Ubc 1992 Fall Xie Shuling PDF

A COMPARTMENTAL MODEL OF HUMAN MICROVASCULAR
EXCHANGE
By
Shuling Xie
B. Sc. (Biomedical Engineering) Shanghai Jiao Tong University, China
A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF
THE REQUIREMENTS FOR THE DEGREE OF
MASTER OF APPLIED SCIENCE
in
THE FACULTY OF GRADUATE STUDIES
CHEMICAL ENGINEERING
We accept this thesis as conforming

to the required standard
THE UNIVERSITY OF BRITISH COLUMBIA
August, 1992
© Shuling Xie, 1992

In presenting this thesis in partial fulfilment of the requirements for an advanced
degree at the University of British Columbia, I agree that the Library shall make it
freely available for reference and study. I further agree that permission for extensive
copying of this thesis for scholarly purposes may be granted by the head of my
department or by his or her representatives. It is understood that copying or
publication of this thesis for financial gain shall not be allowed without my written
permission.
Department of b1-’.9 e4M’1,

The University of British Columbia
Vancouver, Canada
Date Qc-evbc-’r /3 / 992
DE-6 (2/88)
Abstract
To study the distribution and transfer of fluid and albumin between the human circula
tion, interstitium and lymphatics, a dynamic mathematical model is formulated. In this
model, the human microvascular exchange system is subdivided into two distinct com
partments: the circulation and the interstitium. Fluid is transported from the capillary
to the interstitium by filtration according to the Starling’s hypothesis, while albumin

is transported passively by coupled diffusion and convection through the same chan
nels that carry the fluid. Data for parameter estimation are taken from a number of
studies involving human microvascular exchange and include information from normals,
nephrotics, heart failure patients, and also information from experiments on both nor
mals and patients following saline or albumin solution infusions. Transport parameters
are determined by fitting model predicted results to available measurements from the
literature. The best-fit parameters obtained are LS = 43.08 ± 4.62 rnL.mmHg’•h’,
= 0.9888 ± 0.002, Pc,
0 = 11.00 ± 0.03 mmHg, PS = 73.01 mLh
, KF
1 = 121.05
mL .mmHg’h’, and JL,O = 75.74 mL.h ‘. Simulation of the available experimental
data using these parameters gave a reasonable fit in terms of both trends and absolute
valiles. All of the best-fit parameter values are in reasonable agreement with estimated
values based on experimental measurements where comparisons with literature data are
possible. The fully described model is used to simulate the transient behaviour of the
system when subjected to an intravenous infusion of albumin and the predicted values
compare reasonably well with the experimental infusion data of Koomans et al. (1985).
The coupled Starling model is able to successfully simulate the transport mechanisms of
human microvascular exchange system.
11
Table of Contents
Abstract ii
List of Tables viii
List of Figures x
Acknowledgement xiii
1 Introduction 1
2 Physiological Principles Of The Microvascular Exchange System 5

2.1 Capillaries 6
2.1.1 Arrangement of the Capillaries 6
2.1.2 The Composition and Properties of the Blood 9
2.1.3 Structure of the Transport Barrier and the Transport Mechanisms 10
2.1.3.1 Capillary Wall 10
2.1.3.2 Basement Membrane 14
2.2 Interstitial Compartment 14
2.2.1 Structure and Composition of the Interstitium 14
2.2.1.1 Collagenous Fibres 16
2.2.1.2 Elastic Fibres 18
2.2.1.3 Glycosaminoglycans and Proteoglycans 18
2.2.1.4 Interstitial Fluid 19
2.2.2 Physicochemical Properties of the Interstitium 20
111
2.2.2.1 Compliance 20
2.2.2.2 Exclusion 22
2.2.2.3 Colloid Osmotic Behaviour 25
2.3 Lymphatic System 26
2.3.1 Terminal Lymphatics 26
2.3.2 Mechanism of Lymph Formation 28
3 Model Formulation 30
3.1 Introduction
3.2 General Assumptions of Compartmental MVES Models 33
3.3 Coupled Starling Model
3.4 Constitutive Relationships
3.4.1 Circulatory Compliance
3.4.2 Interstitial Compliance
3.4.3 Colloid Osmotic Pressure Relationship
3.5 Normal Steady-State Conditions
3.6 Summary
4 Parameter Estimation And Data Analysis 55

4.1 Parameters to be Determined
4.2 Additional Relationships between the Unknowns
4.2.1 Steady-state Balances at Normal Conditions
4.2.2 Albumin Clearance Relationship
4.2.3 Parameters to be Optimized 59
4.2.4 Parameter Search Ranges • . . 61
4.3 Analysis of Data 63
4.3.1 Experimental Data 65
iv
4.3.1.1 Set A: Saline and Albumin Infusion . . . 67
4.3.1.2 Set B: Acute Saline Infusion 69
4.3.1.3 Set C: Saline Infusion . . 71
4.3.1.4 Set D: Heart Failure 71
4.3.1.5 Set E: Nephrotic Syndrome 73
4.3.1.6 Set F: Saline infusion before extracorporeal circulation 74
4.3.2 Parameter Estimation Strategy 76
4.4 Parameter Estimation Procedure 78
4.5 Numerical Methods and Computer Programs 79
4.5.1 Transient Solutions 79
4.5.2 Steady-state Solutions 79
4.5.3 Computer Programs 80
5 Results And Discussion 82

5.1 Introduction 82
5.2 Results 83
5.2.1 Best-fit Parameters for the Coupled Starling Model 83
5.2.2 The Feasibility of Combining Different Data Sets 83
5.2.3 Simulations Using Best-fit Parameters 89
5.2.3.1 Transient Responses of 11
PL, GPL and VPL after Saline or
Albumin Infusions (Sets A, B and C) 90
5.2.3.2 Simulations of Heart Failure (Set D) 98
5.2.3.3 Simulations of V
1 vs. [PL and fl
1 vs. PL
11 in Nephrotic
Syndrome (Set E) 99
5.2.3.4 Summary of the Simulations using Best-fit Parameters 101
5.2.4 Sensitivity Analysis 101
V
5.2.4.1 Lymph Flow Sensitivity — LS 104
5.2.4.2 Albumin Reflection Coefficient — u 105
5.2.4.3 Capillary hydrostatic pressure at normal steady-state -
Pc,o 105
5.2.5 Péclet Number 106
5.2.6 Verification of Fit 107
5.2.7 Residual Analysis 108
5.3 Validation of the Best-fit Parameters 110
5.3.1 Lymph Flow Sensitivity — LS 110
5.3.2 Albumin Reflection Coefficient — a . . . 113
5.3.3 Permeability-Surface Area Product — PS 114
5.3.4 Fluid Filtration Coefficient — KF . 115
5.3.5 Normal Lymph Flow — JL,O 116
5.4 Simulations of a Single Intravenous Infusion of Human Albumin 117
6 Conclusions 121
7 Future Work 123
Bibliography 125
Nomenclature 134
Appendices 137
A Raw Experimental Data 137
B Calculation Of Error Propagation 144

C Basic Concepts Related To Statistical Analysis 147
D Surface Plot And Contour Plot 149
E Simulations At Best-Fit Parameters 151
F List Of Computer Programs 166

F.1 Parameter List of Steady-State and Transient Simulators 166
F.2 Listing of FORTRAN function XDFUNC 167
F.3 Listing of program PATDYN 208
vii
List of Tables
2.1 Chemical composition of plasma in the human 11

2.2 Classification of connective tissue 15
3.1 Mathematical descriptions of the interstitial compliance relationship . 47

3.2 Normal steady-state conditions for the “reference man” 52
3.3 Coupled Starling model 54
4.1 Unknowns in the coupled Starling model . . 56

4.2 Bounds on u for Pc,o equal to 7 to 11 mmHg 63
4.3 Experinwntal data from Hubbard et at. (1984) 67
4.4 Experimental data from Hubbard et al. (continued) . 68
4.5 Experimental data from Hubbard et al. (continued) . 68
4.6 Experimental data from Doyle et al. (1951) 70
4.7 Experimental data from Mullins et al. (1989) 71
4.8 Experimental data at steady-state for patients with heart failure (1985) 73
4.9 Experimental data from Rein et al. (1988) . 76
5.1 Best-fit parameters corresponding to three tissue compliance relationships 84

5.2 Best-fit LS and u, as well as their confidence intervals for individual data
sets 86
5.3 Experimental data of interstitial hydrostatic pressures vs. lymph flow in
the leg superficial lymphatics 110
5.4 Lymph flow rates in the leg superficial lymphatics and in the thoracic duct 111
viii
5.5 Experimental estimates of PS values 114
5.6 Experimentally determined KF values 116
A.1 Raw experimental data from Hubbard et al. (1984) 138

A.2 Raw experimental data from Hubbard et al. (continued) . 138
A.3 Raw experimental data from Hubbard et al. (continued) 139
A.4 Raw experimental data from Doyle et al. (1951) 140
A.5 Raw experimental data from Mullins et al. (1989) 141
A.6 Raw experimental data from Fauchald (1985) 141
A.7 Raw experimental data from Noddeland et al. (1984) . 141
A.8 PL
11 vs. V
1 for patients with nephrotic syndrome 142
A.9 H vs. PL
11 for patients with nephrotic syndrome 143
ix
List of Figures
2.1 Schematic of the circulatory system in human body 7

2.2 The general patten of the capillary network 8
2.3 Structure and types of capillaries found in the human body 13
2.4 Scanning electron micrographs of collagenous and elastic fibres in human
skin 17
2.5 Relationship between interstitial fluid volume and interstitial fluid pressure 21
2.6 Schematic diagram depicting the exclusion phenomenon 23
2.7 Schematic of the lymphatic system 27
Microstructure of the terminal lymphatics 28
3.1 Schematic diagram of the compartmental model of the MVES 34

3.2 Schematic of the Patlak model 38
3.3 Experimental data of compliance of human lower limb subcutaneous tissue 46
3.4 The “most-likely” human interstitial compliance relationship 48
3.5 Relationship between albumin concentration and total colloid osmotic
pressure 50
4.1 Experimental data for patients with nephrotic syndrome 75
5.1 Best-fit LS and u, as well as their confidence intervals for individual data
sets 85
5.2 Contour plots of OBJ during early and late responses for Hubbard’s data
(1984) 88
x
5.3 Simulations of a 100 mL saline or albumin infusion with 1.4 L fluid intake
during waking hours 92

5.4 Simulations of a 200 mL saline or albumin infusion with 1.4 L fluid intake
during waking hours 94
5.5 Simulations of acute saline infusion in selected patients 96
5.6 Simulation of 2 L normal saline infusion within 2 hours 97
5.7 Simulations of steady-state Vj vs. PL
11 and V
1 vs. P in heart failure
patients 100
5.8 Simulations of V
1 vs. PL
11 and Hi vs. PL
11 in nephrotic syndrome patients 102
5.9 Steady-state effects of graded reduction of plasma oncotic pressure on fluid
and protein exchange 103
5.10 Sensitivity analysis for LS 104
5.11 Sesitivityanlysis for a 106
5.12 Sensitivity analysis for P
0 107
5.13 Residual plot for the best-fit parameters of compliance relationship #3 109
5.14 Plot of .JL vs. P
1 112
5.15 Effect of Koomans’ (1985) albumin infusion on select microvascular ex
change variables 119
D.1 Surface and contour plots of the objective function 150
E.1 Simulations of a 100 mL saline or albumin infusion using compliance rela

tionship #1 152
tionship #2 153
tionship #1 154
xi
tionship #2 155
E.5 Simulations of acute saline infusion in selected patients using compliance
relationship #1 156
E.6 Simulations of acute saline infusion in selected patients using compliance
relationship #2 157
E. 7 Simulation of 2 L normal saline infusion within 2 hours using compliance
relationship #1 158
E.8 Simulation of 2 L normal saline infusion within 2 hours using compliance
relationship #2 159
E.9 Simulations of steady-state V
1 vs. PL
11 and V
patients using compliance relationship #1 160
E.10 Simulations of steady-state V
1 vs. PL
11 and V
patients using compliance relationship #2 161
E.11 Simulations of Vj vs. PL
11 and Hi vs. PL
11 in nephrotic syndrome patients
using compliance relationship #1 162
E.12 Simulations of Vj vs. FL
11 and H
1 vs. PL
11 in nephrotic syndrome patients
using compliance relationship #2 163
E.13 Effect of Koomans’s (1985) albumin infusion on select microvascular ex
change variables using compliance relationship #1 164
E.14 Effect of Koomans’s (1985) albumin infusion on select microvascular ex
change variables using compliance relationship #2 165
xii
Acknowledgement
First of all, I would like to express my sincere gratitude to Drs. J.L.Bert and B.D.Bowen,
for their enthusiastic supervision throughout the course of this work, and for their gra
ciousness when I became a new mother.

Second, I am indebted to Drs. P. Englezos, G. Wong, N. Lee and T. Nicol, for their
helpfully suggestions in statistics.
Similarly, I also give my special thanks to Dr. R. Reed of the University of Bergen,
Norway, for the clinical information.
In addition, I gratefully acknowledge that this work was supported by the Natural
Sciences and Engineering Research Council of Canada and the Norwegian Council for
Science.
Finally, I would like to dedicate this work to my husband Xiao Ping Yang, for his
love and encouragement.
xli’
Chapter 1
Introduction
By virtue of the unique properties of water as a solvent and as medium in which a wide
range of exchanges and metabolic reactions are possible, it plays a very important role in
maintaining homeostasis. Water, as the major component of all living tissues, typically
makes up about 60% of the total body weight. It distributes in two major compartments
— the intracellular compartment within the cells, which retains about 60% of the total
body water, and the extracellular compartment, which retains about 40% of the total
body water. The extracellular water, in turn, exists as two compartments, namely, the
plasma water in the circulating blood and the interstitial water bathing the tissue cells.
The plasma water represents about 10% of the total body water, and the interstitial
water about 30% [95].
The word fluid, which will be used throughout this dissertation, identifies the mixture
of water and non-protein components dissolved in the water. The maintenance of the
composition and volume of this aqueous phase is critical to the vital functions of the
human body. The regulation of composition and volume, to a large extent, can be
described by system and control theory. Feedback control is the typical control strategy
used for regulating the microvascular exchange system, which consists of the capillaries,
the interstitium and the lymphatic system. Using the feedback signals, the microvascular
exchange system is capable of reacting to changes in its environment by passively altering
its own properties so that the pre-perturbation state can be achieved again. Thus, under
normal conditions, the composition and volume of the plasma and interstitial fluid remain
1
Chapter 1. Introduction 2
in a very narrow range and the body functions normally.

The utilization of mathematical models in the description of the biological behaviour
of systems is now common practice. The advantages of mathematical models are self-
evident. The human body is well recognized to be a complex control system. When
physicians attempt to diagnose and correct the malfunctioning of the system, they are
faced with the problem that most physiological and biochemical state variables are in
fluenced by too many factors to be grasped by the unaided human mind. Therefore,
reliable mathematical models as a complementary approach to physiological experimen
tation is of potential importance to aid the clinician in gaining insight into these intricate
interactions.
Several models of microvascular exchange have been developed [7, 32, 106]. These
models require information available in the literature concerning the normal steady-state
-values of volume and protein content and transport parameters, and use this- information,
along with relevant auxiliary relationships, to predict the responses of the microvascular
exchange system after perturbations. The current model uses the same general compart
mental approach and mechanistic descriptions as many of these earlier models. However,
it differs from the latter in one important respect: whereas the previous models assume
the values of transport parameters a priori, in the current model these are determined on
the basis of a statistical fit of the model predictions to selected experimental data. The
present work is a continuation of an earlier study carried out by Chapple [13]. Chapple
modelled the microvascular exchange system by using the uncoupled Starling model and
the plasma leak model to represent the transcapillary exchange of fluid and proteins. The
coupled Starling model is used in the current study. The coupled Starling model was
found to yield the best statistical fit between the model predictions and the experimental
data for nephrotic patients [14]. Furthermore, it is generally thought that the coupled
Starling model provides the most accurate description of the transcapillary protein flux
[73].
The objectives of the current study are:
1. to formulate a coupled Starling model for describing the microvasdillar exchanges

in humans;
2. to assess and assemble all of the available literature data for the response of the
microvascular exchange system to both diseaseinduced and artificially applied per
turbations;
3. to design a reliable parameter estimation procedure;
4. to obtain a set of best-fit transport parameters so that the model is fully described
and can be used to simulate various experimental or hypothetical situations;
5. to validate the mathematical model.
If a reliable model of microvascular exchange system in the human can be developed,

the potential benefits and uses are manifold. One of the foreseeable benefits is that
these kinds of models could be used for pretesting therapeutic procedures on individual
patients in certain disease states, e.g. for the on-line simulation of trial fluid therapy for
burn injured patients and patients undergoing extra-corporal circulation, etc.. Bert et al.
[4] have developed a dynamic model to describe the distribution and transport of fluid
and plasma proteins between the circulation, interstitial space of skin and muscle, and
the lymphatics in the rat under burn condition.
The thesis is organized in the following manner. Chapter 2 reviews the basic phys
iology relevant to the microvascular exchange system. This chapter provides a physical
basis for better understanding the transport mechanisms of fluid and proteins within the
system. Chapter 3 develops a compartmental model based on the coupled Starling rep
resentation of the transcapillary fluid and protein transfers. The necessary constitutive
relationships and the normal steady-state conditions of the system are also presented
in this chapter. Chapter 4 describes the optimization procedure designed to obtain the
best-fit transport parameters. The experimental data used in statistical fitting are as
sessed and the numerical techniques used in the current work are reviewed. Chapter 5
presents the results of the parameter estimation procedure and the simulations obtained
using these best-fit parameters. Statistical procedures are used to evaluate the reliability
of the best-fit parameters. Finally, the parameters and model are validated from a phys
iological point of view. Chapter 6 summarizes the conclusions drawn from the current
study and Chapter 7 makes recommendations for future work. For the convenience of
the reader, all mathematical symbols used throughout the thesis are listed and defined
in a special Nomenclature section following the text.
Chapter 2
Physiological Principles Of The Microvascular Exchange System
Many physiological systems involve the maintenance of the milieu interieur, or home
ostasis, so that optimal function can be fulifihled. Milieu interieur is defined by Claude
Bernard [84] as the pervasive extravascular and extracellular space in which all cells
bathe. The cardiovascular system, which consists of the heart and a series of blood
vessels forming a closed network, plays an important role in enabling homeostasis to be
achieved. It supplies oxygen and nutrients necessary for life to the tissues and carries
away metabolic waste products from the tissues. Oxygenated and nutrient rich blood
is pumped out of the left ventricle of the heart, flows through arteries and arterioles,
then reaches the capillary beds, which are the primary sites where materials, e.g. oxy
gen, plasma proteins, vitamins, hormones, heat, etc., are transported across the capillary
walls to the surrounding tissue space called the interstitium. Meanwhile, metabolic-end-
products, e.g. carbon dioxide, water and heat, are collected from the tissue. As a result of
these exchanges, blood becomes oxygen depleted and is collected by venules before being
transported, via large veins, back to the right atrium. Rhythmic muscle contractions and
one-way valves force the blood to flow in one direction. When the muscles in the wall of
the right ventricle contract, blood is pumped into the pulmonary artery and hence passes
to the lungs where the transfer of gasses with the inspired air occurs. Oxygenated blood
then returns to the left atrium by the pulmonary veins, finally emptying into the left
ventricle. On the other hand, interstitial fluid containing plasma proteins drains from
the interstitium and is returned to the blood circulation via the lymphatic system. The
5
Chapter 2. Physiological Principles Of The Microvascular Exchange System 6
entire circulatory system is illustrated in Fig. 2.1.

The current investigation is concerned with the microvascular exchange system. It
consists of three components: capillaries, interstitium, and the lymphatic system. The
structure and functions of these components will be discussed in this chapter.
2.1 Capillaries
2.1.1 Arrangement of the Capillaries
The microcirculation consists of arterioles, capillaries, and venules. Capillaries are tubes
of 5 to 10 m in diameter and their walls consist of a single layer of flattened endothelial
cells, 0.1 to 0.3 jim in thickness, with nuclei that sometimes bulge into the lumen [59].
The so-called “capillary count” (i.e. the number of capillaries visible in a cross-section of
a tissue per square millimeter of area) has been measured in red skeletal muscle in dog,
and has been found to be about 1000 capillaries/mm
. Thus the distance between blood
2
capillaries averages only about 140 tm and individual cells are seldom more than 40 —
80 gum from a capillary surface [93]. These numerous microscopic vessels form a complex
meshwork which has the general pattern shown in Fig. 2.2. Most physiologists agree that
the local circulation rate should be in accordance with the needs of every tissue as well as
the variant physiological states of the subject. Therefore the capillaries are able to open
or close depending on the local requirements of the system. Whether the capillary is off or
on is controlled by the precapillary sphincter. When the sphincter muscle contracts, the
channel closes and vice versa. The dilation and constriction of precapillary sphincters
produce a continuously changing pattern of flow through the capillary network. In a
particular segment of the capillary bed, the blood may flow rapidly through one channel
for a period of time, then cease to flow or even flow in the opposite direction, depending
on which sphincters are open. Normally, only around 5 — 10% of the total available
Capillaries
Arlercs to head and

upper exItemilies
Capiltties
Figure 2.1: Schematic of the circulation systems in human body [17].

