport resist ance of each tissue element has been lumped into the term MTCj.

The MTCj can be related to the tissue diffusivity and the capillary permeability with the following equation:

where Dj is the effective solute diffusivity for each tissue and (pa)i is the capillary permeability (p) times the area density (a) for the tissue. The term p incorporates the contributions from the two pores that permit passage of solute. This equation implicitly assumes that there are no blood flow limitations.

For a diffusion-limited solute (MW less than 6,000Da), the concentration profile in the tissue can defined as


where Ci is the tissue concentration and x is the distance into the tissue.

Peritoneal Surface Contact Area

In consideration of Equation (1), a major factor that determines the rate of mass transfer across the peritoneum is the peritoneal surface contact area (Ai) between the peritoneal solution containing a therapeutic drug or dialysate and the peritoneum. As illustrated in Figure 1, transfer will not occur between the vessels located in the tissue and the cavity without contact of fluid on the overlying surface. Although some authors have discounted the three-dimensional nature of the transport barrier and equate the perfused vascular area to the peritoneal surface area, animal and human studies have demonstrated that rate of solute transfer is directly dependent on the peritoneal contact area. In human studies, increasing the volume of fluid within the peritoneal cavity increases the surface contact area, which increases the creatinine mass transfer proportionately. With the use of relatively large volumes in rodents and human dialysis patients, only 30 to 40 percent of the total anatomic peritoneal surface area is in contact with the solution.

Contact surface area is likely not distributed proportionally between parietal and visceral tissues. Although the visceral peritoneum makes up approximately 60 to 70 percent of the mammalian anatomic peritoneum, evisceration in rodents has been shown to decrease the peritoneal mass transport only 10 to 30 percent. Transfer rates of small solutes across different surfaces of the visceral and parietal peritoneum, independent of surface area, have been shown to be essentially equivalent. Therefore, the actual distribution of the fluid contact area may not make a difference in determination of the overall average mass transfer rate. Pathological changes in the peritoneum, such as the development of adhesions that restrict free flow of fluid in the cavity, may alter the distribution.

Modulation of Transport Barrier: Normal Physiology

Altering Surface Contact Area

A problem may develop in IP chemotherapy if the residence time of the solution in contact with the carcinomatous target is short. The goal of intraperitoneal chemotherapy is to expose 100 percent of the peritoneal surface to the therapeutic solution for a maximal duration. Typically, this is performed in humans by infusing 2L of peritoneal dialysis fluid into the cavity and allowing it to be absorbed. Rates of fluid transfer are typically unimportant to the chemotherapist, since most of these patients have intact kidneys and can excrete the absorbed fluid. Increased surface area during intraperitoneal chemotherapy would be very advantageous to treatment of metastatic carcinoma. If the solution containing the drug is in contact with the surface of the tumor for 10 minutes out of a 24-hour period there will likely be very little drug deposited into the tumor. use of relatively high concentrations of diacetyl sodium sulfosuccinate (DSS) in rodents resulted in 100 percent of the peritoneal surface area in contact with the fluid, but toxicity was observed. A further problem occurs in some patients with extensive carcinomatoses who develop severe adhesions, which bind together portions of the visceral and parietal peritoneum, restricting the movement of fluid to all parts of the peritoneal surface and limiting therapy. Surface-active agents may be useful in patients with end-stage carcinoma, but testing in animals should be undertaken prior to use in humans to elucidate potential toxicity.

