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Nephrology Unit, University of Rochester Medical School, Rochester, New York.
Correspondence to Dr. Michael F. Flessner, Box 675, 601 Elmwood Avenue, University of Rochester, Rochester, NY 14642. Phone: 716-275-4517; Fax: 716-442-9201; E-mail: Michael_Flessner{at}URMC.Rochester.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Results of animal studies (6) in our laboratory indicate that a much smaller area than the total area found on dissection is available for transport. Individual mass transfer coefficients (MTC) of different surfaces of the peritoneum were multiplied times the area (A) of each of the surfaces measured after killing the animal and dissecting the abdominal cavity. By summing the MTC x A products of all of the tissues surrounding the cavity, we calculated an estimate of the mass transfer-area coefficient (MTAC) for the whole cavity. In a separate set of animals, the MTAC for the entire cavity was measured in intact rats with a large volume of dialysis solution (50 cc in 300-g rat) and was found to be 25 to 30% of the sum of the MTC x A. This discrepancy between calculated MTAC and measured MTAC suggested that much of the area was not available for transport during a large-volume dialysis. A separate set of animals were then dialyzed with an intensely staining dye for 1 h to detect those surfaces that came in contact with the solution. Large parts of the peritoneal surface had no staining, i.e., one side of the cecum, colon, and the stomach and large parts of the abdominal wall and diaphragm. Although qualitative, this observation demonstrated that large portions of the peritoneum were untouched by solution while the animal was in an anesthetized, quiescent state.
Vigorous shaking of anesthetized animals or surface active agents that were added to the peritoneal solution has resulted in marked increases in mass transfer. Levitt et al. (7) measured the rate of transport of urea, creatinine, and glucose in rats at rest or agitated with an orbital shaker and found a fourfold increase in MTAC, in good agreement with our studies. Others (8) have carried out studies analogous to Levitt's and have found similar results. Penzotti and Mattocks (9) used dioctyl sodium sulfosuccinate (DSS) in rabbits and were able to demonstrate a three- to fourfold increase in the mass transfer of small solutes. Leypoldt (10) carried out experiments with 0.005% DSS in rabbits and calculated a 50% increase in mass transfer of creatinine. If we presume that the maneuvers of agitation or surface active agents primarily affect the A of the MTC x A, then all of these studies in animal models provide indirect evidence that fluid in the quiescent peritoneal cavity comes in contact with only approximately 25 to 30% of the total peritoneal area.
Our hypothesis in this study is that even with relatively large volumes, only a fraction of the peritoneal surface is available to physiologic salt solutions in the cavity. We hypothesized further that maneuvers such as use of a surface-active agent or severe agitation result in an increase in surface area in contact with the fluid. To address these hypotheses, we carried out a study in mice to measure the area of contact relative to the peritoneal area under a variety of conditions.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Surgery was carried out after loss of the blink reflex and withdrawal reflex. A trocar was used to make a midline penetration in the lower abdominal wall, and a small catheter was passed into the peritoneal cavity. This was sutured closed with a purse stitch. In longer term experiments (24 h), no catheter was placed, but an intraperitoneal injection was made directly via a syringe and a 22-gauge needle. To maximize the surface area covered by the fluid, the volume injected in all experiments was 10 ml. This volume was scaled from a 2.5-L volume in a 70-kg human by the formula Vmouse = 2500 ml(0.025 kg/70 kg)0.7 = 10 ml (11). This method of scaling results in larger volumes in small animals than would be calculated on purely a "per kg" basis; these volumes, however, do result in intraperitoneal hydrostatic pressures that closely mimic those in humans. The animals tolerated this volume well without respiratory difficulties. At the end of the designated period of time for the protocol, the animal was killed with an overdose of pentobarbital. The abdomen was then opened, the remaining solution was drained, and the carcass was rapidly frozen in isopentane, cooled to -70°C.
Isotopic Tracer and Solutions
To mark the peritoneum that is in contact with the intraperitoneal
solution, we dissolved 125I-IgG (anti-rabbit IgG, no. IM-134;
Amersham Corporation, Arlington Heights, IL) in all peritoneal solutions (25
µCi/10 ml). Four different batches of labeled IgG were used in the study.