Meriole
Arteriovenous
anastomosis
True
capillaries
Thoroughfare
channel
Venule
Figure 2.2: Schematic diagram showing the general pattern of the capillary
network [53].
chapter 2. Physiological Principles Of The Microvascular Exchange System 9
capillaries in the human adult at rest are open [93]. But during exercise, the number of
open capillaries can increase 10-fold or even 20-fold to fulfill the metabolic requirement.
By virtue of its enormous membrane surface and relatively low velocity of blood flow,
capillary beds undertake more than 90% of the fluid and solute transfers between the
circulation and tissues, while the other part of the circulation, e.g., the small arterioles
and venules, only account for a small amount of the duty.
2.1.2 The Composition and Properties of the Blood
Blood is a transport medium for nutrients and wastes. A constancy of blood composition
is vital for survival and the mechanisms that operate to keep it constant are vital processes
of homeostasis.
Blood is a suspension of erythrocytes, leukocytes, platelets, and other particulates
iii a. complex solution of dissolved gases, salts, proteins, carbohydrates, and lipids. The
specific gravity of whole blood ranges from 1.055 to 1.065 [85]. In a 70kg healthy adult,
the average blood volume is considered to he about 5 litres, which is approximately 7%
of the body weight. Rapid loss of large amounts of blood has very serious consequences.
With a rapid loss of 800 mL (about 15% of the total blood volume), a drop in arterial
blood pressure is prevented by constriction of arteries and veins. However, the heart rate
will increase and the cardiac output will fall. With greater blood loss, for example 30 —
40% of the total blood volume, a state of shock will be induced.

When a sample of blood is drawn from a person, it is initially set aside in a test
tube. Heparin is added to prevent blood clotting. Then the tube is placed in a centrifuge
to accelerate separation. After a few minutes, the blood is separated into two layers.
Blood cells sink to the bottom and their volume is normally close to 45% of the total
volume. The straw-colored supernatant liquid, called plasma, is a cell free fluid. The
specific gravity of plasma varies between 1.028 and 1.032 [85]. The ratio of blood cells to
total blood volume is expressed as the hematocrit. Extremely low hematocrit, say 0.15,
is called anemia, while the opposite is called polycythemia.
After removing the cellular elements from the blood, an analysis of the chemical
composition of plasma typically yields the results depicted in Table 2.1. Despite the
fact that chemical substances are constantly entering and leaving the blood stream, its
general composition is relatively uniform in the higher-order animals. As can be seen
from the table, about 90% (by weight) of the plasma is water. Proteins account for
about 7 - 9% of the total weight. Some of these proteins are also found elsewhere in the
body, but when they occur in blood, they are called plasma proteins. Plasma proteins
exert an osmotic pressure (around 25 mmHg) which influences the passage of water and
other solutes through capillaries. The globulins, classified as a
, a
1 ,
2 and ‘y globulins,
have a wide range of molecular weights varying from 100,000 to 450,000 [53]. Albumins
constitute the majority of the plasma proteins (55 - 64%) and possess &relatively low
molecular weight of the order of 68,000. Also, albumins are not transported freely across
the intact vascular endothelium. Therefore, they provide a significant colloid osmotic
pressure gradient between the blood and the interstitium which greatly influences the
transmembrane exchanges of water and other solutes.
2.1.3 Structure of the Transport Barrier and the Transport Mechanisms
The transport rates of water and solutes across the capillary wall are determined by
three factors: transmural driving forces, transport barrier properties and its surface area.
Here, the transport barrier means the capillary wall and the basement membrane.
2.1.3.1 Capillary Wall
Capillaries of different tissues vary considerably, both anatomically and functionally. For
example, in the skin, there are arteriovenous anastomoses (AVAs) which are wide-bore,
Constituent Concentration (g/100 mL)

Proteins 6.0 8.0
-
Albumin 3.4 5.0

-
Total globulin 2.2 4.0

-
Transferrin 0.25
Haptoglobin 0.03 0.2-
Hemopexin 0.05 0.1-
Ceruloplasmin 0.03 0.05

-
Ferritin 0.015 0.3 -
Nonproteins
Water
Cholesterol 0.14 0.25
-
Glucose 0.07 0.11

-
Urea nitrogen < 0.02

Uric acid < 0.008
Creatinine < 0.002
Iron < 0.0002
Table 2.1: Chemical compositions of plasma in the human [74].

direct channels between the arterioles and venules (see Fig. 2.2). The AVAs are under
neurogenic control; their shunting capabilities enable them to reduce heat loss through
the skin during exposure to cold.
The capillary wall is made up of a number of microscopic structures, some of which
affect the transcapillary exchange. Those that have been observed and are thought
by most physiologists to play a role in transcapillary exchange are intercellular clefts,
fenestrae, and pinocytotic vesicles (Fig. 2.3). Intercellular clefts are the junctions between
endothelial cells. They can be loosely joined to form large pores or tightly joined to form
small pores. Fenestrae are formed by the stretching of some parts of the capillary wall.
They are usually thin, disc-shaped diaphragms. Some of them are open and provide a
minimally restrictive pathway through the endothelium, while others are closed with a
slight central thickening or knob. Inside the cytoplasm of the eridothelium, there are
rnaiy pinocytotic vesiçles which shuttle back and forth between opposing cell surfaces.
They intake fluid and solutes from one side and release them at the other side. These
vesicles may be important in protein transfer. Sometimes the vesicles fuse together and
form a transitory open channel.
The above structures determine the transport properties of the capillary wall. Accord
ing to the degree of continuity, capillaries can be separated into three types: continuous,
discontinuous and fenestrated capillaries (see Fig. 2.3). Continuous capillaries are widely
distributed; characteristically, they are found in lung, brain, kidney as well as skeletal
and smooth muscles. There are no recognizable intercellular openings in this type of
capillary. Fenestrated capillaries have small gaps which are either closed as in endocrine
glands and intestinal villi or open as in renal glomeruli. These gaps usually range from
40 — 60 nm in radius [100]. Discontinuous capillaries have large nonselective gaps, rang
ing from 100 — 1000 nm in radius [100]. These gaps are sufficiently wide to allow large
proteins and even cells to pass through. This type of capillary is typically found in liver,
50
10—40
1. 2. 3.
PLASMA
CONTINUOUS
CAPILLARY
BASEMENT
MEMBRANE
TISSUE
50 2—6
F EN E STR AT ED
CAPILLARY
TISSUE 5—11
40 — 60
1 5.
PLASMA
DISCONTINUOUS
CAPILLARY
TISSUE
100— 1000
Figure 2.3: Structure and types of capillaries found in the human body. 1,
plasmalemmal vesicles; 2, intracellular clefts; 3, fused plasmalemmal vesicle
s;
4, fenestrae; 5, nonselective gaps. Unit of the radius is nm [100].
bone marrow and spleen.
2.1.3.2 Basement Membrane
The basement membrane is composed of several matrix-specific components, including

the structural protein collagen, the glycoproteins laminin and entactin, and a large hep
arm sulfate proteoglycan, which covers the external surface of capillary endothelial cells,
penetrated here and there in discontinuous capillaries but not in the other types. It
provides surfaces on which epithelial cells adhere and assumes a polarized orientation.
The thickness of the membrane averages 30 — 80 nm. The transport properties of the
basement membrane are attributed to the presence of pores. The membrane is negatively
charged, and prevents negatively charged proteins from passing to the interstitium freely
[55].
The transport resistances of the capill-ary wall and the basement membrane are in
series. Both contribute to the selectivity of the harrier. Based on the above discussion,
mass transfer across the barrier can occur by means of convective mechanisms (e.g.
filtration) or by passive mechanisms (e.g. diffusion or vesicular transport).
2.2 Interstitial Compartment
2.2.1 Structure and Composition of the Interstitium
The word interstitium is borrowed from Latin; it generally refers to the connective tissue
space situated outside the vascular and lymphatic systems and the parenchymal cells.
Half a decade ago, interstitium was perceived as an inert, metabolically inactive sub
stance, which only provided support for cells and held tissues together. But this concept
has been extensively revised. It is now appreciated that the interstitium not only pro
vides a framework for parenchymal cells and a space for distribution of blood vessels
Type Examples
Myxoid Nucleus polposus, synovium, areolar connective tissue
Fibrous Tendon, ligament, fascia, dermis
Elastic Ligamentum nuchae, artery
Adipose tissue White fat, brown fat
Muscle Striated muscle, smooth muscle
Vascular tissue Artery, capillary, vein
Cartilage Hyaline cartilage, fibrocartilage, elastic cartilage
Bone Compact bone, trabecular bone
Table 2.2: Classification of connective tissue.
and nerve fibers, but it also provides a suitable transport medium for nutrient and end
metabolic waste products between cells and capillary blood. In physiological situations,
various exchanges occur between the interstitium and the circulatory compartment and
lymph, but these exchanges are in a dynamic equilibrium.
According to their anatomical structure and physiological function, connective tissues
can be classified into many types (Table 2.2). These tissues are extremely heterogeneous
both in their cellular population and composition. The cell component may occupy
from 5% (e.g. tendon, cartilage, bone) to 95% (e.g. muscle, fat) of the tissue volume.
These cells serve various functions. Some of the cells synthesize and degrade the in
terstitial components (e.g. bone cells), while the others maintain a specialized internal
function (e.g. muscle cells have active contractile function). The compositon of intersti
tia varies not only from one tissue to another, but also from domain to domain within
the tissue. Most interstitia are intimate composites of two phases: the structural macro
molecules and interstitial fluid. The structural macromolecules include collagens, elastin,
glycosaminoglycans (GAGs) and proteoglycans. Interstitial fluid consists of water, salts,
plasma proteins, 02, C0
, hormones, vitamins, etc.. The basic structure of interstitia
2
is similar. It can be described as an elastic, three-dimensional gel-like structure which
chapter 2. Physiological Principles Of The Microvascular Exchange System 16
is produced by the complex aggregation of collagenous and non-collagenous components

by covalent, electrostatic, and hydrogen bonds. The following discussion will emphasise
the characteristic components of the interstitium (i.e. collagenous fibres, elastic fibres,
GAG, proteoglycans), as well as the composition of the interstitial fluid.
2.2.1.1 Collagenous Fibres
Collagenous fibres are the soft, flexible, white fibres which are a characteristic constituent
of all types of connective tissues. In normal adult skin, they account for 70 — 75% of
the dry weight [104]. They are composed of bundles of fibrils which can be visualized
with the scanning electron microscope (Pig. 2.4 a). These bundles range from one to
several hundred microns in diameter, but their texture may be loose enough to admit
molecules as large as plasma proteins between the individual fibrils. These fibrils inter
sperse with GAGs and can glide smoothly past each other. The collagen molecule is the
basic structllral unit of collagenous fibres and the most common protein in the body. It
is a triple-helical molecule that is assembled from the coiling of three peptidic a-chains.
The arrangement of amino acids in each chain shows a characteristic periodicity (i.e.
every third amino acid is glycine, see Fig. 2.4 b). Each chain contains approximately
1000 amino acids and has a molecular weight of around 100 kDa [29].
The collagen molecule is biosynthesized from a precursor known as procollagen. Pro
collagen is enzymatically trimmed of its nonhelical ends and spontaneously assembles
into fibrils extracellularly. These fibrils interact with each other in the direction parallel
to the axis of each molecule and form the well organized collagen fibers.
Collagenous fibres determine the strength and elasticity of the tissue. They demon
strate poor elasticity but excellent mechanical strength.
(a) (b)
C 87 . 1
(c)
Figure 2.4: Electron micrographs of collagenous and elastic fibres. (a) collage-.
nous fibres have a regular banding patern(x45,000) [103]; (b) triple-helical
collagen molecule; (c) elastic fibres in human skin after removal of other
extracellular matrix components. The fibres are randomly oriented and of
varying size [90].
2.2.1.2 Elastic Fibres
Compared to collagenous fibres, elastic fibres account for only a small fraction of connec
tive tissue, 2 — 4% of the dry weight in normal adult skin [104]. Nonetheless, they play
an important role in terms of providing long-range, reversible elasticity and resilience.
Elastic fibres contain two structural components. Under the electron microscope,
the predominant component appears amorphous and is called elastin (70 90%); the
secondary one has a distinct appearance and each unit is referred to as a microfibril (not
shown on Fig. 2.4 c). Elastin is a unique protein which is composed of hydrophobic
amino acid sequences. The individal hydrophobic chains crosslink and form a random
configuration. This results in a very insoluble protein that possesses properties analogous
to rubber. The microfibrils are composed of several glycoproteins that vary in size from
25k to 34k daltons. They can exist in fibrillar arrangements or as aggregates independent
of their association with elastin.
2.2.1.3 Glycosaminoglycans and Proteoglycans
Glycosarninoglycans (GAGs), formerly called mucopolysaccharides, distribute widely in
most tissues. However, except for hyaluronate, GAGs do not exist in vivo as free poly
mers. Instead, these GAGs normally covalently link to a core protein at the terminal end
and form compounds which are called proteoglycans.
The general structure of GAGs consists of three levels. The first level is an unbranched
chain of repeating disaccharide units in which one of the monosaccharides is an amino
sugar (hexosamine) and the other is usually a hexuronic acid. The type and number
of disaccharide units vary in different GAGs. Four basic types of GAGs are recognized
and defined according to the type of hexosamine: hyaluronic acid, chondroitin/dermatan
sulfate, heparin/heparan sulfate, and keratin sulfate. The second level is the charged
side groups connecting to the chain. These side groups, e.g. the carboxylate group
(—COOj, the sulfate ester group (—0 — SOT), and the sulfamino group (—N — SO),
are all negatively charged. The third level is the spatial arrangement of the backbone
and the side groups. The backbone and the side groups form fibrils up to several hundred
microns in length. The fibrils are folded every few hundred angstroms so that instead of
being long linear molecules they are actually jumbled, folded, springlike coils occupying
a space having a diameter of several hundred millimicrons [49]. GAGs interact with
proteins, collagens and proteoglycans and form a continuous gel-like substance. GAGs
demonstrate a highly hydrophilic character.
Knowledge of the structure of the proteoglycans in tissues other than cartilage is
incomplete. In cartilage, the average proteoglycan molecule consists of a core protein to
which about 100 chondroitin sulfate chains and 30-60 keratin sulfate chains are attached.
The core protein is approximately 250 kDa and about 300 urn in length. The protein
portion constitutes only 5 — 10% of the entire molecule, and the rest of the molecule
consists of complex carbohydrates. In the presence of hyaluronate, protein cores bind to
the hyaluronate chain and form aggregates [16]. The high charge density permits these
molecules to attract a large volume of water and contribute to the ability of proteoglycans
to absorb compressive loads.
2.2.1.4 Interstitial Fluid
Interstitial fluid is a filtrate of blood. It consists of the same nonparticulate components

as plasma except it has lower macromolecule concentrations. Interstitial fluid is the
continuous bathing media through which nutrients diffuse to the parenchymal cells and
metabolic-end-products arrive at the lymphatics.
2.2.2 Physicochemical Properties of the Interstitium
The physicochemical properties of the interstitium are determined by the structure, com
position, and physicochemical conditions of the compartment. In this section, the com
pliance of the interstitial space, exclusion caused by the macromolecules, and colloid
osmotic behaviour will be discussed.
2.2.2.1 Compliance
From the previous section, we know that collagen molecules can glide a short distance
along the axis of the fibre, but the amount of movement is limited by the interaction
between the molecules. Also, collagen is in a ribbon-like arrangement in some tissues.
Therefore, when an external tensile force is applied to this structure, the fibre will be
stretched out. When the external force is removed, the fibre will be drawn back and
regain its original state. This specific property is called elasticity. Moreover, elastic
fibres like GAGs and proteoglycans have spring-like configurations; therefore they all
possess an elastic behaviour similar to springs.
The compliance of human tissues is a poorly understood property, but one which
is very important to microvascular exchange. It involves the interaction between the
fluid and the solid components of the interstitium, the state of charge of the structural
components, the fibrillar organization, composition, etc.. For reasons of convenience,
compliance (FCOMPI) in current study is defined by
FCOMPI = //P
1
AV (2.1)
1 is the change in interstitial volume when the interstitium is subjected to a

where 1.V
hydrostatic pressure change, AP
. To some extent, it determines the degree of elasticity
1
of the interstitial space. The interstitium has high compliance if small changes of inter
stitial pressure can induce large changes in the interstitial fluid volume. When pressure
C
w
z
Cl,
4
—e
+110 +120 4430

CHANGE IN LEG WEIGHT (per cent)
Figure 2.5: Relationship of interstitial fluid pressure to change in leg weight

during progressive increase in interstitial fluid volume. Weight is correlated
with fluid volume. Each curve represents results from a separate dog leg [34].
is plotted against volume, the reciprocal of the slope of the curve is the compliance of
the interstitial space at a certain volume. Even though knowledge of human tissue com
pliance is incomplete, studies on other animal tissues suggest that the pressure-volume
curve should be sigmoidal [34, 2], as exemplified by Fig. 2.5. Low compliance occurs
at
low and normal interstitial volume. This is one of the tissue’s passive mechanisms
for
preventing dehydration and edema. When the volume decreases, 1 P decreases signifi
cantly. Thus the driving force for filtration to the interstitium increases and preven
ts
Chapter 2. Physiological Principles Of The Microvascular Exthange System 22
further dehydration. When the volume increases, Pj increases significantly to decrease

fluid filtration and hence prevent edema. High compliance occurs at high V
. This makes
1
the interstitium serve as an overflow reservoir to help maintain a constant plasma volume.
At very high water contents, the tissue volume is constrained by the boundaries of the
tissue which therefore exhibits, once again, a low compliance. At this stage, the plasma
volume will increase due to the elevation in the driving force for absorption.
2.2.2.2 Exclusion
Exclusion refers to fact that two or more objects of any volume can not overlap and
occupy the same space at the same time. This phenomenon exists in the interstitium
and was first described by Ogston and Phelps in 1961 [65].
To depict the exclusion phenomenon more clearly, two models are introduced. One
is the sphere-and-rod model (Fig. 2.6 b). The spheres represent plasma proteins and
the rods represent structural components of the interstitia. In this model, the center of
the sphere is not accessible to a volume of 7rl(r
3 + rr)
2 surrounding the rod, where rr
is the radius of the rod and 1 is its length; r
3 is the radius of the spere. This volume
is called the excluded-volume (VEX). The other model is closer to the real situation in
the interstitium. It is a sphere located inside a random network of rods. The excluded-
volume fraction for this model has been calculated to be 1 — e_ ,
2
(rS+T)
where L is the
total length of the rods per unit volume (Fig. 2.6 c). The above models can be used
in hypothetical descriptions of the exclusion phenomenon, but because the organization
within the interstitium is not well defined, they can be used only to estimate the excluded
volume of the interstitium. VEX is determined by many factors. There are different sizes
of collagen, elastin, GAGs and proteoglycans which contribute to limiting the volume
available to the plasma proteins. The spatial arrangement of the fibres greatly affects
the value of VEX. For example, a larger number of smaller fibres arranged randomly
A 8
——--
-F
1;
‘ I I
‘I I
Figure 2.6: Schematic diagram depicting the exclusion phenomenon. (a) two
spheres can’t occupy the same space at the same time; (b) sphere-and-rod
model; (c) a sphere located inside a random network of rods [16].
Chapter 2. Physiological Principles Of The Microvasculai Exchange System 24
causes much greater exclusion than an equal weight of a smaller number of larger fibres
in an orderly lineup [6]. In addition, exclusion is also affected by the nature of the charge
on the proteins and the various structural components they interact with. For example,
both GAGs and albumin are negatively charged. Because similarly charged entities repel
one another, albumin is excluded by GAGs to a greater extent than other fibrils which
have a similar size but are uncharged. Since the structural components differ from tissue
to tissue, the exclusion effect is tissue dependent.
The best way to study exclusion inside interstitium is through in vivo experimenta
tion. Unfortunately, the results of only a few in vivo studies are available. One way to
estimate VEX is to use a multiple-indicator technique. One indicator has a very small
molecular size (e.g. sucrose, Cr-EDTA) and its exclusion other than by solid structures
can therefore be neglected. The other indicator is the excluded material under investi
-gation, e.g. albumin, globulin. It is generally believed that collagenous fibres play an
important role in excluding plasma proteins. Other materials might also play an impor
tant role. This issue is not yet clarified. In vivo studies show that the excluded-volume
fraction by collagenous fibres ranges from 25% to 53% of the volume of the interstitial
matrix [6, 5, 86].
Due to exclusion, the interstitial space available to the plasma proteins is less than
the interstitial fluid volume; consequently, the effective protein concentration and chem
ical activity of the protein is greater than the mass of plasma proteins divided by the
interstitial fluid volume. The colloid osmotic pressure, which depends on the protein
concentration, is therefore sensitive to the interstitial exclusion phenomenon.
2.2.2.3 Colloid Osmotic Behaviour
Because capillary walls restrict protein movement, changes in the concentration of body
fluids will affect the movement of water between fluid compartments due to the phe
nomenon of osmosis. Osmosis is the movement of water across a semipermeable mem
brane from an area of lower solute concentration to an area of higher solute concentration.
Although the term osmosis specifically refers to the movement of water only, to a smaller
degree, osmosis also affects the movement of solutes. The forces of friction cause some
solutes to be carried along with the water. This is termed solvent drag.
The driving force for osmosis is the difference in osmotic pressures on both sides
of the membrane. Colloid osmotic pressure is caused by a relative deficit of permeating
molecules on one side of the membrane versus the other side. It should be mentioned that
colloid osmotic pressure (or oncotic pressure) is the osmotic pressure exerted by proteins.
This applies to the circulation as well as the interstitium. Albumin, for example, exerts
oncotic pressure within the blood vessels and helps maintain the water content of the
blood in the intravascular space.
The normal plasma colloid osmotic pressure is approximately 25 — 30 mmHg, which
consists of approximately 19 mmllg due to plasma proteins and 9 mmHg due to cations
held by the Donnan equilibrium effect ‘.
The direction of the colloid osmotic pressure is opposite to that of the hydrostatic
pressure within the interstitium. Together they counteract the oncotic and hydrostatic
forces within the capillary and maintain a dynamic equilibrium between the two com
partments.
There is a good correlation between protein concentration and colloid osmotic pres
sure. This issue will be discussed in more detail in the next chapter. Experiments show
1
N egatively charged proteins attract positive ions and create a high ion density environment, conse
quently causing osmotic pressure. This phenomenon is called the Donnan equilibrium effect [35].
that about 68% of the total colloid osmotic pressure is due to albumin, 6% is due to
globulin, and the rest is due to the other proteins [53].
2.3 Lymphatic System
The lymphatic system is considered to be somewhat in parallel to the blood circulation.