In Equation (1), which describes the rate of mass transfer across the peritoneum in quantitative terms, the rate is directly proportional to the surface contact area. Enhancement of the peritoneal surface area by even 20 percent would increase the rate of mass transfer by 20 percent and could provide enough additional dialytic therapy to improve dialysis efficacy. Increasing the volume from 2 to 3L in average-sized humans has been shown to improve the rate of transfer of creatinine by 25 percent, proportional to the increased surface area in contact with the fluid. In animals, the use of surface-active agents such as DSS has been shown to increase the surface contact area and to proportionally increase the rate of mass transfer. In small rodents, this was shown to also increase the rate of protein loss during the dialysis. Since in chronic dialysis, the fluid is removed from the body and discarded, this additional loss of protein could be detrimental to the patient. At this time, there is no data on the use of surface active substances in the human peritoneal cavity. Low doses of surface-active substances should first be tested in animal models and demonstrated to be safe for chronic use prior to their utilization in human beings.

use of larger volumes to cover more of the peritoneal surface is currently the simplest method of increasing surface contact area. The major factors that determine the tolerable peritoneal volume are the size of the patient, the expansion capability of the abdominal wall, the length of time of the procedure, and the position of the patient. For ambulatory peritoneal dialysis, the volumes are typically 2 to 3.5L. Very few people can tolerate more than this volume in their peritoneal cavity, while carrying out their activities of daily living. on the other hand, a patient undergoing radical resection of metastases in the peritoneum and who is anesthetized might tolerate very large volumes in the cavity while supine and anesthetized. During experimental IP chemotherapy, rates of transfer have also been markedly enhanced by placing two catheters into the cavity after surgical debulking of tumor and perfusing at a very high flow rate into one catheter and removing the fluid from the other. By maintaining a very high drug concentration in the peritoneal cavity and by perfusing the peritoneal surface with a rapid flow rate, the surface area and the concentration difference between the cavity and the blood in the underlying microcirculation were maximized, and these measures caused a doubling of the mass transfer rate of low-molecular-weight drugs from the cavity.

Altering the Mass Transfer Coefficient

A second method of altering transperitoneal transport is adjustment of the mass transfer coefficient (MTC). As shown in Equation (2), the MTc is equal to the square root of tissue diffusivity times the capillary permeability-area density product. By altering any of these terms, one can obtain a modest increase or decrease in the MTC in proportion to the square root of the factor. In the setting of dialysis where maximal rates of transfer are desired, many studies have demonstrated that the use of drugs such as nitroprus-side does increase the clearance of urea, creatinine, inulin, and protein in a dose-dependent fashion. Although there are no data on which term within the (pa) is actually altered, it is assumed that vasodilators increase the vascular surface area per unit volume of tissue or a. Vasodilator substances diffuse into the tissue from the peritoneal cavity and set up a concentration profile similar to the small solute profile in Figure 2. Thus the most marked effect would be close to the peritoneal surface, whereas the vasodilation more than 500 mm from the surface would be much less. Unfortunately, intraperitoneal nitroprusside appears to be limited by a loss of effect after approximately five exchanges with the drug. Removal of the drug from the dialysis solution causes a decrease to the baseline of the permeability. In addition, there may be effects on systemic blood pressure that limit the use of vasodilators in the peritoneal cavity.

In contrast, vasoconstrictors cause an acute decrease in the rate of mass transfer. It is presumed that they work in the opposite fashion by decreasing the perfused vascular surface area. These might be useful in chemotherapy where local absorption into tissue should be maximized, but systemic absorption into general circulation should be minimized. Experiments in animals have shown that these drugs acutely will cause a change, but there is little data in humans. Theoretically none of the vasodilators or vasoconstrictors should change the intrinsic capillary permeability, nor should they change any characteristics of the tissue diffusivity.

The tissue diffusivity can be altered by changing the structure of the extracellular space. As described earlier, a large volume dwell tends to increase the extracellular space of the subperitoneal tissue. Even at very low intraperitoneal pressures of 4mmHg, the extracellular space of the rat abdominal wall doubles. This will translate to a doubling of the effective diffusivity for small solutes, which are restricted to the extracellular space. This may also cause an increase in the rate of diffusion of larger solutes, such as immunoglobulins, which distribute to a much smaller portion of the tissue space because of interactions with the negatively charged matrix molecules. Alteration of the extracellular matrix by decreasing the concentration of hyaluronan or collagen will lead to less macromolecular restriction and a higher rate of transport.

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