Each batch had a specific activity of 12 to 14 µCi/µg, and each batch
was used within 2 to 3 wk, with little change in the specific activity. We
previously tested various batches of this antibody, and there is very little
variation in its nonspecific binding characteristics from batch to batch. As
in our previous studies (12),
before use of the isotope, the free 125I was removed by dilution
with saline and successive ultrafiltrations to limit the free isotope to
<1%. The approximate loss of label from tracer over the time of use of each
batch was typically 5 to 8%. Samples of peritoneal fluid were collected at the
end of each experiment, and the free isotope was determined by precipitation
with 10% TCA (see reference
12) to be <1.5% at 1 h and
<3% at 24 h.
Solutions included an isotonic Krebs-Ringer-Bicarbonate (KRB; see reference 12 for makeup of solution), pH 7.4, 290 mosm/kg, or Dexemel (Icodextrin 4%, 278 mosm/kg, a kind gift from ML Laboratories, PLC, Liverpool, England). In some cases, a surface active agent, the sodium salt of DSS (purchased from Sigma-Aldrich Co, St. Louis, MO), was added to these solutions in concentrations of 0.0005 to 0.5%.
The Icodextrin solution was used because human studies (13) demonstrated that the volume would remain constant for up to 48 h. It was assumed that holding the volume constant would result in a higher value for peritoneal contact area than an isotonic solution that would be absorbed over time (14). However, the 10-ml volume of either Icodextrin or KRB was completely absorbed from the mouse peritoneal cavity after 24 h. The reason for this is that the level of amylase present in rodent tissue is 2 orders of magnitude higher than in humans (15). To verify this, we collected 4-h effluents from six peritoneal dialysis patients who were undergoing peritoneal equilibration tests with 2.5% glucose solutions and from three mice that were dialyzed with the KRB solution. The amylase activity was determined with Sigma Kit 577 (purchased from Sigma-Aldrich Co.) Amylase cannot be determined directly in Icodextrin solutions with this assay, which depends on the metabolism of a starch labeled with a marker; the Icodextrin would compete with the reagent and the resulting determination would be low. Amylase activity in the peritoneal effluent at 4 h was zero in humans, whereas the activity in mice was 168 ± 41 U (mean ± SD).
Experimental Protocols
The goal of protocol I was to determine what proportion of the peritoneal
surface area is actually in contact with the dialysis fluid during a
relatively short dialysis (1 h) and to investigate what effect the following
maneuvers might have on the contact area: (1) vigorous movement of
the animal or (2) a surface active agent in the peritoneal solution.
The dwell time of 1 h was chosen arbitrarily to be long enough for sufficient
labeled IgG to interact with the peritoneum to register the autoradiogram.
Although we previously demonstrated that adsorptive binding of the labeled IgG
occurs in as little as 1 min
(14), the amount bound to the
surface must be sufficient to produce an unambiguous image on the film.
Increasing the amount of radioactivity results in problems of specimen
contamination during slicing and handling. From previous in vitro
binding experiments (12), we
estimated that 1 h produces sufficient binding with molar concentrations that
can be handled safely. We verified this estimate with 1-h binding studies of
the 125I-IgG to mouse abdominal wall under the three conditions of
quiescent, shaking, and with the solution containing 0.5% DSS. The results
showed that at the IgG concentrations used in the experiments, all conditions
produced relative optical densities in excess of 0.5, which registers as a
sharp image on the film. The DSS solution resulted in higher levels of optical
density in the film than with the other solutions, but this did not affect the
analysis because all images are weighted equally (see the section Data
Collection and Analysis).
Three animals each were dialyzed with (1) KRB under quiescent conditions, (2) KRB under conditions of vigorous shaking at the "shaking speed" (>60 cpm) on a vortex mixer (Model G560; Scientific Industries, Bohemia, NY), and (3) KRB with 0.5% DSS. All solutions contained the 125I-IgG, which labeled the peritoneum in contact with the solution. After dialysis for 1 h, each animal was killed, the cavity was drained, and the carcass was frozen. Tissue samples were collected and analyzed as below.
Protocol II was designed to answer the question, "Does the time of dwell change the contact area?" Presumably, peristalsis would distribute the fluid to different regions of the peritoneum and broaden the overall exposure. Under anesthesia, the animals (n = 3 for each solution) received an injection of the following solutions, each containing the labeled IgG: (1) KRB or (2) the solution containing 4% Icodextrin. After injection of the 10 ml, the mice were allowed to wake up and ambulate freely around the cage and eat and drink ad libitum. At the end of 24 h, each animal was killed, the cavity was opened to check for residual fluid, and the carcass was frozen. Tissue samples were collected and analyzed as below.