It is a network of terminal and collecting lymphatic vessels in the body that drain the
interstitial fluid back to the blood circulation (Fig. 2.7). The drainage is important in
fluid and plasma protein distribution and transport in the body. The cells bathed by the
lymph, namely, lymphocytes, are primarily responsible for the specificity of immunolog
ical responses.
2.3.1 Terminal Lymphatics
The terminal (or initial) lymphatic is the part of the lymphatic system that is involved
with collection of interstitial fluid in the microvascular exchange system. It is an irregular,
microscopic, blind end conduit which consists of a single layer of overlapping endothelial
cells. The differences between a terminal lymphatic and a blood capillary are that the
former has a much thinner wall but its diameter is much larger (15 — 20 pm) and its
basement membrane is highly attenuated and frequently absent completely.
It is well recognized that terminal lymphatics are discontinuous, with open junctions
between endothelial cells (except those in brain, spinal cord and ocular space). Some
workers have even identified some ultrastructures around these junctions. For example,
Leak [51, 50] observed anchoring filaments that attach the basement membrane to the
adjacent collagenous and elastic fibres. The unattached sites around the junctions form
flaps which are called lymphatic endothelial microvalves, as shown on Fig. 2.8 [90, 12].
The microvalves become more obvious during distension of the lymphatics. The anchoring
Chapter 2. Physiological Principles Of The Microv.ascular Exchange System
27
Figure 2.7: Schematic of the lymphatic vessels in an area of bat wing

at a
bifurcation of two large vascular channels: terminal lymphatics
(irregular
black bulbs), collecting lymphatics (black bold lines), blood vessels
(shaded),
and capillaries (thin lines) [15j.
I
Figure 2.8: Microstruture of the terminal lymphatics. When the anchoring
filaments are tightened, the microvalves are open and the lymphatics are
filled; when the filaments are loosened, the microvalves are closed and the
lymphatics are emptied [90, 12]. -
filaments and the microvalves are of potential importance in supporting the postulated
transport mechanism for lymph which will be disscussed later. Collecting lymphatics
into, which initial lymphatic fluids derived from the interstitium continuously drain are
distinguished from terminal lymphatics by the appearance of macroscopic bileaflet valves
and smooth muscle intima, and by the fact that they contract spontaneously [37]. The
bileaflet valves are one-way valves and hence prevent backflow. The collecting lyinhatics
finally converge at the thoracic duct and, through the duct, lymph is returned to the blood
circulation.
2.3.2 Mechanism of Lymph Formation
The question concerning the mechanism by which the interstitial fluid is transported into
the terminal lymphatics has long been disscussed but still remains controversial.
The first postulated mechanism is that lymph is formed by the periodic contraction
of the terminal lymphatics which is caused by its own smooth muscle. This mechanism is
supported by research on bat wing lymphatic endings [38, 62]. These endings have their
own smooth muscle and rhythmic pressure pulsations have been recorded [38]. However,
the bat wing is a notable exception. No similar observation has been reported in any
other tissue. A detailed review of the microanatomy of terminal lymphatics in different
organs has been presented [90].
The second postulated mechanism is considered to be more common. In this postula
tion, lymph is formed by the contraction of the tissues surrounding the terminal endings.
Muscle contraction, intestine motilities, skin tension, vasomotion, etc., stretch the an
choring filaments and expand the terminal lymphatics. The unattached microvalves are
opened, and with a small pressure gradient, interstitial fluid is pushed into the lymphatics.
During the relaxation of these organs, the filaments loosen, the bileafiets overlap and the
microvalves are closed. With the spontaneous contraction of the collecting lymphatics,
lymph is then drained out of the terminal lymphatics.
Initial lymph is generally assumed to have the same composition as interstitial fluid
due to the large intercellular junctions and the incomplete basement membrane, both
of which result in a nonsieving in the terminals. Some investigators have observed
hyaluronate present in the prenodal lymph [77]. After the lymph passes through the
lymph nodes, some components are degraded and the composition of the lymph changes.
But whether the assumption that compositions of initial lymph and interstitial fluid are
the same is correct or not still needs to be proven [2].
Chapter 3
Model Formulation
3.1 Introduction
With the development of computer sciences, a new interdisciplinary approach for studying
biological systems has appeared. Computer modelling has provided researchers with a
powerful tool for better understanding intricate systems, which are generally influenced
by too many factors to be grasped by the unaided human mind.
In studies of the microvascular exchange system (MVES), many different mathemat
ical models have been developed on the basis of the Starling’s hypothesis. To elucidate
his hypothesis, Starling wrote [96]:
Although the osmotic pressure of the pro teids of the plasma is so insignif
icant it is of an order of magnitude comparable to that of the capillary pres
sures; and whereas capillary pressure determines transudations the osmotic
pressure of the pro teids determines absorption. Moreover, if we leave the
functional resistance of the capillary wall to the fluid through it out of ac
count, the osmotic attraction of the serum for the extravascular fluid will be
proportional to the force expended in the production of the latter, so that
at any given time, there must be a balance between the hydrostatic pressure
of the blood in the capillaries and the osmotic attraction of the blood for the
surrounding fluids. With increased capillary pressure there must be increased
transudation until equilibrium is established at a somewhat higher point, when
30
Chapter 3. Model Formulation 31
there is a more dilute fluid in the tissue spaces and therefore a higher absorbing
force to balance the increased capillary pressure. With diminished capillary
pressure there will be an osmotic absorption of salt solution from the extravas
cular fluid until this becomes richer in pro teids; and the difference between it
(proteid) osmotic pressure and that of the intravascular plasma is equal to the
diminished capillary pressure.
The center of the hypothesis is that the fluid and protein exchanges across the capillary
wall are governed by the hydrostatic pressures and colloid osmotic pressures on both
sides of the wall. This is a fundamental basis of all mathematical models of the MVES.
Based on their particular interests, investigators have set up different models which were
used to investigate specific aspects of the system. For example, Rippe and Haraldsson
[83] set up a mathematical model to investigate the role played by different sized pores
- in the mass transfer across the capillary wall. Others, such as Arturson et al. [1], were
more interested in the overall regulation of body fluid. Hence, in their models, not only
transport mechanisms across the capillary wall were considered, but also the influence of
hormone release and renal function.
According to the spatial distribution properties of the parameters which describe the
system, MVES models are divided into two types: lumped parameter or compartmental
models and distributed parameter models. In compartmental models, all the variables
under consideration are spatially invariant, i.e. any changes in those variables are consid
ered equal and simultaneous throughout the volume for which the laws of conservation
(mass, energy, and momentum) have been established. These models can be represented
in terms of algebraic equations (static systems) or ordinary differential equations (dy
namic systems). In the distributed parameter model, however, some or all of the variables
are not the same throughout the whole system volume at any given time, i.e. the values
of the variables are spatially varying. Ordinary differential eqilations (one-dimensional

static systems) or partial differential equations (multi-dimensional and/or dynamic sys
tems) are required to describe these types of models.
Currently, our interest is in compartmental models of the MVES. A distributed pa
rameter model, developed by other members of the research group [101, 102], was used
to investigate the fluid and protein transfers inside an idealized interstitium. For corn
parmental models, based on different assumptions about the structure and transport
mechanisms of the capillary-interstitium interface, different mathematical descriptions of
the fluid and protein transport across the capillary wall have been developed. Chapple
[13] studied two such models, referred to as the uncoupled Starling model and the plasma
leak model, and used these in an overall MVES model to simulate experimental data from
nephrotic patients. In the uncoupled Starling model, albumin is assumed to pass through
the capillary wall by convection along with the filtrate from the ircu1ation to the intersti
tium, and by diffusion which takes place via a separate pathway. These two mechanisms
are non-interacting and hence the name uncoupled Starling model. In the plasma leak
model, it is assumed that two types of pores exist in the capillary wall, namely, the
so-called small and large pores. Albumin is hypothesized to pass through the capillary
wall by convection through the large pores and by diffusion through other parts of the
wall, but is completely rejected by the small pores. In the current study, the coupled
Starling hypothesis (or the Patlak formulation) will be used. This macromolecule trans
port mechanism is considered to better reflect the true nature of transcapillary exchange.
Details of the model formulation will be discussed in the following sections.
3.2 General Assumptions of Compartmental MVES Models
One of the goals of this work is to fomulate a mathematical model which describes the
normal behaviour of the MVES. As we know, all computer models involve varying degrees
of simplification of the real system. By making appropriate assumptions, a complex
system can be replaced by a more simple model which simulates, at least approximately,
the behaviour of the real system. This provides an economical and productive approach
for studying real systems as long as the results of the simulations are valid.
From Chapter 2, we know that the MVES consists of capillaries, interstitium, and
terminal lymphatics. It is a complex biological system. Some structures and properties of
the system are still unknown or controversial. Therefore, simplifying assumptions must
be made. The goal of this chapter is to develop a compartmental model of the MVES.
Thus, the first question which arises is how many compartments should the MVES be
divided into?
In the present model, the MVES is divided into two compartments, the circulation
and a general tissue compartment (Fig. 3.1). The capillary-interstitium interface, which
consists of the capillary wall and its basement membrane, lies between these two compart
ments. It is obvious that lymph and blood can each be treated as a single compartment
due to their physical separation from the interstitium. However, comparatively speaking,
it is more problematic to lump the various tissues which exist in the human body into
a general interstitial compartment due to their heterogeneities in properties, form and
function (see Table 2.2). Iii previous modelling studies of rats [41, the interstitium was
separated into individual skin and muscle compartments, since, on a weight basis, they
are the two largest tissues in the body. However, this separation is not reasonable in
human studies because of the lack of information on human tissues. The most complete
Figure 3.1: Schematic diagram of the compartmental model of the MVES.

set of information on humans is available for subcutaneous tissue and dermis. Fortu
nately, 50 — 70% of the total interstitial fluid is stored in loose connective tissue such as
skin and as little as 10% in muscle [2]. Also. results from the rat model indicate that
skin and muscle compartments behave similarly [76]. Therefore, the properties of the
general interstitial compartment will be assumed to be approximately equal to those of
subcutaneous tissue.
The microscopic geometry of both the capillary and the interstitium, which make up
an exchange unit, also supports the compartmental assumption. Here, an exchange unit
is defined as the cross-sectional area through which fluid and proteins must travel from
the capillary to the nearest terminal lymphatic. The exchange unit for subcutaneous
tissue has been estimated to be less than 8.1x10
2
i
4 m in area [113]. Assuming the
exchange unit is a square, the distance between the capillary and the nearest terminal
lymphatic will be around 0.03 1
um. The time required for fluid and solute molecules to
diffuse across the exchange unit is a few seconds (unpublished results from I. Gates).
But typical perturbations to the system usually last for hours. Compared with hours, a
few seconds are instantaneous. Therefore, the compartmental method is an appropriate
approach in MVES modelling.
The second question concerns the assumptions made about each compartment. First,
since we are dealing with lumped parameter models, each compartment is assumed to
be homogeneous, i.e. whatever changes happen in one place occur throughout the whole
compartment volume simultaneously. Other important assumptions include:
• All plasma proteins are referenced to a single protein species, albumin. This is
justified by the fact that albumin accounts for more than 50% of the total plasma
protein in humans and, by virtue of its smaller molecular weight and greater net
charge, it accounts for approximately 65% of the total plasma colloid osmotic pres
sure.
• Ions can pass through the interface freely, hence, the effect of ions can be neglected.
• Cellular components are considered to be stable in both compartments. During the

system perturbations investigated in the dllrrent study, the volume and composi
tions of intracellular fluid are unchanged. Parenchymal cells are always in dynamic
equilibrium with extracellular fluid.
• Physicochemical properties of macromolecules, such as GAGs, proteoglycans, col
lagenous and elastic fibres, remain unchanged throughout the perturbations. Com
pliance of the interstitial compartment is assumed to follow the “most likely
human compliance relationship which will be discussed later. Excluded-volume is
-
constant and is not affected by tissue edema.
• Action of the kidneys in overall fluid balance is very rapid compared to the dynamics
associated with the MVES.
The MVES is not an isolated system. Thus the third question concerns the assump
tions about the surrounding environment. The effects of nervous system and hormone
release on the MVES is considered only indirectly in the current study.
In summary, the MVES is simplified to two homogeneous compartments, the circu
lation and the interstitium. Fluid and albumin are the only significant species within
the system. Mass exchanges take place at the capillary-interstitium interface and at the
terminal lymphatics due to passive driving forces.

3.3 Coupled Starling Model
When the principle of mass conservation is applied, the following equation applicable in
both the circulation and the interstitium can be derived:
Accumulation of S = Inflow of S — Outflow of S + Generation of S — Consumption of S
where S denotes fluid or albumin content. If the generation and consumption terms equal
zero, the above equation simplifies to
Accumulation of S Inflow of S — Outflow of S (3.1)
This form of the conservation of mass equation will be used to simulate perturbations
involving a step change of one of the driving forces at zero time.
According to the different equations which are used to define the flowrates of S in
or out of the system, MVES models can be classified depending on the mechanism of
transcapillary exchange. Several mechanisms, such as those described by the Patlak [10]
as well as uncoupled Starling and plasma leak models, have been investigated in our
research [13]. Because the Patlak formulation requires fewer fitting parameters than
the plasma leak model and provides a more reasonable coupling of protein diffusion and
convection than the uncoupled Starling model, it will be used throughout this work.
The coupled Starling model, which is sometimes called the Patlak model, is a ho
moporous model. In this model, the pores in the capillary membrane are assumed to
be a single size and this size is characterized by the value of the albumin reflection co
efficient (o). Fluid is transported from the capillary to the interstitium by filtration
according to the Starling hypothesis described earlier. Solutes (i.e., albumin) are trans
ported passively by diffusion and convection through the same channels that carry the
fluid and thereby coupled. Interstitial fluid is drained back to the circulation by lymph.
Chapter 3. Model Formulation
38
BLOOD CAPiLLARY INTERSTITIUM

LWALJ
Figure 3.2: Schematic of the coupled Starling model.
The hydrostatic pressure within the capillary is represented by a single value termed the
capillary hydrostatic pressure, Pc (see Fig. 3.2).
The quantitative analysis of the fluid filtration flow across a membrane was first
introduced by Staverman [97] and was further developed by Kedem and Katchalsky
[43].
In their analyses, Starling’s hypothesis was expressed by the following equation:
JF=KF[PCPI7(11PL—llI)] (3.2)
where JF denotes the fluid filtration rate; P and 11 denote hydrostatic and colloid
osmotic
pressures, respectively; and subscripts C, PL, and I denote capillary, plasma
, and inter
stitium, respectively. KF is the filtration coefficient .
1
(mLh’ .mmHg ) and its value is
determined by the hydraulic conductivity and total area available for fluid
transport. a is
the albumin reflection coefficient and its value is determined by the proper
ties (e.g. size,
charge) of the solute molecule and the channel (i.e. pore) through which
solute molecules
pass. If ci = 1, the membrane is perfectly impermeable to solute and the full osmotic
pressure of the solution opposes filtration; if ci = 0, the membrane allows solute molecules
to pass through freely and the osmotic pressure of the solution offers no resistance to
filtration. The filtration rate is proportional to the net Starling driving force (bracketed
term in Eq. 3.2).
Albumin is transported across the membrane by diffusion with the superimposition
of convection. Bresler and Groome [10] solved the one- dimensional convective-diffusion
equation for a uniform cross-section pore to derive the following equation for transmem
brane albumin transport:
/ CFL — CI,Av exp(—Pe)

Qs=JF1—ci). 33
1 — exp(—Fe)
where Fe is the modified Péclet number given by
Fe = (1 — ci). JF/PS (3.4)
Here Qs denotes the albumin transport rate from the capillary to the interstitium (g/h),
C denotes albumin concentration (g/L). CJ,Av is called the effective interstitial albumin
concentration and is calculated as the interstitial albumin content divided by the intersti
tial volume available to albumin (Vr,Av), which will be discussed later. PS is the product
of membrane permeability to albumin and the membrane surface area (mL/h) and used
to describe diffusive exchange across the capillary wall. The modified Péclet number, Fe,
is therefore the ratio of the imposed (plug flow) velocity to the diffusion velocity of the
solute.
By rearranging Eq. 3.3, the albumin transport rate can be partitioned into two com
ponents, i.e.,
Qs = JF (1 — ci) . CPL + i_e(x1p(Pe . (CPL — CI,Av). (3.5)

where the first term is referred to as the convective component and the second term as
the diffusive component. Equation 3.5 is not equivalent to the sum of the uncoupled
convective and diffusive solute transports through a single channel [13], i.e..
Qs = JF (1 — a). [(CpL + CI,Av)/

] + FS
2 (CPL — CI,Av). (3.6)
Thus it can be seen that the convective and diffusive transfers of albumin in the Patlak
model mutually influence each other.
Interstitial fluid is drained back to the circulation compartment by lymph flow. As
discussed in Chapter 2, bileaflet valves on terminal and collecting lymphatics ensure
unidirectional lymph flow. Under normal conditions, the lymph flowrate, JL, is always
assumed to be positive, i.e. lymph always flows from the interstitium to the terminal
lymphatics. It is also assumed that the composition of the initial lymph is the same as
that of the interstitial fluid. Therefore, there is no difference in colloid osmotic pressure
between the lymph and interstitial fluids. Hydrostatic pressure in the interstitium is
assumed to be the only driving force for lymph flow deviations from the normal baseline
level. A linear relationship between the lymph flowrate and the tissue hydrostatic pressure
of the type developed by Bert et al. [4] for their rat model is also employed in the
current human model. During tissue overhydration, the lymph flowrate, JL, is assumed
to increase proportionally to the change in interstitial hydrostatic pressure by a factor
LS, which is called the lymph flow sensitivity 1

(mL.mmHg
. h’). Thus,
= JL,O + L5 (Pi — ) when P

0
,
1
F 1 Pi,o (3.7)
where JL,O is the lymph flowrate at normal steady-state conditions (mL/h). As discussed
in Chapter 2, this normal lymph flow is formed by the contraction of the tissues surround
ing the terminal lymphatics, as well as by the spontaneous contraction of the collecting
lymphatics.
During tissue dehydration, another linear relationship is used, namely
JL JL,O 1
(P — PJ,Ex)/(PI,o —
PI,Ex) when P
1 <P
0
,
1 (3.8)
FI,EX is the interstitial hydrostatic pressure when the tissue dehydrates till the intersti
tial fluid volume is equal to the excluded volume (VI,Ex). This is considered to be the
limit to which the tissue can be dehydrated. At this condition, the lymph flow, according
to Eq. 3.8, ceases completely, i.e. JL = 0. Further dehydration is beyond the scope of
the current discussion, because it would be accompanied by drastic changes in the struc
ture and properties of the interstitium, e.g. cell dehydration, fiber and macromolecule
breakdown, etc.. Such changes conflict with the assumptions made at the beginning of
this chapter.
Because of the non-sieving character of the terminal lymphatic walls (o is assumed to
be zero), plasma proteins within the intersititium are assumed to be transported across
the wall solely by convection with lymph flow. Therefore, the albumin exchange rate
across the lymphatic wall, Qr, is given as the product of the lymph flowrate and the
albumin concentration in the interstitium:
QL = Jr C
1 (3.9)
Equation 3.9 assumes that, once the plasma protein solution from the available volume
enters the lymphatics, it mixes with the interstitial fluid leaving the remaining portions of
the mobile fluid volume according to their relative volumes; therefore, C
1 is used instead
of CI,Av.
Now the mass balances for the circulatory and interstitial compartment can be writ
ten more specifically. The fluid and protein balances, respectively, for the circulatory
compartment become
dVp/dt = JL — JF +D
1 (3.10)
and
dQpL/dt = QL — Qs + D
2 (3.11)
where D denotes external perturbations to the system, e.g. fluid infusion (D positive),
protein infusion (D
2 positive), urine output (D
1 and D
2 negative), etc.. For the interstitial
compartment, the two balances become
dV
/
1 dt = JF — JL (3.12)
and
clQj/dt = Q —
(3.13)
If both compartments are at steady-state, then the left hand sides of Eqs. 3.10 — 3.13 are
set to zero, i.e. the fluid volumes (VPL and V
) and albumin contents
1 (QPL and Qi) in
both compartments remain constant.
3.4 Constitutive Relationships
When the dynamic characteristics of the microvascular exchange system are studied,
some variables are subject to variations with time until a new balance is obtained. These
variations involve the changes in volume, concentration, hydrostatic and colloid osmotic
pressures, etc.. Thus, in order to complete the description of the model, it is necessary to
establish additional, constitutive relationships between these variables. In this section,
three such relationships will be discussed, i.e. the circulatory compliance, the interstitial
compliance, and the relationship between albumin concentration and colloid osmotic
pressure.
3.4.1 Circulatory Compliance
Due to the microscopic nature of the capillaries, the techniques for measuring capillary
hydrostatic pressures, P
, are not yet reliable. Therefore, it becomes necessary to relate
0
Pc to variables which can he measured directly. It is believed that Pc is dependent on

the arterial pressure, FAA, and venous pressure, PVV according to [72]:
Pc = [(Rvv/RAA) . FAA + Pvv]/[1 + (Rvv/RAA)} (3.14)
where RAA and Rv are the precapillary and postcapillary resistances, respectively. The
physical meaning of the above equation is obvious. However, the use of Eq. 3.14 is
problematic, because the resistances are also unknowns and cannot be measured directly.
(Only FAA and PVV can be measured easily.)
Because the blood vessels (particularly on the venous side) are distensible, changes in
arterial and venous pressures result in changes to another measurable output, the plasma
volume, VPL. Circulatory compliance, FCOMPC, is defined as the ratio of the change
in plasma volume to the change in capillary hydrostatic pressure, i.e.,
FCOMPC = AVPL/PC (3.15)
which is similar to the definition of interstitial compliance (Eq. 2.1). From Starling’s hy
pothesis, we know that there are other factors (e.g. colloid osmotic pressures, transport
properties of the membrane) besides the capillary hydrostatic pressure which determine
the plasma volume. Other active mechanisms associated with hormonal, neural or my
ological behaviour which will not be considered directly in this study may also affect the
circulatory compliance. In fact, for humans, there are insufficient data even to establish
a quantitative relationship between Pc and VPL. Thus for the sake of simplicity, a linear
relationship is assumed to apply, i.e.
FCOMPC = LVPL//PC = constant
or
Pc = Pc,o + PC,GRAD• (VPL — VpLO) (3.16)

where PC,GRAD is the reciprocal of the circulatory compliance.

Since, to our knowledge, PC,GRAD has never been measured in humans, therefore, an
estimate of its value is needed. Bert et al. [4] estimated PC,GRAD = 5.05 mmHg/mL in
the rat microcirculation by statistically fitting a set of fluid volume distribution data as
a function of total fluid volume. This value is scaled for use in the current human model
by ensuring that equal fractional increases in plasma volume for both the rat and human
give rise to equal elevations in capillary hydrostatic pressure. In the rat, PC,GRAD = 5.05
mmHg/mL corresponds to an elevation in P of 30.91 mmHg when VPL is raised to twice
of its normal level, (from 6.12 mL to 12.24 mL), i.e. PC,GRAD = 30.91 mmHg/6.12 mL.
In human, with a normal plasma volume of 3200 mL (the normal values for human will
be discussed in next section), to satisfy the scaling criterion, PC,GRAD should be equal to
30.91 mmHg/3200 mL = 0.009659 mmHg/mL.
3.4.2 Interstitial Compliance
The interstitial compartment is considered to be a storage reservoir for body fluid. Inter
stitial compliance, FCOMPI, therefore, is an important property which can markedly
affect the distribution of body fluid. It is defined by Eq. 2.1. Although there is a general
awareness of the importance of the interstitial compliance, very little actual information
about it is available in the literature. Reed and Wiig [109, 79, 110, 111] have conducted a
series of experiments to study the interstitial compliance relationship in mammals other
than humans. After studying the compliance characteristics of skin and skeletal mus
cle in rat, cat and dog, they concluded that the compliance of both skin and skeletal
muscle follows a similar trend: low compliance during severe tissue dehydration, mod
erate compliance between moderate dehydration and moderate overhydration, and high
compliance during severe tissue overhydration. Experimental data from the rat [109, 79]
were fitted and used in compliance relationships for the skin and muscle compartments
in the rat microvascular model of Bert et al. [4].

The only experimental data on human tissue compliance known to the author is from
Stranden and Myhre [99]. They studied 46 patients with unilateral leg edema. The tissue
hydrostatic pressure, F
, was measured in subcutaneous tissue by the wick-in-needle
1
technique. The subcutaneous tissue volume increase was calculated as the difference
in volume between the edematous and the contralateral leg. The results are shown
in Fig. 3.3. The “most-likely” human interstitial compliance #1 (see later discussion)
is also plotted on the figure. The data are too scattered to assign a particular fit to
them. However, it was found that the compliance varied significantly at different levels
of interstitial tissue hydration: P
1 increased markedly with increasing subcutaneous tissue
volume in patients with moderate edema (0 — 100% subcutaneous tissue volume increase),
but insignificant further increase in P
1 was observed with additional edema (100 - 600
Under these circumstances, a so-called “most-likely” human interstitial compliance

relationship is constructed on the basis of the information from Stranden and Myhre as
well as that from Reed and Wiig. With a 210 % increase in interstitial fluid volume,
the interstitial hydrostatic pressure increases 2.9 mmHg in human subcutaneous tissue
[99], while in the rat skin, interstitial hydrostatic pressure increases only 2.4 mmHg [79].
The “most-likely” human interstitial compliance is therefore constructed by scaling the
interstitial hydrostatic pressure of rat according to:
PI,HUMAN —
PI,HUMAN,O = (PI,RAT —
PJ,RAT,o). (3.17)
and by scaling the interstitial volume according to:

VI,HUMAN.O
VI,HUMAN = VI,RAT ( VI,J?AT,IJ
) (3.18)
where the subscripts “HUMAN” and “RAT” have the expected meanings. The subscript
“0” refers to the normal value. VI,HUMAN,O equals to 8.4 L. PI,RAT and V1,RAT are a
46
E 5- . •.
E
- 4- . . . . a..
3-
•
.‘ 2- • ..
•
C
3 0-
•
0,
I.
G -3-
C
I I I I I I I I
0 200 400 600 800

Subcutaneous tissue volume increase (%)
Figure 3.3: The interstitial fluid pressure-volume relations

hip in patients fol
lowing arterial reconstruction for femoropopliteal ather
osclerosis. • repre
sents patients with postoperative edema. represents patie
nts without post
operative edema (mean±SD). represents healthy cont
rols. Number of sub
jects investigated is bracketed below [99]. The solid
line is the “most-likely”
human interstitial compliance relationship.
Dehydration: Pi = —0.7 + 1.96154 x 1 (V 8.4 x i0)

3
10 —
Intermediate: cubic spline interpolation (see subroutine SPLINS)

Overhydration:
Compliance #1 1 = 1.88 + 1.8 x 10—
P (Vi
5 — 1.26 x iO)
Compliance #2 Pi = 1.88 + 5.0 x 1(V
5
10— — 1.26 x 10)
Compliance #3 Pi = 1.88 + 1.05 x 1
(V
4
10— — 1.26 x i0)
Table 3.1: Mathematical descriptions of the interstitial compliance relation

ship.
series of discrete data points obtained from the skin compliance relationship in the rat
microvascular model [4]. The “most-likely” human interstitial compliance so generated
is plotted as the solid line (compliance #1) in Figs. 3.3 and 3.4. Figure 3.3 shows that
the selected curve is a reasonable representation of the experimental data points.
The relationship is artificially separated into three regions: the “dehydration segment”
1
(V 8.4 L), the “intermediate segment” (8.4 L < V
1 < 12.6 L), and the “overhydration
segment” (V
1 12.6 L). The confidence of the overhydration region is considered to be
the lowest, therefore, two other overhydration compliances (compliance #2 and #3) are
generated by arbitrarily increasing the slope in this region, while the other two regions
remain the same as that in compliance relationship #1. The mathematical descriptions
of the three compliance relationships are summarized in Table 3.1.
3.4.3 Colloid Osmotic Pressure Relationship
Since colloid osmotic pressure is caused by the fact that solute molecules can not readily
diffuse through the semipermeable capillary membrane, it is natural to assume that there
is some kind of correlation between protein concentration and colloid osmotic pressure. In
1963, Landis and Pappenheimer [47] derived three empirical equations to relate albumin,
globulin, and total protein concentrations to colloid osmotic pressure. However, in the
5.0
0.0-
tzO
Compliance curve 1
-5.0 -
PJ’.P Curvej2 -
cQmpU..cc. w’x. -.
0.0 tOM 20.0 30.0 40.0

v
(
1 L)
Figure 3.4: The “most-likely” human interstitial compliance relatio

nship [13].
current model, the single protein species albumin has been chosen to be respresentative
of all protein species because:
1. it is about 50 % of the total protein mass;
2. it actually accounts for 65 % of the total osmotic pressure by virtue of its smaller
molecular weight and greater net charge; and
3. the measurements of its content and concentration are the most widely reported.
Therefore, we chose to determine the relationship between the albumin concentration

and the total colloid osmotic pressure so that, in case one of them is given, the other
can be calculated. Chapple [13] has developed such a relationship by a least squares
fitting of the data collected from the circulatory compartment of patients with nephrotic
syndrome [31, 63, 241. Nephrosis is a kidney disease which causes a lowering of the blood
protein level. The fitted relationship was forced to pass through the point PL =
11 0 wheu
CFL = 0. First, second, third and fourth order polynomial curve fits were attempted.
Because a difference in the variance of fit of less than 1 percent was found between the
first and second order relationships and because the higher order polynomials produced
non-monotonic behaviour within the range of interest, the linear relationship
3
in—
‘—‘FL — 1.522 x ,u TT
“FL 3.19
was selected as the best choice. In Eq. 3.19, the units of CPL and FL
11 are g/mL and
mmHg, respectively. This relationship as well as the experimentally measured data points
are plotted on Fig. 3.5.
Landis and Pappenheimer [47] had earlier determined the following relationship be
tween total protein concentration (C) and total colloid osmotic pressure (H):
fl = 2 + 9.0 x 10-6 x C
0.21 x C + 1.6 x i0 x C .
3 (3.20)
50
50.
C)
C)
10.0 20.0
II (mmHg)
Figure 3.5: Relationship between albumin concentration

and total colloid os
motic pressure [31, 63, 24].
The good agreement between Eq. 3.19 and Eq. 3.20 over the concentration range of
interest shows that neglecting protein differences does not affect the LI values significantly
[14].
Because of the difficulties in collecting interstitial fluid, very little information about
the interstitial compartment is available. If it is assumed that the relative osmotic activity
of albumin to that of the total proteins is similar in both the interstitium and plasma,
then it is reasonable to apply Eq. 3.19 to the interstitial compartment as well, i.e.
CI,AV = 1.522 x i0 LI
. (3.21)
Note that the effective albumin concentration is used since albumin is excluded from
some of the tissue volume.
3.5 Normal Steady-State Conditions
In order to study the transient responses of the MVES after the system is disturbed, an
initial point from which these transient responses deviate must be specified. This initial
point is taken to be the normal steady-state conditions in the current study.
As we know, different individuals possess different body weights, fluid volumes, pres
sures, chemical compositions, etc.. To help normalize these individual differences, a
“reference man” is introduced. The “reference man” is:
• a healthy male 170 cm in height and 70 kg in weight;
• in a supine position; hence location-dependent values such as colloid osmotic and
hydrostatic pressures are taken at heart level of the thorax, if possible.
To make comparison convenient, the normal steady-state conditions of the “reference

man” in the current model are the same as those used by Chapple [13], and they are
Variable Circulation Tissue References

, mL
0
V 3200 8400 [21, 106, 94, 56, 26]
VEX, mL — 2100 [76](assumed value)
ll, mmHg 25.9 14.7 [23, 46, 64, 27]
, g/L
0
C 39.4 16.8 calculated from Eq. 3.19 and 3.23
CAV,O, g/L — 22.4 calculated from Eq. 3.21
Qo, g 126.1 141.1 calculated
PA,o, mmHg 5.92 — [106]
Pv,o, mmHg 24.54 — [106]
,o, mmHg
1
F — -0.7 [108]
Table 3.2: Normal steady-state conditions for the “reference man”.
listed in Table 3.2. There are several points about Table 3.2 that should be emphasized
here. First, the normal fluid volumes in both compartments are confidently known. The
values have been further verified by more updated information. Fauchald [25] measured
the plasma volume by using injections of I - labelled albumin in 16 normal subjects,
and found the normal range to lie between 2.8 L — 3.5 L. Applying the same technique,
Noddeland et al. [63] measured the normal range of plasma volume at 3.1 L — 4.1 L.
These workers also measured the extracellular fluid volume (ECV) allowing a calculation
of the interstitial fluid volume as Vi,o = ECV — VPL,O. In this manner, Fauchald and
Noddeland et al. found that the normal range of interstitial fluid volume lay between
6.0 L — 11.3 L and 7.1 L — 12.2 L, respectively. These measurements made us feel more
confident about the fluid volume values listed in the table.
The second point concerns the excluded-volume, VEX. The degree of exclusion is
expressed in various ways. Sometimes, it is based on the matrix space instead of the
“free-fluid” space (i.e. V
)
1 , while sometimes, it is based on the excluding material’s
volume or weight alone. These different bases make it difficult to use the information
available in the literature. Moreover, there is little information concerning exclusion in
human tissues. Therefore, an assumed excluded-volume fraction (i.e. VEX/VI,o) of 25%

is used. This value is close to that estimated by Bell et al. [3]. In their studies on dog
hindpaw skin, albumin was excluded from an average of 26% of the sucrose space. Here,
it is assumed that, since sucrose is a relatively small molecule, the sucrose space equals
the interstitial fluid volume; in other words, the exclusion of sucrose can be neglected.
25% exclusion corresponds to an excluded-volume of 0.25 x8400 mL = 2100 mL.

The third point concerns the effective albumin concentration in the interstitial com
partment, CI,Av. It is defined as the ratio of interstitial albumin content to the interstitial
fluid volume available as distribution space for that protein, i.e.
CI,Av = /(V
1
Q — VEX) (3.22)
It is the effective interstitial albumin concentration rather than the actual interstitial al
bumin concentration that-determines the interstitial colloid osmotic pressure. Thus, given
111,0 (experimentally measured), CJ,Av,o can be calculated from Eq. 3.21, and accordingly,
the interstitial albumin content, Q’,o from Eq. 3.22 if Vi,o and VEX are known. The in
terstitial albumin concentration required in the lymph drainage expression (Eq. 3.9) is
obtained from
1
C = Q
/
1 Vj (3.23)
A similar equation applies to the plasma albumin concentration, i.e.
CPL = QPL/VPL (3.24)
3.6 Summary
A summary of the complete set of equations required by the coupled Starling model is
listed in Table 3.3.
H H H H II II II II
CD
1’9
I II _—
CD q
I— -__- I -‘ lJ Cl)
C) I 0
c_— i2I
‘- j IC) CD
CD I
‘-(i)IC) I CD
—I H I—.
lIc )—Le
. Cl’_-
DI
(I
:
C
Cl)
C
Cl)
C)
0
I.
‘— S—
Cl)
I-
—
-.
II
CD
H
e-l
q
CD
I
-.
C3
--- .
Chapter 4
Parameter Estimation And Data Analysis
In this chapter we will first describe the design of the parameter optimization procedure,
then present the experimental data collected from the literature, and finally discuss how
to use these data to obtain the unknown parameters for the coupled Starling model.
4.1 Parameters to be Determined
A review of the mathematical descriptions of the microvascular exchange system in Chap
-ter- 3- reveals that there are some constants which are determined only by the physico
chemical properties of the system. These constants are called the internal parameters
of the MVES model. Their values used in the model affect the fluid and protein distri
bution within the MVES significantly. For example, the fluid filtration coefficient, KF,
the diffusive permeability coefficient, PS, the solute reflection coefficient, a, the normal
lymph flow rate, JL,O, and the lymph flow sensitivity, LS, are all internal parameters
which characterize the transport properties of the capillary wall and the terminal lym
phatics; KF reflects the hydraulic conductivity, PS mirrors the permeability to albumin,
and a represents the sieving property of the capillary wall. JL,O and LS characterizes
the efficiency of the lymphatic system in removing accumulated interstitial fluid. These
parameters are assumed to remain unchanged at the constant value assigned to them
throughout the duration of whatever perturbation is applied to the MVES. One of the
objectives of the current study is to determine the optimal values for these parameters.
55
Chapter 4. Parameter Estimation And Data Analysis 56
Unknown Description
LS lymph flow sensitivity (mL.mmHg’.h
)
1
a albumin reflection coefficient
Pc,o capillary hydrostatic pressure at normal steady-state (mmHg)
KF the fluid filtration coefficient (mL.mmHg’.h
)
1
PS permeability-surface area product (mL .h’)
JL,O normal lymph flow (mL.h’)
Table 4.1: Unknowns in the coupled Starling model.
Generally, there are two approaches for dealing with transport parameters in com
partmental models:
1. assume values based on literature information for human or related animal MVESs;
2. treat them as unknowns and determine their values by statistically fitting model
predictions to available measurements from the literature.
Because some of the aforementioned parameters have not been measured directly in
humans or even in animals, and some have only been measured inaccurately (these details
will be discussed in Chapter 5), the latter approach is selected in the current study.
The normal capillary pressure, Pc,o has also never been measured directly in humans.
In addition, the constitutive relationship between the interstitial pressure and the in
terstitial fluid volume, P
1 F(V
)
1 , can only be estimated (see Table 3.1). Thus, the
capillary pressure, Pc,o, is added to the list of unknown model parameters listed in Ta
ble 4.1, while the three interstitial compliance relationships discussed in Section 3.4.2
are introduced into the model one at a time to test how they influence the results of the
parameter estimation procedure.

4.2 Additional Relationships between the Unknowns
Of the six unknowns parameters listed in Table 4.1, three can be eliminated via additional
relationships which exist between these parameters. These relationships will be discussed
in the sections that immediately follow.
4.2.1 Steady-state Balances at Normal Conditions
Two equations can be derived from the fluid and protein mass balances which must exist
in the intersititial or circulatory compartments under normal steady-state conditions.
At normal steady-state, the fluid balance can be written as
JF,O — JL,O = 0 (4.1)
and the protein balance as
Qs,o — QL,O = 0 (4.2)
When we substitute Eqs. 3.2, 3.3 and 3.9 into Eqs. 4.1 and 4.2, we obtain, respectively,
the following two equations relating KF, PS, JL,O, a and Pc,o:
KF [Pco 0
,
1
P — a (HPL,o — L[’,o)] — JL,O = 0 (4.3)
and
. [CPLO 1
CIAvoexp(PeO)
JF,O . (1 — a) — JL,O 0
,
1
C = 0 (4.4)
The degrees of freedom for a model is equal to the number of unknowns minus the number
of relationships between these unknowns. Thus, when Eqs. 4.3 and 4.4 are introduced,
only four degrees of freedom remain, i.e. only four unknown parameters need to be
specified to completely characterize the model.
4.2.2 Albumin Clearance Relationship
In addition, several workers have investigated the clearance rate of 125

1-radiolabelled (or
1-radiolabelled)
3
‘ 1 albumin from the subcutaneous tissue in humans. It is assumed that
injecting the tracer does not alter the normal steady-state conditions of the system.
The interstitial albumin disappearance half-time, ,
112 is defined as the time required to
T
eliminate 50% of the total introduced labelled albumin from interstitium to the lymphatic
system or to the circulatory compartment. A small dose of labelled albumin (10 — 30
[LCi) is injected subcutaneously, and its disappearance rate is registered by a Geiger
counter at the injection site at various time intervals [22]. The percentage of the initial
radioactivity is plotted as a function of time on a semilogarithmic graph allowing T
172 to
be determined as the slope of the disappearance curve [48]. The rate of disappearance
of albumin from the interstitial compartment is defined as the albumin turnover rate,
A1bTQ (fraction lost pr hdur). Thus, A1bTO and T

112 are related by
(1 — A1bTQ)T1/2 = 0.5 (4.5)
The average value of T

112 obtained by several investigators [48, 39, 28] is 33.4 hours.
From Eq. 4.5, A1bTQ is therefore calculated to be 2.05% per hour.
A mass balance for the labelled species yields the following equation:
(4.6)
where the * superscipt indicates a tracer quantity. Upon substituting Eqs. 3.3 and 3.9,
Eq. 4.6 becomes:
dQ 0
C, CZAV,o exp(—Peo)
(
—
—
— —
F,0
1 exp(—Peo)
—
— L,0 (4 7)
.
According to the definition of albumin turnover rate, at t = 0,
dQ*I =
AlL
iWTQ
17
VI,O
fY*
Also, at t = 0, there is no labelled albumin in plasma, so that CLO = 0. Furthermore,

since CZ
0 = / Vj,o
0
Q, and CZAv,0 = /(V
0
Q,
,
1 o — VEX), substituting into Eqs. 4.7 and 4.8
(at t = 0) and then setting them equal yields
JF,O (1 a) exp(—Peo)
. — .
JL,O
0 (4.9)
—
+ — AibTo —
[1
—
— exp(—Peo)1(Vi,o VJ,Ex)
— V
0
,
1
where
— (1 — a). JF,O
—
0
Fe
Eq. 4.9 provides a third relationship between the unknown parameters of the model.
Thus, of the six unknowns listed in Table 4.1, only three are independent. As a conse
quence, only three parameters need to be determined by fitting available response data,
the other three can then be calculated from Eqs. 4.3, 4.4 and 4.9.
42.3 Parameters to be Optimized
The albumin reflection coefficient (a), the lymph flow sensitivity (LS) and the capillary
hydrostatic pressure at normal steady-state (Pc,o) were selected as the three parameters
to be determined by statistically fitting the model predictions to the experimental results.
The selection of these three parameters was based on the following criteria:
1. the parameters must be physiologically important to the system;
2. the parameters should be sensitive to the estimation procedure;
3. the parameters must be independent each other.
LS does not appear in the normal steady-state mass balances nor in the albumin clearance
relationship; therefore, it must be selected. We don’t know which among KF, PS, JL,O,
a and Pc,o is more important physiologically, but we do know that a ranges from 0 to
1. Hence, because of its convenient bounds, a was chosen as another parameter to be
optimized continuously within these bounds. Finally, Pc,o was chosen to be the third
parameter investigated because its bounds can also be estimated, as is discussed in the
next section. Because the optimization program (see Section 4.5.3) is robust enough to
solve a three-dimensional problem and since a single set of the parameters is required
for validation purposes, we chose to optimize LS, a and Pc,o continuously, instead of
treating as a discrete variable in the statistical fitting procedure as Chapple (1990)
did in his study using nephrotic syndrome data.
Once values for a, LS and Pc,o have been specified, the remaining three parameters,
KF, PS, and JL,O can be calculated from the following equations obtained by manipu
lating Eqs. 4.3, 4.4 and 4.9:
A1bTQ
JL,O = (1—cr).ecp(—Peo) (4.10)
[1—exp(—Peo)J(VJ,o—VJ,Ex) +
(1 — a). JL,O
P5= CJ,o—(1—o-)CJ,Av,Q]
(4.11)
ln[ —)CpL,o
1
CI,o—(
and
JL,O
KF = (4.12)
Pc,o — Pi,o — a. (IIPL,O —
At this point, the model is completely defined. Thus, knowing the initial conditions
of the system and the perturbation, we can solve the four coupled ordinary differential
equations, Eqs. 3.10, 3.11, 3.12 and 3.13, to find the transient or steady-state responses of
volumes and protein contents in both the interstitial and the circulatory compartments.
In the process, the protein concentrations, osmotic pressures and hydrostatic pressures
of the system are also calculated.
4.2.4 Parameter Search Ranges
To save computational costs, bounds that encompass the region within which physiolog
ically feasible parameter values must lie were calculated.
The upper and lower bounds on Pc,o are the same as those used by Chapple [13]. The
upper limit was obtained by assuming that a trariscapillary pressure gradient of 1 mmHg
is maintained under normal steady-state conditions. Thus, since Pi,o = —0.7 mmHg,
fli,o = 14.7 mmllg and PL,O =

11 25.9 mmHg, and since the maximum Pc,o is obtained
when o 1, then Pc,o < 11.5 mmHg. The lower limit was obtained on the basis of
experimental measurements of venous capillary hydrostatic pressure (P,o 6 mmHg)
[2]; thus, Pc,o > 6 mmHg. The search range of Pc,o, therefore, is chosen to be:
7.0 pc,o 11.0 mmHg.
- As was discussed in Section LB is independent of the steady-state mass balance.