Protocol III was designed to establish the dose response of the additive DSS: how much surface area was in contact with the solution versus the concentration of DSS. Because the use of surfactants has been associated with increased protein loss (10), the total protein concentration of the peritoneal effluent was determined with Sigma Diagnostic Kit 690-A. The procedure was the same as in protocol I, but the solutions were made up of KRB with (1) 0.05% DSS, (2) 0.005% DSS, and (3) 0.0005% DSS. All solutions contained the 125I-IgG, which labeled the peritoneum in contact with the solution. After dialysis for 1 h, each animal (n = 3 for each DSS concentration) was killed, the cavity was drained, and the carcass was frozen. Tissue samples were collected and analyzed as below.
Data Collection and Analysis
The frozen carcass was sliced in whole cross sections, 20 µm thick, with
a Hacker-Bright Cryotome (Model OTF; Fairfield, NJ). After three to four
sections were collected, the entire block was sliced 2 mm down to the next
sampling point, where several cross sections again were collected. This was
repeated for a total of 10 sampling points, which spanned the entire
peritoneal and pelvic cavities. These sections were than placed against x-ray
film (Kodak Biomax MR film; Kodak Corp., Rochester, NY) for 1 to 3 wk to
develop autoradiograms. It was assumed that the autoradiograms of each
sampling level represent the linear measurement of tissue in contact with the
solution in the cavity in the plane of sampling. The tissue sections that
corresponded to the autoradiograms were stained with standard hematoxylin and
eosin to highlight the anatomic peritoneum.
To quantify the area of contact (or "wetted area") and the area
of the anatomic peritoneum, we imaged individual autoradiograms and the
corresponding histologic slides (MCID; Imaging Research, St. Catherines,
Ontario, Canada), and the linear measurement of each area was determined by
manual tracing within the digital image. All portions of the autoradiogram
that corresponded to peritoneal surface were included in the analysis
irrespective of the optical density. No attempt was made to quantify the
amount of radioactivity at different surfaces. If the optical density was
above background and represented a tissue surface, then its linear dimension
was determined. The principle of measurement is based on the assumption that
the surface of the peritoneum is made up of a complex collection of cylinders,
each of which has an area equal to the product of the tissue dimension d (2
mm) between sampling points (equivalent to the height of the cylinder) times
the circumference of the cylinder (C) as determined from the linear dimension
in each image. Figure 1 gives a
simplified depiction of the principle. To estimate the area of the irregularly
shaped light bulb, cross-sectional circumferences (Ci) through the
light bulb are measured at intervals of d. The area of the light bulb may then
be approximated by the following equation:
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In the same way, we can determine the area in each of 10 sampling levels of
the mouse peritoneal cavity. The ratio (R) of the wetted area to that of the
anatomic peritoneum at each sampling point is calculated by the following
equation:
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The average of R at all sampling levels (Rmean) and the R from
the sum of all
were calculated for the purposes of analysis. No significant difference was
found between Rmean and Rsum; therefore, only
Rmean ± SEM is reported. Results are compared with the
unpaired t test or one-way ANOVA in NCSS (Number Cruncher Statistical
Systems, Provo, UT). A statistic is considered to be significant if the
probability of a type 1 error is P < 0.05.
As a check on this measurement technique, direct measurements of the peritoneal area were compared with anatomic areas calculated from the first equation. The comparison cannot be carried out in the same animal because our technique requires the carcass to be frozen and sliced to create thin cross sections of the cavity. Therefore, the peritoneal tissues of six separate animals with similar weights to six animals in protocol III were dissected, and their areas were measured directly. The Areaanatomic of each of six animals of protocol III was calculated with the first equation. The mean of these six areas was then compared with the dissected areas with the unpaired t test (NCSS, see above).
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Results |
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The experiments in protocol I demonstrated that even with large volumes, the area of contact was limited in the quiescent animal but increased with shaking or with use of a surface-active agent. Figure 2A displays the histologic section of a quiescent mouse treated with KRB along with the corresponding autoradiogram (Figure 2B; presented with a reverse spectrum in which the bright areas are those in which the fluid is located or has made contact). Figure 2, C and D, shows an area at a similar sampling point in the mouse peritoneal cavity; however, the effect of DSS on the fluid contact is seen clearly in the autoradiogram when compared with that of Figure 2B. As shown in Figure 3, a large volume (10 ml) of isotonic KRB solution during a 1-h dwell in an anesthetized, quiescent mouse comes in contact with 0.43 ± 0.03 of the total peritoneal area. Vigorously shaking the animal increases Rmean (±SEM) to 0.54 ± 0.03 (P < 0.05). Addition of 0.5% of an anionic surfactant, DSS, to the KRB in a quiescent animal increases the ratio of contact to 1.07 ± 0.03 (P < 0.001). These findings uphold our hypothesis that only a fraction of the anatomic peritoneal surface is available to the typical salt solution in the cavity under quiescent conditions. The data also provide direct evidence that use of agitation or a surfactant increases the contact area in the peritoneal cavities of mice.