Thus there is no restriction imposed on LS from these mass balance equations and LS
may range from zero to infinity. To reduce computational costs, LS is assigned the
bounds:
0 LS 500 mL mmHg’ hr’
. .
In most cases, the value of LB which produces the best fit is significantly less than the
artificially imposed upper limit.

Because KF, PS, and JL,O must be positive, the possible values of a must be restricted
accordingly. Since JF,O is positive (which is equal to JL,O at normal steady-state), then
to ensure that KF remains positive in Eq. 3.2,
Pc,o — Pi,o — 0-. (H,o —

> 0 (4.13)
or,
0
P, — Pi,o
(4.14)
L[PL,O — 111,0
Since a < 1, therefore, 1 — a 0. And normal lymph flow is assumed to be positive, i.e.,
JL,O > 0. To ensure that PS remains positive, then from Eq. 4.11
>0. (4.15)
Solution of the above inequality accounting for the mathematical restriction which exists
in the evaluation of logarithms, gives
CPL,0 —
I,0
<a 1. (4.16)
CPL,0
To ensure that JL,O remains positive, then according to Eq. 4.10
(1a) exp(—Peo)
— .
+ > 0 4 17
[1 — exp(—Peo)](Vj,o VI,Ex) 0
,
1
V —
Rearranging Eq. 4.11 gives,
(1— a) JL,O —(1—a). CI,Av,oj

—1 n
—
(418)
PS — (1 — a) CPL,0
Taking exponentials on both side of the above equation gives,
e(l_JL0
Ci,o — (1 — a) CI,Av,o
(4.19)
0
,
1
C — (1 — a) CPL,0 .
or, according to the definition of the Péclet number (Eq. 3.4),
C
0
,
1 — (1 — a) CpL,o
e_Pe0
(4.20)
,o
1
C — (1 — a) CI,Av,o
Upon substituting Eq. 4.20, Eq. 4.17 can be simplified as
1 (VIO — V1Ex)
a> [CPLO — C1,o . (CpL,o — CJ,Av)]. (4.21)
CPL,0 ,V
1
o
Also, since CJ,Av,o = Q1,0/( V

0
,
1 — VI,Ex) and Cj,o = /V then
1
Q
0
,
= (VIO _EX)
. CI,Av,o (4.22)
P,o (mmHg) clmjn amax

7 0.574 0.688
8 0.574 0.777
9 0.574 0.866
10 0.574 0.955
11 0.574 1.000
Table 4.2: Bounds on a for Pc,o equal to 7 to 11 mmflg.
Substituting Eq. 4.22 into Eq. 4.21 yields
CI,Avo —
a> . (4.23)
CI,Av,o
The range of a values which simultaneously satisfies inequalities 4.14, 4.16 and 4.23 is
found to be
CPL,0 — 0
Ci, —
}
.
CFL,0 PL,O
11 — 111,0
The upper bound is chosen to be either 1 or (Pc,0 — PI,o)/(llpL,o — ui,o), whichever is

smaller. The latter expression, as can be seen, depends on P,
. The actual bounds on
0
a for Pc,o values ranging from 7 to 11 mmHg are listed in Table 4.2.
4.3 Analysis of Data
Ever since the general principles of the Starling hypothesis for transcapillary fluid ex
change were widely accepted, measurements of the Starling forces and other related
factors in the MVES have interested many investigators. After years of exploration,
reliable approaches for measuring many of these factors have been developed. General
knowledge of these measuring techniques will assist us in evaluating the quality of the
available experimental data.
For example, interstitial colloid osmotic pressure data can be obtained by:
1. direct sampling by micropipettes and catheters. The drawback of the method is

that the applied suction could increase the net capillary filtration and thereby
influence the interstitial protein concentration [86, 87];
2. implanted capsules or wicks based on the assumption that a fluid compartment in

contact with the interstitium will finally attain the same protein concentration and
hydrostatic pressure as the free-fluid phase of the interstitium [23];
3. noninvasive blister suction method [80]. This method is subject to the same criti
cism as per # 1 above.
The wick technique is the most widely used method and is generally thought to be the
most representative and accurate. Once the interstitial fluid is collected, the interstitial
colloid osmotic pressure can be measured directly by an osmometer, and protein concen
tration
can be determined by using a number of methods. Blood samples are easy to
collect; therefore, plasma osmotic pressures and protein concentrations can be determined
immediately using these same techniques.
Alternative methods for the measurement of hydrostatic pressures in interstitium
include [2]:
1. the use of chronically implanted perforated plastic capsules (with diameters of 1

cm or more);
2. use of a wick or a wick-in-needle (with a needle outer diameter of 0.6 mm);
3. the micropuncture technique (with a micropipette tip diameter of 2 — 4 [tm).
In all these methods, the interstitium is connected to a low-compliance manometer

through a fluid-filled tube. However, it is impossible to place a micropipette or nee
dle inside the capillary because the capillaries have internal diameters of 5 — 10 m only.
Thus, to the knowledge of the author, no one has so far directly measured the capillary
hydrostatic pressure.
The methods for the measurement of plasma volume and interstitial volume are based
on the dilution principle. A measured amount (Q) of a suitable tracer substance is
administered by injection. After equilibrium throughout the whole body is attained
and corrections are made for metabolic losses of the tracer, the concentration (C) of
the substance is measured in a suitable sample of the body water. The volume of the
compartment (V) is then given by the relation, V = Q/C. The dilution agents used in
the measurement of extracellular fluid volume (ECV) include insulin, sucrose, mannitol,
sodium thiocyanate and the radioactive ions, 35
SO, 82
Br and 24
Na+. Tracers used
in the measurement of plasma volume include Evans blue dye, ‘

1-labelled
3 1 albumin or
Cr-labelled erythrocytes. The interstitial volume is then calculated as Vi
51 = ECV—VPL.
In this section, we begin by preseiiting all of the available literature dataon humans
which we hope to include in the parameter estimation procedure. We then analyze each
data set in detail to determine whether it really provides information about the problem
under study and whether the measured results can reflect the relationships between the
dependent variables and the parameters we investigated. Finally, we discuss how these
different data sets can be combined and used in the optimization procedure.
4.3.1 Experimental Data
Six sets of useful data were found by an extensive search of the literature. The quantities
reported in these independent studies include colloid osmotic pressures, fluid volumes,
protein contents and protein concentrations, which were measured by applying the various
techniques discussed in the previous section. Each quantity has a different set of units,
e.g. pressure has units of mmllg, volume has units of mL, etc.. In order to make these
different measurants comparable, we have chosen to convert all of them into percentage
changes, so that they are unitless and can, therefore, be compared directly.
For the transient data, this conversion is based on the following equation:
X%=XtX0 xlOO
xo
where X denotes the quantity measured in the experiment and subscripts t and 0 indicate
quantities measured at a particular time and just prior to the perturbation (t = 0),
respectively. For the steady- state data, the conversion is based on the equation:
= X - XNQRM
x 100
XNORM
where X and XNORM represent the same variables measured in a patient and in a normal
subject, respectively.
This normalization procedure has several advantages. First, as was mentioned, it

makes all the measured quantities unitless so that they can be compared. Second, it
converts the magnitude of all the quantities into a similar range, again so that they are
more comparable. For example, before conversion, Vj has a value of around 8400 mL and
, a value of about —0.7 mmHg. It is difficult to compare 8400 mL with —0.7 mmHg.
1
F
But, after conversion, their percentage changes are usually less than 100% as can be seen
in sections which follow. Third, using percentage changes simplifies the normalization
process because it eliminates the differences in baseline values of variables in different
experiments. For example, consider the variable VPL. In one experiment, the initial
plasma volume may be 2547 mL, while in another it may be 3227 mL. If percentage
changes are used, the differences in starting values are eliminated automatically.
Only the modified data, based on the normalization procedure discussed above, are
presented in the section which follow. The raw experimental data are listed in Appendix
A. For each of these six sets of results, the objectives, perturbations, quantities measured
and sample sizes of the experiments are described in detail below.
Time (hr) -1.5 1 3 6 9 12

Saline, 100 mL Mean 0.00 -3.37 -0.41 -2.86 -4.09 -7.36
N=4 SD + 0.00 5.85 8.43 7.09 6.63 10.16
Albumin, 100 mL Mean 0.00 2.04 -0.41 -2.45 -1.64 -4.50
N=4 SD + 0.00 11.11 10.19 7.64 9.73 6.33
Saline, 200 mL Mean 0.00 -3.73 -0.83 -1.66 2.07 -0.41
N=4 SD ± 0.00 16.94 10.94 11.71 19.88 14.71
Albumin, 200 mL Mean 0.00 13.28 12.86 6.22 8.30 6.64
N=4 SD ± 0.00 12.51 20.36 14.87 17.93 13.24
Table 4.3: Percentage change in plasma colloid osmotic pressure at room tem
perature. t = 0 designates the end of the infusion period [41].
4.3.1.1 Set A: Saline and Albumin Infusion
To study albumin-induced plasma volume expansion, Hubbard et al. [41] infused eight
healthy male volunteers with solutions of saline or saline plus albumin over a 1.5 hour
period in a thermoneutral enviroment. Four of them were raiadomly assigned to a low
dosage treatment, i.e. intravenous infusion of 100 mL saline or 100 mL saline with 25 g
albumin, while the other four were assigned to a high dosage treatment, i.e. 200 mL saline
or 200 mL saline with 50 g albumin. Just before the infusion and 1, 3, 6, 9 and 12 hours
post-infusion, plasma volume was measured by dye dilution using indocyanine green,
plasma osmotic pressure was measured using an oncometer, and total plasma protein
content was determined by commercial tests. The results are tabulated in Tables 4.3,
4.4 and 4.5 (for FL,
11 VPL and QFL, respectively) in terms of percentage changes from
pre-infusion values. Both average changes and standard deviations are provided. During
the observation period (0-13.5 hours), an average net weight gain of 1.4 kg due to fluid
intake occurred. This will be considered as part of the perturbation. Therefore, the total
fluid inputs were 1500-1600 mL.
The same perturbations are input into the model to predict the transient responses.
Time (hr) -1.5 1 3 6 9 12

Saline, 100 mL Mean 0.00 1.80 0.59 3.52 7.41 6.56
N=4 SD + 0.00 38.10 38.25 39.17 39.99 39.35
Albumin, 100 mL Mean 0.00 11.04 10.30 11.66 10.82 10.52
N=4 SD ± 0.00 41.82 45.62 45.10 43.14 43.34
Saline, 200 mL Mean 0.00 5.00 4.50 5.00 3.38 5.24
N=4 SD ± 0.00 19.75 17.37 16.25 18.41 17.67
Albumin, 200 mL Mean 0.00 13.25 11.88 7.85 8.72 9.74
N=4 SD ± 0.00 18.41 14.79 15.61 14.84 16.36
Table 4.4: Percentage change in plasma volume at room temperature. t = 0

designates the end of the infusion period [41].
Time (hr) -1.5 1 3 6 9 12

Saline, 100 mL Mean 0.00 0.04 1.14 0.81 3.56 3.64
N=4 SD ± 0.00 6.60 7.27 7.55 6.16 6.29
Albumin, 100 mL Mean 0.00 9.41 8.31 7.25 7.67 6.57
N=4 SD ± 0.00 5.54 5.42 7.21 5.52 6.12
Saline, 200 mL Mean 0.00 0.77 3.08 4.10 4.32 5.51
N=4 SD ± 0.00 6.19 7.48 7.60 9.15 9.88
Albumin, 200 mL Mean 0.00 19.06 15.60 12.56 10.38 11.58
N=4 SD ± 0.00 10.44 9.32 7.99 8.29 8.25
Table 4.5: Percentage change in plasma albumin content at room temperature.

t = 0 designates the end of the infusion period [41].
However, because QPL VPL x CPL, the results presented in the three tables are not
independent. Only VFL and CPL, the measured quantities, are selected to be compared
with the model predictions.
4.3.1.2 Set B: Acute Saline Infusion
To study the effect of rapid intravenous infusion of physiologic saline solution on the
pulmonary arterial and capillary pressure of otherwise normal human subjects, Doyle
et al. [18] studied twelve adult men convalescing from noncardiac ailments. In each
case, 900 — 1000 mL of normal saline solution were injected intravenously in 6.5 — 13
mm. Blood volumes (BV) and hematocrits (HCT) were measured both pre-infusion
and post-infusion. Plasma volumes were then calculated from VPL = BV. (1 — HCT). In
some patients, e.g. Patients #4, #8 and #10, the plasma volume kept increasing after the
infusion, (which seems physiotogically unreasonable); while, in some other patients, e.g.
Patients #3, #5, #9 and #12, the plasma volume response to the infusion was uncertain
(i.e., only two points were measured). These data sets were therefore eliminated from
further consideration, leaving only five sets to be used in the parameter estimation. These
data, in terms of their absolute values as well as percent changes from normal conditions,
are presented in Table 4.6, along with estimates of their standard error. Unfortunately,
no replicated measurements were carried out; hence, approximations of experimental
errors are used. The estimate of the standard error (SE) is based on the assumptions
that an error of ±316 mL/m
2 of body surface area was associated with the measurements
of blood volume [18] and that the hematocrit readings were accurate. The calculation of
the estimated standard error is illustrated in Appendix B.
Patient # Remarks VPL AVPL SE

(rnL) %
Control 2547.4+331.3 0.00 26.01
1 l000mL/9.5mins 3182.5±361.8 24.93 30.45
38 mm. after infusion 2766.0±342.8 8.58 27.58
Control 3227.9±342.3 0.00 21.21
2 l000mL/llmins 4031.2±366.1 24.89 24.59
60 mm. after infusion 3726.9+358.0 15.46 23.33
2382.2±273.7 0.00 22.98
6 l000mL/l3mins 2927.2+300.3 22.88 26.72
Control 2292.8±303.1 0.00 26.44
7 l000mL/llmins 2956.9±336.1 28.96 31.71
Control 2606.0+286.9 0.00 22.02
11 900mL/9rnins 3122.3+311.2 19.81 25.13
40 mm. after infusion 2817.2+297.7 8.10 23.33
Table 4.6: Percentage change in plasma volume after rapid saline infusion [18].
VFL (mL) CPL (g/L) QPL (g)

t=0 hr 3200 34 108.8
- ±5 ±16
t=2.5 hr 3541 30 106.2
±1177 +5 ±53
Percentage 10.66 -11.76 -2.39
change (%) +36.78 ±27.68 +63.07
Table 4.7: Experimental data from Mullins et al. [60]. Infusion starts at t =
0, and lasts for 2 hours (N = 111).
4.3.1.3 Set C: Saline Infusion
In this study, Mullins et al. [60] examined 126 patients with multiple (but non-cardiac)
diseases. In their experiments, 2 L of normal saline were injected intravenously over a
two-hour period. Only 111 patients tolerated the entire dosage. Hemoglobin, hematocrit,
total protein and albumin were measured before and after the infusion. Hemoglobin con
tent is assumed to remain constant throughout the study. Hence, the percentage change
of albumin concentration (ACpL%) and plasma volume (AVpL%) can be calculated (see
Appendix B) and compared with the results predicted by the model using the same per
turbation. All data in this set (Table 4.7) are quantitatively significant because each
data point represents 111 repeat measurements. Also, since QFL VPL x CPL, only VPL
and CPL were selected for use in parameter estimation.
4.3.1.4 Set D: Heart Failure
Patients suffering different extents of heart failure were examined in two different studies.
In Fauchald’s [25] experiment, 13 patients with heart failure were studied, 7 of whom
had diuretic-resistant fluid retention with anasarca. Noddeland et al. [63] examined
22 patients who had angina pectoris in another independent experiment. FL
11 and H
were measured in both experiments. Noddeland et al. also measured the interstitial
hydrostatic pressure F
, and Pc was then estimated as the isogravimet’ric capillary pres
1
sure, Pc,iso .
From the filtration equation JF = KF• [Pc — Pi — u (HpL — fl)j, we
know that only when JF = 0, Pc = Pc,iso. Because the filtration rate is relatively
low under normal condition, thus, the approximation of Pc,iso as Pc seems reasonable.
They found a linear relationship between P’ and the right atrial pressure (RAP), i.e.
Pc = 0.62RAP + 6.8. Pc was not measured in Fauchald’s experiment, therefore, this

relation is used to estimate the capillary hydrostatic pressure Pc in his patients. VPL
and ECV were also measured; accordingly, Vj was calculated from the difference between
ECV and VPL. The results are listed in Table 4.8. The mean value of each group is
used, so these data points are also quantitatively significant. Note that the pressures are
normalized arithmetically with respect to the values for reference man, i.e.,
Hi,j,NORMALIZED = Hi,j + (Ho — Hj,o), (4.24)
where the subscripts i and j indicate, respectively, the specific data point and the data
set undergoing normalization, and H represents the normal colloid osmotic pressure of
reference man. Also the fluid volumes are proportionally normalized with respect to the
value for reference man, i.e.,
Vi,j,NORMALIZED = x , (4.25)
where Vo represents the normal fluid volume of reference man.

Physiologically speaking, during the early stage of heart failure, the MVES still be
haves normally [105]. The most pathological condition studied in heart failure as part of
this work is for the condition of anasarca. It is believed that at this stage of heart failure,
‘Isogravimetric capillary pressure equals the total pressure opposing net filtration of fluid from the
capillaries, i.e. Pc,iso = P
1 + o (IIPL Hi). It is not a measure of the actual capillary pressure, in
—
principle.
Anasarca Heart Failure Angina Pectoris Normal

(N=7) (N=13) (N=22)
PL
11 mmHg 20.3 23.4 24.0 25.9
Hi mmHg 8.1 10.4 12.2 14.7
Pc mmllg 20.1 16.91 11.45 10.0
1 mL
V 13120 12040 7450 8400
SD 17340 15420 6750 —
/V?7o 56.2 43.3 -11.4 —
SD 206.4 183.6 80.4 —
Table 4.8: Experimental data at steady-state for patients with heart failure.
patients begin losing dry tissue. Consequently, the protein content in the interstitium
will be severely lowered. As well, the tissue structure will change [57]. Patients in this
condition are not considered to have normal MVES parameters and are therefore not
considered in this study. Thus, the corresponding data point (see Table 4.8) has been
eliminated from further consideration.
In the parameter estimation procedure, PL,
11 H, and Pc are fixed at the values
tabulated in Table 4.8, because these values are thought to characterize the different
extents of heart failure. Thus, the only Starling force component which can be altered
is the interstitial hydrostatic pressure. Parameter estimation in this case is based on the
differences between experimental and predicted /V

1 values.
4.3.1.5 Set E: Nephrotic Syndrome
The data from chronic nephrotic patients which were used in Chapple’s [13] study are
also included in the current investigation. The nephrotic syndrome is characterized by
proteinuria (i.e. excessive urinary excretion of plasma proteins) sufficient to induce hy
poalbuminemia (i.e., a plasma albumin content below that of normal) and edema. Ex
periments show that patients with nephrotic syndrome exhibit a normal microvascular
exchange behaviour, which is altered by changes only in the Starling forces [26, 91, 58].
The kidney allows protein loss but the rest of the system otherwise behaves normally.
Koomalls [46], Fadnes [24], Noddeland [64] and Fauchald [27] have studied the tran
scapillary forces and fluid distributions in chronic nephrotic patients. All of them reported
data relating H to FL
11 (see Fig. 4.1, lower panel), but only Fadnes et al. [24] measured
Vj at different PL
11 (see Fig. 4.1, upper panel). All of the data are normalized following
the same procedure as that used in Chapple’s study [13], i.e., pressures (LI
1 and IIFL)
are normalized arithmetically with respect to the normal steady-state values of reference
man (Eq. 4.24); while the fluid volumes are normalized proportionally (Eq. 4.25).
In the parameter estimation procedure, the circulatory compartment is assumed to
behave as an infinite source/sink of both fluid and proteins and the interstitium is allowed
to change its fluid and albumin contents to attain the steady-state corresponding to each
perturbed PL
11 value.
4.3.1.6 Set F: Saline infusion before extracorporeal circulation
Before 13 patients with coronary artery disease were operated on using extracorporeal
circulation, Rein et al. [80] injected intravenously 1500 - 2000 mL of Ringer’s acetate.
was measured subcutaneously on the chest using the blister suction method and
ll represents the average colloid osmotic pressure during the suction period (1.5 hrs).
PL
11 was measured in a blood sample collected from a cubital vein. P
1 was measured
as well, but was not used in the parameter estimation, because, after investigation, we
found that the error in P
1 controlled the fit. The reason for this is that Pj has the low
negative baseline value of —0.7 mmHg in the model. Using the best-fit parameters of
tissue compliance relationship #3 (which will be discussed in Chapter 5), the injection
of 1750 mL Ringer’s acetate will cause an elevation in P
1 of around 1.63 mmHg. This
corresponds to a AP
%
1 = 1.63/(—0.7) = —233%. According to Eq. 4.26, this point will
Chapter 4. Parameter Estimation And Data Analysis .75
50.0-
37.5-
25.0-
•.
12.5
•• .‘
t
0.0
0.0 5.0 10.0 15.0 20.0 25.0 3(
1T(mmHg)
- 20.0-
16.0-
12.0-
.. $
8.0-
. .
a a
4.0-
• 3.•a
• •. •
•.
I I I I
0.0 5.0 10.0 15.0 20.0 25.0 30.0
(mmHg)
Figure 4.1: Normalized data for patients with nephrotic syndrome [13]. The
upper panel has 18 points and the lower panel has 66 points, all of which are
included in the parameter estimation procedure.
“FL (mmHg) ll (mmHg)

t=0 hr 24.1 14.7
±1.1 ±0.9
t=3 hr 17.5 13.7
±1.2 ±1.2
Percentage -27.4 -6.8
change (%) ±8.3 ±13.9
Table 4.9: Experimental data from Rein et al. [80]. Blister suction method
was used to measure Hi, hence, All
1 represents the average osmotic pressure
during the suction period (1.5 hrs).
contribute to the objective function by 5843 units. Compared with the OBJmjn of 74.57
units (from Table 5.1), we can see that this point will dominate the shape of the surface
plot if it is included in the parameter estimation procedure. Hence, it was eliminated in
the current study. The useful results are tabulated in Table 4.9. Although the MVES
apparently behaves normally for these patients convalescent from non-cardiac diseases,
we suspect that the blister fluid does not represent the true interstitial fluid. Therefore,
we eliminated data set F from the parameter estimation procedure.
4.3.2 Parameter Estimation Strategy
First, we analyse the suitability of the experimental data for the parameter estimation
task at hand. Except for Set D and Set E, all the other experimental data sets use at least
a 900 mL fluid infusion within a short period. Now, let us discuss how the system will
likely be affected by 1000 mL fluid infusion. Assume that the 1000 mL of fluid is quickly
redistributed to the interstitium after it is injected intravenously, and that the plasma
volume is therefore essentially unchanged. This is the typical physiological response of

the MVES to fluid infusion. According to the model, an extra 1000 mL of fluid in the
interstitium will increase Pj from -0.7 to 0.86 mmHg, i.e. AP 1.5 mmHg. With LS
ranging from 0 to 300 mL.mmHg’•h’, the lymph flow, therefore, could increase up
to 450 mL•h
1 above the normal level. Thus, the lymph flow sensitivity will affect the
MVES lymph flow return rate moderately when the system is subjected to a perturbation
at this value of fluid infusion.
For an albumin infusion, 25 g of albumin in plasma will increase the plasma colloid
osmotic pressure by approximately 5 mmHg, while 50 g will cause PL
11 to increase by
approximately 10 mmHg. Since JF = KF• (P — Pj — g. (IIPL —
Hi)), we know that
a will influence the MVES filtration rate and, consequently, the plasma volume, plasma
colloid osmotic pressure, etc., which are the quantities being compared between the model
predictions and experimental results. This is only a simplified analysis; in the real model,
many factors will be affected by these perturbations. Nevertheless, we can still conclude
that the experimental data do provide the information about the parameters under study
andean be used to estimate the parameters that we-are interested in.
Second, we will discuss how these different data sets may be combined in the param
eter estimation procedure. We have to keep in mind that, when these different data sets
are combined, it is done so on the assumption that the transport parameters for these
different groups of people are similar and independent of age, sex and degree of health.
To combine these different data sets, the first question that must be asked is how to
make the different measured quantities comparable. The solution to this issue, that is,
the use of percentage changes, was discussed at the beginning of this section.
The second question is how to evaluate the importance of each data point within
each set. To solve this problem, each point was assigned a weight factor, W. If the
point represents an individual value, then W = 1/SD. This means that points which
have a high degree of uncertainty associated with them (i.e. high SD) are weighted less
(i.e. small 147). If the point represents the average value of a measurement repeated n
times, then W = n/SD, i.e., the standard error of the mean (SE = SD//) is used
to calculate the weight factor. This implies that if an average value is used, that point is
quantitatively more important, and n times more weight should be given to that point.
In addition, because most of the data sets concern transient responses, the model
predictions must be compared with the experimental data point at that specific time. As
a convenience, the vertical distance instead of the shortest distance (which was used in
Chapple’s studies) between the prediction and measurement was selected for parameter
estimation purposes.
4.4 Parameter Estimation Procedure
To obtain the best-fit values of u, LS, and Pc,o, the weighted least squares fitting criterion
is selected. Thus, the parameter estimation procedure is based on finding the values of
the unknown parameters which will minimize an objective function, OBJ, formed by
summing, over all data points, the squares of the vertical distances between the measured
and predicted percent changes, i.e.
OBJ = wi,j(Ax%epij — j
2
X%simjj) © given LS, a, Pc,o (4.26)
i=1 j=1
where N denotes the number of data sets and M denotes the number of data points in
the ith data set. The weight for each data point reflects the importance or accuracy of
that point. The objective function is calculated iteratively inside the limits on a, LS,
and Pc,o, and those values which produce the minimum objective function (OBJmin) are
the best-fit parameters.
4.5 Numerical Methods and Computer Programs
4.5.1 Transient Solutions
To find the transient response of the MVES after a perturbation, the set of four simul
taneous first—order nonlinear ordinary differential equations listed in Table 3.3 must be
solved. These equations represent mass balances of fluid and proteins in both the in
terstitial and the circulatory compartments. They are integrated over time using the
Runge-Kutta-Fehlberg method with error control [40]. The advantage of employing this
method is that the local time step size is adjusted (i.e. in sharply curved regions the step
size will be smaller, while in slowly-changing regions it will be larger) so that the cumu
lative error over the entire time interval can be maintained below a prespecified value.
This saves computational time and costs. In the present study, the maximum allowable
error is set to 0.01 mL and 0.01 g for fluid volume and protein content, respectively.
4.5.2 Steady-state Solutions
The steady-state solutions are obtained by solving the set of simultaneous nonlinear
algebraic equations that result when the accumulation terms of the ordinary differen
tial equations are dropped. The numerical technique employed to accomplish this task
is Newton’s iterative method [11]. In this method, the non-linear equations are trans
formed to a set of linearized equations. The required partial differentials (to calculate the
coefficients of the Jacobian matrix) are approximated by finite differences. The resulting
linear algebraic equations are solved by Gauss elimination incorporating full pivot selec
tion. The maximum allowable error is also set to 0.01 mL and 0.01 g for fluid volume
and protein content, respectively.
4.5.3 Computer Programs
The optimization routine used in current study is the UBC NLP, which is a nonlinear
function optimization program. The parameter values which yield a global minimum
in the objective function are obtained by invoking the subroutine GRG (in which the
generalized reduced gradient method is employed) or subroutine NLPQL (in which a
slightly modified version of the quadratic approximation method of Wilson et al. [89]
is employed) from the interactive monitor program, NLMON. The monitor program
provides an interface to the nonlinear optimizing routines. To use the monitor program,
a FORTRAN function subprogram named XDFUNC must be supplied to evaluate the
objective function. This function subprogram is listed in Appendix F. Since the current
study deals with a constrained optimization problem, a subprogram named XDCONS
must also be provided to evaluate the constraint functions; it is also listed in Appendix F.
In addition, because the Objective function éan not be expressed analytically, by default,
the monitor provides numerical approximations of the first and second partial derivatives
using central differencing.
The monitor is invoked by issuing the MTS command
$RUN FUNC.0 + NA:NLMON
where FUNC.0 is a file containing the compiled versions of the aforementioned subpro
grams (i.e. XDFUNC and XDCONS). The monitor takes care of the difference in the
calling sequences among the different routines. The global optimum is found by rerun
ning the program using several different starting points. If all runs return the same point
as the optimum, it is assumed that the optimum solution is the global one. Upper and
lower bounds are set as the search ranges of the parameters. The step size used in the
calculation of numerical derivative (DELTA) is set to l.D—3.
Besides the minimum of the objective function, the monitor program can also provide
important statistical information about the best-fit parameters, such as covariance and
confidence interval. Some basic concepts related to the statistical analysis are explained
in Appendix C. For detailed information on how to use the monitor program, refer to
the manual of UBC NLP.

Appendix F also includes the routine that simulates the transient response of the
uncoupled Starling model to a specified perturbation according to Koomans’ experiment
and also determines the final steady-state conditions of the system following the distur
bance.
Chapter 5
Results And Discussion
5.1 Introduction
Now that the mathematical model has been formulated (Chapter 3) and the parameter
estimation procedure has been established (Chapter 4), in this chapter, the best-fit pa
rameters for each independent data set will be presented separately. Following that, the
possibility of combining these different data sets will be investigated. Then the best-fit
parameters for the combined data set (including Sets A — E) for the coupled Starling
model determined by employing the least squares method will be presented. With these
statistically determined parameters, the model is fully described and is used to simulate
variolls experimental situations. The simulations are compared with the experimental
results in terms of both the trends and the fit.
Because statistical fitting between the experimental data and the model predictions
during parameter estimation is one of the major characteristics of the current work, a
considerable amount of attention will be devoted to the parameter estimation procedures
in the following discussion. Statistical analyses are included in the discussion to evaluate
the reliability of the estimated parameters. Sensitivity analyses are carried out to inves
tigate how the transport parameters influence the objective function. The correctness
of the computer program and its ability to converge to a set of known parameters are
also investigated (see Section 5.2.6). Residual analysis is carried out to investigate the
distribution of the errors between the predicted and the experimental data.
82
Chapter 5. Results And Discussion 83
Finally, the model is validated by comparing the best-fit transport parameters with
available literature values, and by comparing simulation predictions with the measured
dynamic behaviour of nephrotics following an albumin infusion [45], a set of data which
has not been used for and hence is independent of the parameter estimate procedure.
5.2 Results
5.2.1 Best-fit Parameters for the Coupled Starling Model
One of the major goals of the current study was to obtain a set of best-fit mass exchange
parameters for humans so that the model becomes fully described and can then be applied
to various clinical and experimental situations.
Using the estimation procedure described in Chapter 4 and applying it to all 138
data points, three sets of best-fit parameters corresponding to the three different tissue
compliance relationships were obtained and are listed in Table 5.1. From the table, we can
see that all three compliance relationships give a similar fit to the experimental data, with
a maximum difference in OBJmjn of less than 6 units, or about 7%. Clearly, compliance
relationship #3 produces the lowest OBJmin and hence will receive the highest degree
of interest in the following sections. The best-fit Pc,o values were relatively consistent
at about 11.0 mmHg. The best-fit u values increase slightly as the tissue compliance
decreases during overhydration, i.e., as the compliance changes from relationship #1
to #3. The best-fit LS values decrease when the tissue compliance decreases during
overhydration.
5.2.2 The Feasibility of Combining Different Data Sets
As was discussed in Section 4.3.2, the validity of combining data from individual patients
having different diseases to obtain a single, comprehensive set of parameters is based on
Compliance # 1 2 # 3
LS (rnL.mmHg
.h’)
1 53.04±0.31 52.57+5.27 43.08±4.62
C.I. (L,U) (52.43,53.64) (42.24,62.90) (34.03,52.13)
U 0.9560±0.005 0.9761±0.018 0.9888±0.002
C.I. (L,U) (0.9453,0.9666) (0.9399,1.0000) (0.9840,0.9936)
pc,o (mmHg) 10.95±0.05 10.99±0.17 11.00±0.03
C.I. (L,TJ) (10.86,11.04) (10.66,11.33) (10.95,11.05)
PS (mL.h’) 71.68 72.52 73.01
KF (mL.mmHg’.h’) 83.99 101.08 121.05
JL,O (mL.h’) 77.26 77.06 75.74
Fe 0.0487 0.0254 0.0116
OBJmin 79.67 77.68 74.57
Table 5.1: Best-fit parameters and their confidence intervals, as well as the
associated transport coefficients corresponding to the three tissue compli
ance relationships. C.I. denotes confidence interval (see Appendix C for its
calculation); L and U denote lower and upper limits respectively.
the assumption that all the subjects involved in those independent studies have similar
microvascular exchange transport coefficients.
To test the possibility of combining the data collected for the current study with those
from nephrotic patients used by Chapple [13], each data set was analysed separately and
the statistical best-fit parameters and their confidence intervals were obtained (Table 5.2).
This test must be done before a single, valid set of parameters can be obtained. Because
P
0 0 was treated as a discrete parameter during the parameter estimation procedure
for nephrotic patients and because Pc,o = 11 mmHg is believed to produce the most
reasonable fit to the experimental data [13], therefore, for the sake of convenience, in all
cases shown in Table 5.2, tissue compliance relationship #3 with Pc,o = 11 mmHg was
employed.
In order to visualize the fits corresponding to each set of data, the confidence limits as
well as the optimum values for LS and cr listed in Table 5.2 are plotted on Fig. 5.1. In the
000.0
500.0
0 Set A Hubbard et al.)

XSet B Doyle et al.)
V Set C Mullin.s et al.
)@Set D Heart failure
400.0 • Set E Nephrotic syndrome)
= Combined data
300.0- -
200.0-
100.0’
0.0- I I L:J V
•
0.5 0.6 0.7 0.6 0.9 1.0
U
Figure 5.1: Best-fit LS and a’, as well as their confidence intervals for individual
data sets. The results correspond to tissue compliance relationship
#3 with
Pc,o = 11 mmflg.
Set # LS Confidence Interval ci Confidence Interval

A 0.0 0.0 LS 55.4 0.9630 0.9614 ci 0.9646
B 232.5 0.0< LS 600.0 1.0000 0.8332< ci 1.0000
C 0.0 0.0 LS 172.4 0.9855 0.9517 ci <1.0000
D 79.0 0.0< LS 600.0 0.9886 0.5744< ci 1.0000
E 42.7 31.1 LS 54.3 0.9892 0.9579 ci 1.0000
Combined 39.9 39.5< LS 40.3 0.9829 0.9765< ci <0.9893
Table 5.2: Best-fit LS and ci, as well as their confidence intervals for individual
data sets. The results correspond to tissue compliance relationship #3 with
Pc,o = 11. mmHg. “Combined” represents the best- fit parameters obtained
when data Sets A, B, C and D are combined.
ci direction (i.e., x-direction in the figure), the confidence intervals for these independent
data sets all overlap, with the narrowest interval being that of Set A, ranging from 0.9614
to 0.9646, and widest being Set D, ranging from 0.5744 to 1.0. The best-fit ci values
ranged from 0.9630 (the best-fit ci of Set A) to 1.0 (the best-fit ci of Set B); the majority
were around 0.98. It can be said with certainty that the different subjects investigated
in experiments A to E have similar albumin reflection coefficients (ci).
In the LS direction (i.e., y-direction in Fig. 5.1), the best-fit LS values ranged from
0 to 232.5 mL.mmHg’.h’. Once again, all the confidence intervals for LS overlap each
other to a great extent. Best-fit values for LS for Sets B and D have particularly large
confidence intervals, covering the entire range we investigated (0 — 600 1
mL.mmHg
. h’).
The reason why some data sets are not sensitive to LS may be explained as follows. In the
model, the lymph flow sensitivity affects the MVES by altering the lymph flow rate: i.e.,
JL = JL,O + LS (P
1 — F
)
0
,
1 . That the objective function is not sensitive to LS may result
from the fact that, in Sets B and D, AP

1 is always close to zero. That is, the experimental
data depict very small changes in V
. These result in very small changes in P
1 1 so that
JL does not change significantly. However, this is not the situation in most experiments
as discussed in Section 4.3.2, i.e., by approximation, 1 L of infused saline may cause an

increase ill interstitial hydrostatic pressure of about 1.5 mmHg. In real systems, the lack
of sensitivity of the LS parameter estimation may also relate to the time dependence
of lymph flow (personal communication with R.K. Reed.). Unfortunately, there is no
quantitative information about such effects nor have we included delays in lymph flow
in the present model. This is perhaps one of its defects. For Sets B and C, data are
collected in less than 2.5 hours and we suspect that the lymphatic system had not been
fully triggerred during the period investigated. To prove this hypothesis, we separated
the data of Set A into two parts; one is the so-called early response corresponding to t
3 hrs post-infusion; the other is the late response corresponding to 9 t < 12 hrs
post-infusion. From Fig. 5.2, we found that, in the early response, the objective function
is not sensitive to LS, i.e., the contour lines are vertical; while in the late response, the
objective function is sensitive to LS. Even though the predicted best-fit LS of the late
response equals to zero, Fig. 5.2 B provides much more information about the behaviour
of the lymphatic system than does Fig. 5.2 A, suggesting that the lymphatic response
has not been fully triggerred at the earlier time. The procedure used for generating the
contour plots is detailed in Appendix D.
When data Sets A, B, C and D are combined, we found that the best-fit LS and a
are 39.9 1
.h and 0.9829, respectively, with 95% confidence intervals of 39.5
mL.mmHg
LS 40.3 mLmmHg’.h’ and 0.9765 a 0.9893. It can be seen that the best-fit
a and LS values and the confidence intervals for Set E (see Table 5.2) are very similar
to those of the combined data set, and the 95% confidence intervals overlap to a large
extent. Thus, we conclude that the MVES in uephrotic patients behaves normally and
that the nephrotic data can be combined with the other data collected for parameter
estimation purposes in the current study.
0.80 0.85 0.90

SIG
Figure 5.2: Contour plots of OBJ during early and late responses for Hubbard’s
data [41]. A represents the early response, t3 hrs; B represents the late
response, 9 hrst12 hrs.
It should also be mentioned that the best-fit parameters for the nephrotic data ob
tained for the coupled Starling model by applying the shortest distance least squares
criterion were [14]:
a = 0.996
LS 39.8 1
.h
mL.mmHg
.
These parameters are similar to the best-fit parameters obtained by the current parameter
estimation procedure. This agreement adds further to our confidence in the reliability of
the current parameter estimates presented in Table s.2.
In summary, there is a total number of 138 experimental data points which can
be used for parameter estimation purposes. The subjects include healthy males, adult
men convalescing from non-cardiac ailments, patients with some degree of heart failure,
-
- -patients-with non-cardiac multiple-system diseases, patients with nephrotic syndrome and

normals. All of these subjects are considered to exhibit normal microvascular exchange
behaviour. We can therefore say that the current study represents a general investigation
of the human microvascular exchange system under normal conditions.
5.2.3 Simulations Using Best-fit Parameters
By just looking at the OBJmjn value, it is difficult to tell how well the experimental data
are fitted. Does the model predict the correct response trends after the microvascular
exchange system is perturbed? Has each independent data set been uniformly well fitted?
Or are some sets fitted very well, while others are poorly fitted? The best way to answer
these questions is to compare each set of experimental data with the corresponding model
simulation results obtained using the best-fit parameters.

5.2.3.1 Transient Responses of llpj, CPL and VPL after Saline or Albumin
Infusions (Sets A, B and C)
To properly compare the model predictions with the experimental data, we must also
understand how the MVES responds to the specific perturbations.
The circulation system is regulated by three major factors: (1) neural mediators, (2)
humoral mediators, and (3) the Starling forces. These three factors work together to
make the circulation system self-regulating. There are many delicate pressure receptors
and chemoreceptors on the walls of the blood vessels. If these receptors detect any
changes in blood pressure and/or chemical composition, the nervous system responds to
these changes directly (i.e. by stimulating nerve fibers to control cardiac functions and
vessel contraction or relaxation); or indirectly (i.e. by stimulating the endocrine system

to release hormones which also exert a profound influence on the blood vessels). However,
neural and humoral mediatorsact primarily on the larger vessels of the circulation system.
The microvascular exchange system, on the other hand, is locally controlled by conditions
in the capillaries and in the tissues in the immediate vicinity of the capillaries. These
conditions are generally referred to as the Starling forces.
Suppose a certain amount of isotonic solution is injected intravenously. After the
injection, the plasma volume expands, and its concentration of high molecular weight
solute is diluted. Lundvafl et al. [54] suggested that, in man, there may be particularly
efficient mechanisms for maintaining constant plasma volume via fluid transfer between
the bloodstream and the large fluid reservoir of skeletal muscle and skin. The increased
hydrostatic pressure caused by volume expansion and the decreased osmotic pressure due
to solute dilution are considered to be the driving forces for eliminating extra fluid from
the bloodstream and consequently maintaining constant plasma volume.
After a hyperoncotic solution is injected intravenously, the Starling forces will alter in
the following manner. The capilliary hydrostatic pressure increases due to the increase in
the plasma volume in addition to the capillary colloid osmotic pressure, therefore adding
an additional driving force for fluid exchange. As we mentioned before, the circulation
system has been shown to be self-regulating. If the capilllary wall is permeable to the
solute, the solute molecules will penetrate to the interstitiurn until a balanced osmotic
pressures on both sides of the wall is attained. If the capillary wall is not permeable to
the solute, water is drawn into the bloodstream, thereby diluting the plasma to achieve
the same result. Because the capillary wall is semi-permeable to albumin, both of the
aforementioned movements occur when albumin solution is injected. At the same time,
water as well as solute are removed from the bloodstream due to the increased capillary
hydrostatic pressure. ‘Whether the plasma volume is increased or decreased depends on
which effect dominates.
Figures 5.3 — 5.6 demonstrate the model predictions of the transient responses of the
circulatory system oncotic pressure and volume following saline infusions with or without
albumin. The experimental protocols were described in Section 4.3.1. Since the lowest
OBJmin value was obtained for compliance relationship #3, the best-fit parameters asso
ciated with this compliance were used in generating all of the results shown in Figs. 5.3
— 5.6. Simulations using the parameters obtained for compliance relationships #1 and
#2 are included in Appendix E.