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In protocol II, the effect of a 24-h dwell time was investigated with two different solutions. In all cases, there was less than 1 ml of the original 10 ml remaining in the cavity after 24 h. The results demonstrated no difference in surface contact ratios between two treatments: for KRB, Rmean = 0.88 ± 0.02; for 4% Icodextrin, Rmean = 0.92 ± 0.02. There was no statistical difference between these numbers, but they were significantly different from the KRB solution after 1 h (Figure 3). The data show that any solution, when given enough time in the cavity, will make contact with most of the peritoneal surface.
The experiments in protocol III demonstrated a significant response of contact surface area (Rmean) and protein concentration in the peritoneal effluent with increasing concentrations of DSS in the peritoneal solution. Figure 4 displays the data from these experiments and includes complementary data obtained from protocol I (KRB with no DSS and with 0.5%). The one-way ANOVA that compared Rmean with the DSS concentration was highly significant (F = 68; P < 0.000001). The surface area ratio (Rmean) increases significantly with addition of as little as 0.0005% DSS (P < 0.05 when compared with the control KRB). Likewise, the protein concentration in the fluid after 1 h increases proportionately to the concentration of DSS and proportionately to the area of contact (one-way ANOVA significant at P < 0.0008). That the ratio decreased slightly from 0.05 to 0.5% likely is because these experiments were run on separate lots of animals and were separated in time by several months. From the results, 0.05% DSS seems to produce total contact between the anatomic peritoneum and the solution in the cavity.
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Discussion |
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The R values from 1-h dwells of the marker likely are higher than one would obtain if the experimental dwell were only 1 min in length (this likely would require a very large amount of radioactivity and be fraught with errors of contamination). Peristalsis over 1 h likely distributes the fluid to a larger total area than the contact area at a single point in time. This presumably is the mechanism that causes the R for the control solution to increase from 0.4 at 1 h to 0.9 after 24 h. Despite the limitation in the interpretation of the absolute value of what is the "instantaneous" contact area of fluid in the peritoneal cavity, our findings uphold our hypothesis.
Peritoneal Contact Area
The general equation of mass transfer across the peritoneum is represented
by the following:
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We demonstrated that a relatively large volume of isotonic salt solution in the peritoneal cavity of the quiescent mouse makes contact with approximately 40% of the anatomic peritoneum during a period of 1 h. Furthermore, we showed that shaking the animal or using a surfactant increases the proportion of the peritoneal surface area that is in contact with the solution. Unfortunately, there is no other study with which a direct comparison of results can be made. However, because MTAC = MTC x A, increasing A should increase the MTAC and therefore the rate of mass transfer. To relate observed MTAC variations by others (7,8,9,10) to our results, we assumed that the changes in the MTAC as a result of shaking or addition of surfactant most likely are due to variation in contact or "wetted" area. Unfortunately, the increases in MTAC observed by others do not correlate with our measurements in mice.
Differences in the magnitude of the effect of shaking on the MTAC (shaking rats increased the MTAC by two to four times) noted by Levitt et al. (7) or Zakaria et al. (8) and the surface area changes in our study likely are due to anatomic differences between rats and mice and to the relatively small volumes used in the rats. The 20 ml that these investigators used in the 300-g animals is much smaller than the 66 ml that we would have used with our scaling criteria. Thus, the relative contact area of the quiescent rats likely was much smaller than the area that we measured with 10 cc in 30-g mice. In the same way, early studies with DSS (9) in rabbits used volumes of 60 ml/kg (compared with 400 ml/kg in our study) and demonstrated increases in mass transfer that correspond to increases in contact area of three to four times the baseline. Our 1-h contact area likely represents a maximum attainable in the mouse, and therefore the observed changes are not expected to be as great as in other studies in which the initial contact area likely did not represent a maximum. Because our experiments were not designed to determine the MTAC, we cannot rule out an increase in the MTC portion of the MTAC calculated by other investigators.