Figure 5.3 (A) demonstrates the percentage changes in plasma colloid osmotic pres
sure and plasma volume with time during and after a saline infusion without albumin.
The curves generated by the model correctly represent the response trends of the sys
tern and are in good quantitative agreement with the experimental data. These curves
show that the circulatory compartment remains relatively stable after the perturbation.
Changes in PL
11 and VPL are relatively small compared with the large experimental er
ror associated with the data. For a closed circulatory system, a 1500 mL fluid input, if
(A)
,J,J.iJ -
15.0-
—5.0 I— I
-I-
—25.C‘? I I I I I I I I
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 1 V.
60.0
11. H
35.0-
10.0
—15.0—
—40.0 I I I I I I
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5
Time(hrs)
(B)
15.0-
tz I
—25.0- I I I I I I I I
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0
60.0
35.0-
10.0.; •1’ I F
—15.0-
—40.0- I I I I I
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0
Time(hrs)
Figure 5.3: (A) Simulation of a 100 mLsaline infusion. (B) Simulation of a 100
mL saline infusion with 25 g of albumin. Fluid intake during waking hours (0
— 13.5 hr) is 1.4 L Filled circle: experimental data point (data from Hubbard
et al. [41]); solid line: model simulation. For the best-fit parameters of tissue
compliance #3.
all of it were retained in the circulatory compartment, would correspond to a 47% (=

1500/3200) increase in plasma volume. However, due to the self-regulating mechanisms
of the circulatory system, the plasma volume increases by only 11.5% at 12 hours post-
infusion, corresponding to an actual volume increase of 367 mL. Thus, most of the excess
fluid is shifted to the interstitium. Plasma oncotic pressure decreases slightly (6.27%) due
to the dilution effect of the infused saline. Figure 5.3 (B) represents the response of the
subjects to a hyperoncotic albumin infusion. During the infusion period (-1.5 — 0 hr), the
plasma colloid osmotic pressure increases due to the increase in albumin concentration.
The negative slope of /H% between 0 — 0.64 hr postinfusion is higher than that after
0.64 hr. The steeper slope is due to the rapid loss of injected albumin from the vascular
space [41]. The return of 11
PL to normal afterwards is mainly attributable to the dilution
effect of the 1.4 L fluid intake during waking hours [41]. During the infusion period,
the increase in plasma colloid osmotic pressure is greater than the increase in capillary
hydrostatic pressure; therefore, the plasma volume increases.
Figure 5.4 presents the percentage changes in PL
11 and VPL with time when the vol
unteers (N=4) are subjected to higher dose infusions, i.e. a 200 mL saline infusion or
a 200 mL saline infusion with 50 g albumin (data Set A). The transient responses are
similar to those obtained with lower dose infusions. There is no reason for experimen
tally measured PL
11 to increase to 2.1 % at 9 hours after the 200 mL saline infusion.
This can only be explained in term of the large experimental error associated with the
measurement. Overall, the simulation results fit the experimental data reasonably well
within the error of measurement.
Figure 5.5 (data Set B) illustrates the percentage change in plasma volume which
occurs after 900 — 1000 mL of normal saline were injected intravenously within 6.5 — 13
minutes (specific information corresponding to individual patients is listed in Table 4.6).
The model predictions are in good agreement with the experimental measurements. For
(A)
35.0
15.0
1; —5.0
—25.0
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0
60.0
35.0-
.4
10.0 T
—15.0-
Afl fl
I I I I I I I I I
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0
Time(hrs)
(B)
60.0
35.0-
10.0-i
—15.0-
—40.0 I I I I I I I I I I
—1.5 00 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0
Time(hrs)
Figure 5.4: (A) Simulation of a 200 mL saline infusion. (B) Simulation of a 200
mL saline infusion with 50 g of albumin. Fluid intake during waking hours
(0
13.5 hr) is 1.4 L. Filled circle: experimental data point (data from Hubba
rd
—
et al. [41]); solid line: model simulation. For the best- fit parameters
of tissue
compliance #3.
patient #1, 1000 mL of normal saline was infused within 9.5 minutes. At the end of the
infusion (the peak of the curve), VPL increased by 850 rnL (a 26.6% increase). Hence,
at least 150 mL of the injected solution is transported to the interstitium during the
infusion period (9.5 minutes). Compared with the experimental measurement, i.e., a
24.9% increase, the agreement is good. The model predicts the average filtration rate
during this period is 947 mL/h, which is much higher than the normal filtration rate. At
38 minutes post-infusion, the model predicts a 10.9% increase in plasma volume while a
8.5% increase was measured experimentally. At t=2 hour, the VPL increase is only 224
mL (a 7% increase) and the system appears to be close to steady-state. The 7% increase
in VFL is due to the assumption that within these 2 hours, water lost from skin and
during respiration, as well urine output are negligible because no such information was
presented by the investigators.
-
- Figure 5.6- (data Set C) shows the percentage changes in plasma volume and plasma
concentration following a 2 L normal saline infusion within 2 hours. During the infusion
period (0 — 2 hour), VPL is predicted to increase steadily to a maximum of 3929 mL (a 23%
increase), while CPL decreases steadily to a minimum of 32.4 g/L. Accordingly, FL
11 is
expected to decrease because of the linear relationship between CFL and PL
11 (Eq. 3.19).
Afterwards, both VpL and CPL tend to return to normal. All these trends match the
physiological responses of the MVES after an isotonic solution infusion. The model
predictions at half an hour after the infusion match the experimental measurements very
well within the large experimental errors in terms of both absolute values and percentage
changes. The model predicts that VPL increases to 3659 mL (a 14.36% increase), and
CPL decreases to 34.89 g/L ( a 11.45% decrease); experimentally it was found that PL
11
at 0.5 h post-infusion was 3541±1177 mL and CPL was 30±5 g/L.

Patient #1
20.0
10.0
u.0
0.0 30.0 60.0 90.0 120.0
Patient #2
30.0
20.0
0.0 30.0 60.0 90.0 120.0
Patient #6
30.0
20.0
- 10.0
0o
0.0 30.0 60.0 90.0 120.0
Patient #7
30.0
0.0
0.0 30.0 60.0 90.0 120.0
Patient #11
30.0
20.0
10.0
nfl.
0.0 30.0 60.0 120.0
Time(mins)
Figure 5.5: Simulations of acute saline infusion in selected patients [18]. Dot:
experimental data point; solid line: model simulation. For the best-fit pa
rameters of tissue compliance #.
70.0-
40.0-
10.0-
—20.0-
—50.0-
0.0 1.0 2.0 3.0 4.0 5.0
30.0-
10.0-
-10.0- F
—30.0-
—50.()-
0.0 10 2.0 3.0 4.0 5.0
Time(hrs)
Figure 5.6: Transient responses of plasma volume and plasma albumin con
centration after a 2 L of normal saline infusion within 2 hours [60j. Filled
circle: experimental data point; solid line: model simulation. For the best-fi
t
parameters of tissue compliance #3-
5.2.3.2 Simulations of Heart Failure (Set D)
Chronic heart failure is the pathophysiological state in which an abnormality in cardiac

function is responsible for the failure of the heart to pump at a rate commensurate
with the requirements of the metabolizing tissues. It is frequently caused by a defect
in myocardial contraction. As a result of the deficiency of contraction, the volume of
blood delivered into the systemic vascular bed is chronically reduced, and a complex
sequence of adjustments occurs that ultimately results in the abnormal accumulation of
fluid in interstitia in the body. These adjustments include a rise in venous pressure. The
increment in venous pressure is transmitted to the capillary level and therefore increases
the transcapillary pressure. This will accelerate the transcapillary filtration rate (Eq. 3.2),
and water will accumulate in the interstitium. As V
1 increases, Pi will increase and H
will decrease. In turn, the rise in Pi and the reduction in llj both act to oppose further
increase in JF• In addition, lymph flow increases with the elevation in P
. As the falling
1
filtration and rising lymph flow approach each other, a new steady state is approached.
The current model predicts that interstitial hydrostatic pressure decreases slightly to
-0.85 mmHg for patients with angina pectoris, corresponding to V
1 = 8.3 L, and increases
to 2.35 mmHg for patients with heart failure, corresponding to Vj = 17.0 L for tissue
compliance #3. In the experiments, P
1 was observed to decrease to 0.6 mmHg lower than
control level and Vj was observed to decrease to 7.5 L with a measurement error of +6.8
L for the former [64]. Also, it was reported that during the early stage of heart failure,
some patients have reduced cardiac pump function without edema. This coincides with
our predicted value which is around the normal range of V
. For patients with heart
1
1 was not measured and V
failure, P 1 was observed to be 12.0±15.4 L [25], which contains
the range of the predicted value. These basically match the adjustments which occur in
heart failure as discussed above.
In addition, several studies on animal [19, 36] have shown that there exists a criti
cal capillary hydrostatic pressure at which extravascular fluid accumulates very rapidly,
and the critical pressure is approximately equal to the plasma colloid osmotic pressure.
However, since there are only three points in this data set, it is difficult to predict such
a critical pressure. But it is certain that when Pc exceeds 17 mmllg, massive edema
occurs (see Fig. 5.7).
5.2.3.3 Simulations of V
1 vs. PL
11 and Hj vs. PL
11 in Nephrotic Syndrome
(Set E)
Interstitial edema in patients with chronic nephrotic syndrome is caused by the patho
logical removal by the kidneys of plasma protein from the blood stream which eventually
results in hypoproteinemia.
Thern current model assumes that the lowered plasma colloid osmotic pressure- is the
only cause of edema formation in nephrotic patients. Figure 5.8 was constructed by
decreasing PL
11 step by step at a constant plasma volume, and predicting the steady-
state interstitial volumes and interstitial colloid osmotic pressures which occur for each
new PL
11 value. From this figure, we can see that both Vj and H are well fitted as PL
11
increases. Figure 5.9 shows the steady-state fluid fluxes (i.e. JF and JL) and protein
fluxes (i.e. Qs and QL), as well as the albumin contents in both the interstitial and the
circulatory compartments. Since the tissue begins dehydrating for HPL > 25.9 mmHg,
the lymph flow relationship switches from Eq. 3.7 to Eq. 3.8. Thus, there is an obvious
slope change around PL
11 equal to 25.9 mmHg. The predictions shown in Figs. 5.8 and 5.9
are helpful in investigating edema formation and its mechanisms. In the upper panel of
Fig. 5.8, it can be seen that as PL
11 decreases from 28 to 12 mmHg, V
1 increases from 7.7
to 11.5 L. In other words, V
1 increases 3.8 L as HPL decreases 16 mmHg. As PL
11 falls, the
transcapillary fluid flux and lymph flow both rise to about double their normal levels (see
22.5 25.0
rrP(mmHg)
25.0
20.0
15.0
10.0
5.0 I I
7.5 10.0 12.5 15.0 17.5 20.0
P(mmHg)
Figure 5.7: Simulations of steady-state Vi vs. 11
PL and V1 vs. Pc in heart failure
patients [63, 25]. For the best-fit parameters of tissue compliance
#3.
Fig. 5.9). Due to the loss of plasma proteins from the bloodstream (at HPL = 12 mmHg,
QFL = 58.46 g), the interstitial protein content drops dramatically (at PL =
11 12 mmHg,
Qi = 58.51 g). When PL

11 decreases to 12 mmHg, Pi
1 decreases to 4.1 mmHg. Thus it
can be seen that protein washout (i.e., a net reduction in Qi) is the predominant edema
preventing mechanism during this period. If HPL decreases further, protein washout can
not prevent the further expansion of interstitial fluid volume. According to Fig. 5.8, as
PL
11 decreases from 12 to 4 mmHg, the interstitial volume increases from 11.5 L to 43.5
L, which is a very severe state of tissue edema. At PL =
11 4 mmllg, Qi = 19.5 g and P
1
= 5.1 mmllg. This shows that protein washout does not occur as extensively as when
PL
11 is decreased from 28 to 12 mmHg because most of the protein has already been
washed out, and the increase in tissue hydrostatic pressure plays a more important role
in preventing further edema formation. However, due to the high tissue compliance, the
bcease in P
1 also fails to prevent the edema formation effectively. Thus, massive edema
formation takes place.

A plasma colloid osmotic pressure of 12 mmHg can be regarded as the critical level
below which severe edema occurs. To prevent edema formation, PL
11 must be maintained
above this critical value.
5.2.3.4 Summary of the Simulations using Best-fit Parameters
Based on the above discussion, it is concluded that the model predicts the correct trends
and values after the MVES is perturbed. Each independent data set has been well fitted
by using the best-fit parameters.
5.2.4 Sensitivity Analysis
Though we have obtained three sets of best-fit parameters, we do not know how the
variables (LS, a, and Pc,o) influence the objective function. If a slight deviation from
50.0-
37.5.
25.0-
12.5
fI
0.0 I --I
0.0 5.0 10.0 15.0 20.0 25.0 30.0
PL (mmllg)
20.0-
18.0-
.
12.0
.
8.0- ..
.
a
4.0-
I
•.
0.0 I I I I
0.0 5.0 10.0 15.0 20.0 25.0 30.0
PL (mmHg)
Figure 5.8: Simulations of Vi vs. IIPL and fl1 vs. 1IPL in nephrotic syndrome
patients [24, 46, 64, 27]. For the best-fit parameters of tissue compliance
#3.
350.0
280.0
210.0
140.0
70.0
0.0
.0 5.0 10.0 15.0 20.0 26.0 3 I.0
1.5
1.2
O .6
0.3
0.0 I — I
5.0 10.0 15.0 20.0 Z50 3 3.0
150.0
120.0
90.0
60.0
30.0
0.0
0.0 .0 1Ô.O 15.0 20.0 26.0 30.0
1r(mmHg)
Figure 5.9: Steady-state effects of graded reduction of plasma oncotic pressure

on fluid and protein exchange. For the best-fit parameters of tissue compli
ance #3. The solid line in the last panel is the tissue protein content, the
dashed line is the protein content of the plasma compartment.
250.
50.0 70.0
LS (mi/rn mHg.h)
Figure 5.10: Sensitivity analysis for LS. The analysis is conducted for tissue
compliance #3, Pc,o 11.00 rnmHg and a = 0.9888.
the best-fit value affects the objective function significantly, then the location of this
value must be chosen very accurately. The study on whether the optimum fit is sensitive
to changes in the fitting variables is called a sensitivity analysis. A sensitivity analysis is
helpful in evaluating the degree of reliability of the best-fit parameters.
5.2.4.1 Lymph Flow Sensitivity — LS
To analyse the sensitivity of the objective function to LS, Pc,o and a are fixed at their
best-fit values, LS is varied on either side of its optimum point, and the corresponding
OBJ value is calculated. The results obtained for compliance relationship

#3 (i.e. Pc,o
11.00 mmHg, a = 0.9888) with LS varying from 10 110 mL.mrnllg’.lr’ are shown
—
in Fig. 5.10. The figure demonstrates that raising LS does not affect the fit very much.
For example, OBJmtn is equal to 76.50 units when LS is at its best-fit value of
43.08
1
mL•mmHg’•
. h If LS increases to 60 ,
1
mL•mmHg’• h the OBJ rises only to 80.83
units, 4.33 greater than OBJmin. If LS decreases to 20 rnL•mmHg’.h’, the OBJ
increases to 115.01 units, 38.51 greater than OBJmim. Thus, it is clear that, if LS = 43.08
.h is not the “true” value of the lymph flow sensitivity, then the “true”
1
mL.mmHg
value is “more likely” to be found at a greater value than at a lesser value. This analysis
reveals an asymmetry in the objective function and suggests that regions on one side of the
best-fit value are more likely than regions oi the other side of to yield the “true” value of
the parameter. Such a conclusion can not be reached by simply examining the calculated
confidence interval on LS (Table 5.1), which are symmetrically positioned about the best-
fit value. ÔOBJ/8LS is fiat for LS ranging from 35 to 50 1
.h This interval
mL.mmHg
.
coincides with the 95% confidence interval on LS (Table 5.1), which is interpretated as
the probability of OBJmin falling inside it is 95%.
5.2.4.2 Albumin Reflection Coefficient — a
The sensitivity analysis for a is carried out for tissue compliance relationship #3, Pc,o
= 11.00 mmHg, LS = 43.08 mL•mmllg’.h
, and a varying from 0.8
1 — 1.0. The results
are plotted on Fig. 5.11. The objective function decreases from 172.46 to 80.14 as a is
increased from 0.8 to 0.96. Then it displays a plateau around the best-fit value of a =
0.9888. This plateau exists over the range 0.96 < a < 1.00 where the OBJ values vary
by less than 3.64 units. The optimum a does not appear to be biased towards either
direction in the plateau region.
5.2.4.3 Capillary hydrostatic pressure at normal steady-state — Pc,o
As it was mentioned in Section 3.3.1, the minimum value of Pc,0, below which the model
breaks down, is restricted by the choice of a. With a set to 0.9888, the interval over
which the capillary hydrostatic pressure could be investigated was limited to F,ü
Chapter 5. Results And Discussion
106
0.80 0.85 0.90 0.95 1.00

0•
Figure 5.11: Sensitivity analysis for o. The analysis is conducted for tissue.
compliance #3, Pc,o = 10.8431 mmHg, and LS = 49.7848 mL•rnmH
g’h’.
10.37 mmHg. Therefore, the interval for the sensitivity analysis was selected to be
10.5 Pc,o 15.0 mmHg. From Fig. 5.12, we note that the optimum Fc,o lies between
10.75 to 11.25 mmHg; the objective function increases dramatically when
Pc,o is less
than 10.75 mmHg or greater than 11.25 mmHg. Thus, even though it is still reason
able
physiologically for Pc,o to exceed the upper limit of 15 mmflg, a worse fit to the curren
t
experimental data is definitely obtained when Pc,o 11.5 mmHg.
5.2.5 Péclet Number
The Péclet number is a dimensionless mass transfer parameter which describ

es the ratio
of convective to diffusive exchange. Here, the Péclet number is defined
(according to
Eq. 3.4) as Pe (1 —o}JF/PS, and it represents the importance of convection
compared
to diffusion as a mechanism for transcapillary albumin transfer. From Table
5.1, we note
Chapter 5. Results And Discussion
107
275.
235.0
195.0
C
155.0
115.U
75.’
12.0 12.5 13.0 13.5
0 (mmHg)
P.
Figure 5.12: Sensitivity analysis for F,o. The analysis is conducted for tissue
compliance #3, LS = 43.08 mL-rnn11g’•h’ and o- = 0.9888.
that the Péclet numbers at steady-state for all three compliance relationships are
very
low. Therefore, we conclude that, at steady-state, albumin is mainly transpo
rted by
diffusion.
5.2.6 Verification of Fit
This test is used to check the correctness of the computer program and
its ability to
converge to a set of known parameters [112]. In this test, 138 “error-free”
data points are
generated by solving the model equations using the best-fit parameter
values when the
MVES is subjected to the same perturbations as those stated in Section
4.3.1. The data
generated in this manner are assumed to have no inherent errors. Then
the “error- free”
data are inputted into the program as data to be fitted. The transpo
rt parameters are
assumed to be unknown and the same optimization procedure as that
used with the real
experimental data is followed to find a set of new parameter estimates for these “error-
free” data. Theoretically, if the program is working properly, a set of parameters identical
to the best-fit parameters used to generate the “error-free” data will be estimated.
Using the best-fit parameters obtained for tissue compliance relationship #3, i.e.,
LS = 43.08 mLmmHgh’, o = 0.9888 and Pc,o = 11.00 mmHg, a set of results
corresponding to all of the quantities which were measured experimentally were predicted
by the mathematical model and substituted back into the optimization program. The
best-fit parameters obtained in this way were:
LS = 43.126 mL.mmHg’.h’
a = 0.98877
Pc,o = 11.000 mmHg

with OBJmjn equal to 0.014885. As can be seen by comparing the above set of parameters
with those listed in Table 5.1 for this case, the best-fit values are all reproducibleto at
least three significant figures. Therefore, we are confident that the parameter estimation
procedure is reliable.
5.2.7 Residual Analysis
A check of the normal distribution of the errors can be made by constructing a residual
plot. Here, the errors refer to the differences between the predicted and the experimental
data, or more precisely, the residuals (see Appendix C for the definition of residual).
If the residuals are normally distributed, then this plot should not reveal any obvious
pattern. Although the fitting parameters obtained by the least squares procedure do not
depend on a normal distribution of the errors, the calculation of the confidence interval
will depend on this assumption. The true confidence intervals may differ greatly from the
calculated values if the normality assumption is not satisfied. Therefore, it is worthwhile
checking to determine whether the distribution of the errors is normal.
3
Xsim/SD
Figure 5.13: Residual plot for the best-fit parameters of compliance relation
ship X and X refer to the simulation value and the experimental
measurement, respectively.
A residual plot was constructed for the best-fit parameters of tissue compliance #
3 and is shown in Fig. 5.13. Here, the x coordinate is Xsjm/SD (unitless), i.e., the
simulation value of the coresponding measurement divided by the standard deviation,
and the y coordinate is (Xsim — Xexp)/SD (unitless), i.e., the standardized residual.
From the figure, it is shown that 60 of the 138 standardized residuals are negative and
78 are positive. The residuals scatter at random around the zero line and no trends are
observed. Thus, it appears that the residuals are normally distributed. The residual plot
is also useful for highlighting major departures in the observed values of the data from
anticipated patterns. Here, no pattern of systematic departure of the points around the
zero line is evident. Thus, the residual plot in Fig. 5.13 suggests that each experimental
data point is properly weighted.
Fi (mmHg) JL (mL/h )
+2.0 2.8
+1.0 1.4
+1.0 0.6
+0.5 0.6
Table 5.3: Experimental data of interstitial hydrostatic pressures vs. lymph

flow in the leg superficial lymphatics [98]. L denotes the lymph flowrate in
the leg superficial lymphatics.
5.3 Validation of the Best-fit Parameters
The best-fit parameters listed in Table 5.1 are calculated on the basis of a statistical fitting
between the model predictions and the experimental measurements. In this section,
we try to compare these best-fit parameters with estimated values available from the
literature. Additionally, a comparison between model predictions and experimental data
which have not been used in the optimization would also be very helpful to validate these
best-fit parameters. Unfortunately, no other new data have been found by the author so
far. Thus, Koomans’s data which were used for the same purpose in the previous study
[13] are also used in the current study to make such a comparison.
5.3.1 Lymph Flow Sensitivity — LS
To the knowledge of the author, no one has experimentally determined the lymph flow
sensitivity for humans which is defined as aforementioned. Stranden et al. [98] found
that there was a significant correlation between lymph flow and interstitial hydrostatic
pressure. The data from their experiments on patients with local leg edema is proposed
by the author for a comparison with LS as estimated in this work. The data are listed in
Table 5.3. Note that the lymph flow rate measured in the experiment (denoted by jL) is
Lymph flowrate (mL/h) Source