There is a clear correlation of DSS concentration and the peritoneal contact area and protein transport, as demonstrated in Figure 4. A similar effect on the MTAC of urea was seen by Penzotti and Mattocks (9) in rabbits, with maximal MTAC at 0.05 to 0.5% DSS and diminished effect at 0.001%. As observed by Leypoldt et al. (10), the transport of protein is significantly enhanced with the use of 0.005% DSS and correlates with the surface area in contact with the fluid. In another study in rats (16), 25 ml of 3.86% dextrose with 0.005% DSS caused significant increases in fluid gain over 4 h (to 37 ml with DSS versus 33 ml without DSS) and 20 to 30% increases in urea and sodium clearance to the cavity. Our data showed that the surfactant DSS has a direct effect on the contact surface area. Although this provides a mechanism for the increases in MTAC observed with the use of DSS, it does not rule out the possibility that the MTC was changed simultaneously with the area.
Clinical Correlation
The single study in human dialysis patients has demonstrated that the
contact area of the solution in the peritoneal cavity is 0.55 m2
(5). Depending on the estimate
used for the true anatomic area of the peritoneum
(1,2,3,4),
the ratio of contact area to anatomic area is 30 to 60% in 70- to 80-kg
patients with a 2-L volume in the cavity. The area of peritoneum that is not
in contact with the dialysis solution is a potential site for dialysis
enhancement, because the MTAC = MTC x A, where A is the area of contact.
In patients who are inadequately dialyzed (weekly KT/Vurea <
2.1), a 20% increase in the MTAC may be enough to produce adequate dialysis
and allow them to continue peritoneal dialysis.
As has been demonstrated in this study and by others (7,8,9,10), there are several methods of enhancing the surface area. Lengthening the duration of dialysis will increase the total surface area contacted presumably through the peristaltic movement of the hollow viscera. However, this slow movement may move the fluid from one location in the cavity to another, but it likely will not increase the contact area through which the transfer of solute and water occurs. Maneuvers, such as the violent agitation, that were imposed on the animals (7,8) may not be practical for human beings, but it is intriguing to consider recent data that showed a significant effect on small solute transport by the application of low-frequency vibration to the abdominal wall for three 20-min periods per day (17). Another possible method of contact area enhancement is the use of a surfactant added to the dialysate. Issues of toxicity must be considered carefully with these substances. We observed that 0.5% DSS in the peritoneal cavity of mice resulted in 100% lethality within 2 h. We also observed a direct correlation among DSS concentration, contact surface area, and the protein concentration in the dialysate fluid after 1 h of dwell; protein loss must be investigated before implementing this in long-term dialysis in patients. Another item that must be investigated before human implementation is the long-term effect on the peritoneum and the subperitoneal tissue space that forms the barrier between the dialysis fluid and the blood. Other investigators (18) observed fibrinoid material in the dialysis effluents of two of three rabbits in which a 0.04% DSS solution had been used; this finding suggests that DSS may set up or enhance conditions of inflammation within the peritoneal cavity. We would conclude that all of these maneuvers to increase the contact area during peritoneal dialysis are technically possible, but they require further study for potential complications during long-term use in humans.
The enhancement of the contact area in intraperitoneal therapy may be most beneficial to patients who receive regional (localized or, in this case, intraperitoneally) therapy for metastatic ovarian or colorectal cancers. These small tumor nodules are often not detected during surgical resection of the primary tumor and often result in the death of the patient due to obstruction of the gastrointestinal tract and inanition. An alternative to typical intravenous systemic therapy is the use of regional chemotherapy or immunotherapy, which minimizes the systemic side effects of traditional therapy. A major challenge in intraperitoneal therapy (19) is ensuring that the therapeutic agent reaches all sites of metastases with sufficient dose to treat the cancer. Because these patients typically are not in kidney failure, the agent is placed in 2 L of dialysis fluid and allowed to dwell in the cavity until it is entirely absorbed. From our data, this approach should ensure that more than 90% of the peritoneum comes in contact with the fluid during the first 24 h. However, contact with the therapeutic fluid for a variable amount of time may or may not result in delivery of sufficient dose to treat the metastatic cancer. Use of a surfactant to increase the contact area to the complete peritoneal surface would ensure that the active agent is in contact with the target and can deliver a defined dose over the time of treatment. The potential benefit of using a surfactant in concentration sufficient to ensure contact between the therapeutic solution and all potential sites of metastasis within the peritoneal cavity may outweigh any toxicity of the agent. In contrast to daily dialysis, the peritoneum would be episodically exposed to the agent. Thus, the potential toxicity of the agent would be far less than in the case of dialysis, in which the exposure is continuous.
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