LSL 0.25 [67]
LSL 0.34 [68]
TD 84.0 [20]
TD 70.8 [33]
Table 5.4: Lymph flow rates in the leg superficial lymphatics and in the thoracic
duct. LSL denotes the leg superficial lymphatics; TD denotes the thoracic
duct.
that in the leg superficial lymphatics, which have diameters in the range of 0.1 0.4 mm.
But lymph flow rate (JL) in Eq. 3.7 refers to the lumped whole body flow rate. Therefore
.JL must be converted to a total lymph flow in the thoracic duct which has a diameter of
2 — 3 mm in the neck region (see later discussion). Table 5.4 shows some measurements
of lymph flow in the leg superficial lymphatics (LSL) and in the thoracic duct (TD).
If average values are used, the lymph flow rate in the thorac1cduct is around 260
77.4/0.295) times higher than that in the leg superficial lymphatics. Scaling L by 260,
LS is found to be 400 mL.mmHg’.h’ by linear fitting between JL and (P
1 — F
)
0
,
1 . If
the scale factor is arbitrarily altered to 100 (because of varying topography and caliber of
the cannulated vessels), LS is found to be 154 1
mL.mmHg
. h’ (see Fig. 5.14). In both
cases, normal lymph flows are found to be negative, which is unreasonable and conflicts
with the assumption in the current model and with physiological evidence. This might
be due to a discrepancy in P
0 between the reference man and the patients involved in
,
1
Stranden’s experiments. However, mathematically, this discrepancy does not affect the
slope of the straight line, i.e. LS.
Compared with the LS value estimated by the above procedure, the lymph flow
sensitivity predicted by the model (which ranges from 43.08 to 53.04 mL.mmHg’.h
)
1
tends to be underestimated. The extent of underestimation is difficult to evaluate because
800.0-
600.0-
400.0-
0
200.0-
-o
0.0-
—200.0-
—400.0 I I I
—1.0—0.5 0.0 0.5 1.0 1.5 2.0 2.5
Pi(mmHg)
Figure 5.14: Plot of 1
L vs. F . Filled circles: experimental data obtained by
1
scaling iL (Table 5.3) by 260; open circles: obtained using scale factor of 100;
solid line: 1
L —378 + 400 x (Fi P
,o); dashed line: JL = —145 + 154 x (F
1 —
1 —F
).
0
,
1
the experimental data are too few and too scattered.
Another quantitative criterion was also applied to validate the value of LS. This
criterion is the ratio of maximal to basal lymph flowrate, JLRMB (i.e., JL,MAX/JL,0).
The maximum lymph flowrate is assumed to occur at a cutoff of Vj = 20 L [23]; thus,

according to the tissue compliance relationships, F
1 is calculated to be between 2.01 and
2.66 mmHg. If the estimated basal lymph flowrate and lymph flow sensitivity are assumed
to be correct (see Table 5.1), according to JL = JL,O + LS(F
1 — ,F
1
o), JL,MAX is estimated
to range between 220.5 and 232.1 mL/h for the different tissue compliance relationships.
Thus, predicted values of JEMB range between 3.0 and 5.1. The experimentally observed
values of JLRMB in animal are 5 to 10 [2]. Comparison between the values of predicted and
experimental JLRMB suggest that the model predicted LS values are close to the lower
bound of the experimentally determined LS.
5.3.2 Albumin Reflection Coefficient — a
Experimental estimations of the reflection coefficient (a) have been based either on the
pore estimation method [42] or on steady-state lymph flow analyses. Renkin [82] esti
mated that small pores having an inner diameter of 40 A have a reflection coefficient
for albumin of 0.95, and large pores have a a value of 0.45. Reed et al. [78] estimated
that small pores of 45 A, 50 A, 60 A, and 80 A in radius have a values of 0.966, 0.919,
0.802 and 0.588, respectively. Pore dimensions estimated by many investigators indicate
small pore populations with radii 40 — 50 A in subcutaneous tissue and 60 A in skeletal

muscle; large pore populations have a a radius of around 200 A [73]. The number ratio
of large to small pores is around 1:3500. Therefore, the whole body capillary membrane
a for albumin of 0.936 estimated by Reed et al. [78] seems reasonable.
The steady-state lymphatic analysis used to estimate a is based on the linear protein
flux equations (Eq. 3.6) or the nonlinear equation (Eq. 3.5). Lymph ff6w as well as
protein concentrations in lymph and plasma are measured at two or more steady lymph
flow states produced by elevating venous pressure. The estimation of a is in reality a
problem of solving two equations with two unknowns, a and PS. Rutili et al. [88]
estimated a values ranging from 0.85 to 0.95 for total plasma protein in dog paw using
different mathematical formulations. Renkin et al. [81] reported a values ranging from
0.98 to >0.99 based on their recent study on rat skin and muscle.
Reflection coefficients estimated by both methods are in good agreement with the
values obtained by statistical fitting in current study. It is concluded that the albumin
reflection coefficient is close to unity.
Species Method PS (mL/h/lOOg wet tissue) PS (mL/h) Source

Dog LA 0.707 269.36 [82]
Dog LA 0.593 225.93 [88]
Cat ID 4.530 1725.93 [92]
Rabbit ID 4.434 1689.35 [69]
Human ID 0.467 177.93 [33]
Human ID 2.760 1051.56 [70]
Table 5.5: Experimental estimates of PS values. The PS values were normal

ized per 100 g wet tissue for comparison. LA denotes lymphatic analysis;
ID denotes indicator dilution. Values in the fourth column are calculated by
assuming that skin and skeletal muscle for the whole body weigh 10.1 kg and
28.0 kg, respectively.
5.3.3 Permeability-Surface Area Product — PS
The permeability-surface area product (PS) is the most widely used index to describe
the diffusive characteristics across capillary wall. The penneabilities vary for different
solutes. The PS value used in the present study refers to that for albumin.
Experimental estimates of the permeability-surface area product are typically ob
tained by one of two methods. One is the steady-state protein flux analysis which was
mentioned in the previous section. The other is the indicator dilution method, or sin
gle injection, residue detection method. In the latter method, a single bolus of labelled
albumin is injected intra-arterially and blood samples are collected at time intervals to
analyse their radioactivity. An indicator dilution curve is then constructed to estimate
the permeability-surface area product.
The experimental estimates of PS available in the literature are quite controversial,
especially those obtained by the indicator dilution method (Table 5.5). For the estimated
skeletal muscle and skin for the whole body, weighing 28.0 kg and 10.1 kg respectively, the
total whole body permeability-surface area product ranges from 178 to 1725.93 mL/h.
Paaske et al. [70, 92] pointed out in their reports that the indicator dilution PS values for
both human and animal tissues were 3 to 10 times higher than those obtained by other
methods [88, 82]. However, no explanation for this overestimation was given. Compared
to the values listed in Table 5.1, which are close to 70 rnL/h, it seems that the PS
estimated in the current study is about two times lower than expected, if human tissues
have permeability coefficients similar to animal tissues. But, it should be kept in mind
that the physiological measurements of PS are highly uncertain.
5.3.4 Fluid Filtration Coefficient —
Experimental determinations of the capillary filtration coefficient (KF) in human have

been limited to two methods: the venous occlusion method [57, 91, 54, 52] and the
osmotic transient method [71, 44]. Both methods are developed based on the Starling
equation, he., -
JF=KF[Pc—PI—o(HPL—f11)].
The venous occlusion method is based on the assumption that a change in Pc is the
only source for the change in fluid filtration rate (JF) when venous pressure is raised
or lowered, at least at times near the perturbation. The osmotic transient method is
based on the assumption that a change in PL
11 is the change in driving force which
dominates JF variations after the injection of a hyperoncotic albumin solution. The
transcapillary filtration rate is determined with the aid of a well-balanced volume piston
recorder connected to the plethysmograph which can record the changes in tissue volume.
Plasma volume is assumed to remain constant. The capillary filtration coefficient is
calculated as the filtration rate divided by the concomitant pressure change.
Table 5.6 presents the experimentally determined KF values for mixed tissue (skin and
skeletal muscle) in human. The table contains a wide range of values. Most investigators
KF (mL/(min.mmHg.100g soft tissue)) KF (mL/(mmllg.h)) Reference

0.0012 27.43 [91]
0.0036* 82.30 [71]
0.0046k 105.16 [44]
0.0058 132.59 [52]
0.0077 176.02 [57]
0.054 1234.44 [54]
Table 5.6: Experimentally determined KF values. All these measurements were

made in human by the venous occlusion method except * were measured by
the osmotic transient method. Values in the second column are calculated by
assuming that skin and skeletal muscle for the whole body weigh 10.1 kg and
28.0 kg, respectively.
report a KF value of around 0.005 mL/(min.mmHg•lOOg tissue) by using the venous

occlusion method with increases in venous pressure of 30 — 60 mmHg. However, Lundvall
et al. [54] suggested that such high increases of venous pressure may lead to closure
of the precapillary sphincters, thereby reducing the capillary surface area available for
transcapillary exchanges. Also, it may cause large decreases in regional blood flow. If
these postulates are tenable, they will cause an underestimation of the experimental KF
values. Lundvall et al. reported a ten times higher KF value (0.054 mL/(min.mmHg.100
g tissue)) by increasing venous pressure by only 1.6 mmHg. A similar magnitude of KF

was also estimated by Chapple [13] based only on fitting data from nephrotic patients.
Whether such a high KF value is reasonable remains to be further confirmed. The KF
values estimated in the current study, ranging from 83.99 to 121.05 mL.mmHg’.h’,
are well within the range reported by most investigators.
5.3.5 Normal Lymph Flow — JL,O
Direct measurements of lymph flow in human have been made mostly either in the leg
lymphatics or the thoracic duct. Lymph flow rate in the leg superficial lymphatics is
simply measured by determining the volume of lymph collected in a calibrated syringe

connected to the cannula during a measured period of time. Lymph flow is found to
occur only simultaneously with the lymph pulse [67].
The normal lymph flow rate (JL,o) in the current model refers to the lumped whole
body flow rate. Therefore, comparisons should only be made between the estimated JL,O
and the lymph flowrate measured in the thoracic duct. Measured thoracic duct flows
are of the order of 1 — 3 mL/min, or 60 — 180 mL/h [75]. The normal lymph flowrates
predicted in the current study are within the lower side of the normal range at about 78
mL/h for all tissue compliance relationships.
5.4 Simulations of a Single Intravenous Infusion of Human Albumin
In Section 5.2.3, model simulations of transient responses of the microvascular exchange

- system subject to salineor albumin infusion, and simulat-ions of heart failure and nephrotic
syndrome were presented. All these data have been used in the parameter estimation
procedure; therefore, it is not surprising that these data are well represented by the model
predictions. To test further that the parameters obtained based on the aforementioned
data are generally applicable to simulations of a microvascular exchange system which
exhibits normal behavior, a comparison was made between the simulation predictions
and the dynamic results from an experimental study by Koomans et al. [45]. The data
from Koomans’ study have not been used in the parameter estimation procedure. Hence,
such a comparison is considered to be a partial validation of the model and its estimated
transport parameters.
Koomans’ experiment was designed to study the fate of a single intravenous infusion
of human albumin in 10 patients with nephrotic syndrome. In their experiment, 60 g
of human albumin in 300 mL of solution were infused continuously over a period of 1.5
hours. Plasma volume, and colloid osmotic pressure in both interstitium and plasma were
measured before and immediately after the albumin infusion, as well as at 1 and 24 hour
post-infusion. Urinary albumin loss was observed to be 10.5 g/day before infusion and
26.4 g/day during the first day after infusion. Accordingly, the excess albumin excretion
rate was 15.9 g/day. The 300 mL of infused fluid was observed to be excreted within the
first 24 hours post-infusion. In addition, patients were reported to possess an average
pre-infusion interstitial fluid volume of 18.25 L. Plasma volume, measured experimen
tally, was very close to normal. Plasma and interstitial colloid osmotic pressures were
determined from the steady-state simulations of nephrotic patients (see Fig. 5.8), which
were 10.574 and 3.304 mmHg, respectively. Thus, the corresponding albumin contents
in both circulatory and interstitial compartments could be calculated (albumin content
= volume x albumin concentration, and albumin concentration can be determined from
the colloid osmotic pressure relationship, see Eqs. 3.19 and 3.21). Starting with these
initial conditions, the model predictions of the transient responses when the system was
subjected to the same perturbations as the experimental counterpart, are presented in
Fig. 5.15. Figure 5.15 shows that the model predictions are in good agreement with
the experimental data in terms of both absolute values and trends. Both PL
11 and VpL
follow a uniform pattern of initial increase and subsequent decrease which starts immedi
ately after infusion. The pattern bf change in the interstitial fluid evidently differs from
that in the plasma: after a slight initial increase, Il rises further during the 24 hours
post-infusion. All these trends are consistent with those reported by the experimenters
[45]. The bottom panel shows the distribution of albumin during and after infusion. The
continuous accumulation of interstitial albumin mass during the 24 hours post-infusion
proves that part of the infused albumin disappears into the interstitium where it causes
an increase in tissue fluid oncotic pressure [45].
Finally, the good agreement between the model predictions and the experimental
25.0
20.0-
S 15.0
4 10.0-
5.0 -
I I I
12.0 24.0 36.0 48.0
6.0-
5.0-
4.0-
3.0- I
2.0-
1.0-
D.C
12.0 24.0 36.0 48.0
150.0
100.0-
QPL
a 50.0- QI
C’
0.0- I I I
0.0 12.0 24.0 36.0 43.0
Time(hrs)
Figure 5.15: Transient responses of UPL, [1, VPL as well as

QPL and Qi after
single infusion of 60 g of human albumin solution [45]. Solid lines represe
nt
the dynamic responses of the model. Dotted lines represent the steady
-state
values obtained by running the program for a long time. Experi
mental data
are shown as filled circles with error bars.
data in the form of absolilte values shows the suitability of the estimator we chose
(Eq. 4.26). The best-fit transport parameters, which were estimated by minimizing the
sum of squares of the differences between model predictions and experimental data in the
form of percentage changes, are also applicable for predicting the absolute values. This, in
turn, shows that the initial values of the reference man (see Table 3.2) are representative
of those of the majority of human beings.
Chapter 6
Conclusions
Based on the discussion in the previous chapter, it is concluded that the coupled Starling
model is capable of providing good descriptions of microvascular exchange and fluid and
albumin distribution in the human. According to statistical fitting results, the best-fit to
the available experimental information is obtained with tissue compliance relationship #3
and the transport parameters LS = 43.08 + 4.62 1
mL•mmHg
h ’, a = 0.9888 ± 0.002,
Pc,o = 11.00±0.03 mmHg, PS = 73.01 mL•h’, KF = 121.05 mL• mmHg’.h
, and
1 JL,O
= 75.74 mLh
. Simulations of the available experimental data using these parameters
1
gave a reasonable fit in terms of both trends and absolute values. All of the best-fit
parameter values so obtained were in reasonable agreement with estimated values based
on experimental measurements where comparisons with literature data were possible.
The fact that the albumin reflection coefficient is near unity indicates that transcapil
lary osmotic forces are very similar in magnitude as the transcapillary hydrostatic forces.
Therefore, osmotic effects play an important role in transcapillary exchange. In addition,
the low values of the Péclet number for all three compliance relationships indicate that
diffusion is the dominant mechanism of transcapillary protein transport under normal
conditions.
The good agreement between the best-fit parameters obtained by studying normal
subjects and those obtained for chronic nephrotic patients suggests that the microvascu
lar exchange system behaves close to normal in chronic nephrotic patients. For patients
121
Chapter 6. Conclusions 122
suffering from mild nephrotic syndrome, protein washout (i.e. a net reduction in in
terstitial protein content) is the predominant edema preventing mechanism. For those
suffering from severe nephrotic syndrome, all edema preventing mechanisms fail, leading
to a rapid expansion of the interstitial fluid volume.
Finally, the transient simulations of Koomans’ albumin infusion experimental data,
which have been used as an independent test of the validity of the transport parameters
obtained by statistically fitting between the model predictions and other experimental
data for humans, further proved that the coupled Starling model can successfully simulate
the transport mechanisms of the microvascular exchange system in the human.
Chapter 7
Future Work
The recommendations for future work include the following two aspects:
1. Further improve the current model for the normal microvascular exchange system.
Improvements might include:
(a) Replacing the “most-likely” human tissue compliance relationship by the ex

perimentally determined tissue compliance relationship when clinical measure
ments of this property become available. One can then investigate how close
the -“most-likely” compliance relationship is to the real one. -
(b) Dividing the generic tissue compartment into two compartments, i.e., a skeletal
muscle compartment and a skin compartment, when the properties of these
two separate compartments become available.
(c) Considering the influence of cellular component.
2. Develop a new model to study the behavior of the microvascular exchange system
after a burn injury. Because of the limited amount of information available for
humans, the microvascular exchange system in the burn model should probably be
divided into three compartments as the first step in developing a more comprehen
sive model. The three compartments would be the circulatory, normal tissue and
burned tissue compartments. The transport parameters obtained in current study
could he used to describe the transport characteristics of the normal tissue. Some
of the transport properties will be subject to a transient adjustment due to the
123
Chapter 7. Future Work 124
burn injury [8, 9]. Using available data from burn patients a similar optimization
procedure is recommended for finding the optimal parameters which describe these
transient adjustments. Such a model is of potential use as an aid in monitoring
fluid resuscitation in burn injured patients.
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Nomenclature
Symbol Meaning Units

Aib Albumin
BV Blood volume (ml)
C Concentration of albumin (g.1’)
D Perturbation (g.h’ or ml.h
)
1
ECV Extracellular volume (ml)
F( ) Function of
FCOMFI Tissue compliance relationship (ml.mmHg’)
HCT Hematocrit
J Fluid transport rate (ml.h)
K Fluid transport coefficient (ml.mmHg
.
1 h’)
Length (m)
L Length or lower bound
LS Lymph flow sensitivity )
1
(ml.mmHg.h
OBJ Objective function value
F Hydrostatic pressure (mmllg)
FCOMPC Capillary compliance (ml.mmHg’)
Fe Péclet number
PS Permeability-surface area product of )
1
(ml.h
capillary with respect to albumin
Q Albumin content (g)
134
Nomenclature 135
Q Albumin transport rate )

1
(g.h
r Radius (m)
RAP Right atrial pressure (mmHg)
SD Standard deviation
SE Standard error
T Time (h)
U Upper bound
V Volume (ml)
W Weight factor
H Colloid osmotic pressure (mmHg)
a Albumin reflection coefficient
Change
Superscripts and Subscripts

AV Interstitial volume available to albumin
C Capillary
D Diffusion
EX Excluded
exp Experimental value
F Filtration
GRAD Gradient
HUMAN Human
I Interstitial compartment
Nomenclature 136
iso Isogravimetric
L Lymph
max Maximum value
mm Minimum value
NORM Normal steady-state
FL Plasma
RAT Rat
RMB Ratio fo maximal to basal level
S Solute
sim Simulation value
TO Turnover rate
o Normal steady-state
1/2 Half-time
* Tracer properties
Appendix A
Raw Experimental Data
137
Appendix A. Raw Experimental Data 138
Time (hr) -1.5 1 3 6 9 12

Saline, 100 mL Mean 24.1 -0.8 -0.1 -0.7 -1.0 -1.8
N=4 SD ±0.4 ±1.0 ±0.7 ±0.6 ±1.5
Albumin, 100 mL Mean 24.8 0.5 -0.1 -0.6 -0.4 -1.1
N=4 SD ±1.6 +1.4 ±0.8 +1.3 +0.5
Saline, 200 mL Mean 24.0 -0.9 -0.2 -0.4 0.5 -0.1
N=4 SD +2.3 ±0.8 +1.0 ±2.9 ±1.7
Albumin, 200 mL Mean 24.2 3.2 3.1 1.5 2.0 1.6
N=4 SD +0.9 ±2.8 +1.6 +2.3 ±1.2
Table A.1: Change in plasma colloid osmotic pressure (mmHg) at room tem
perature. t = 0 designates the end of infusion.
Time (hr) -1.5 1 3 6 9 12

Saline, 100 mL Mean 2,727 49 16 96 202 179
N=4 SD ±883 ±140 ±155 ±154 ±142 ±132
Albumin, 100 mL Mean 301 281 318 295 287
N=4 SD +160 ±270 +244 ±198 ±206
Saline, 200 mL Mean 3223 161 145 161 109 169
N=4 SD ±394 ±223 ±148 ±110 ±186 +155
Albumin, 200 mL Mean 427 383 353 281 314
N=4 SD +147 +36 ±66 ±50 ±95
Table A.2: Change in plasma volume (mL) at room temperature. t = 0 desig

nates the end of infusion.
Time (hr) 4.5 1 3 6 9 12

Saline, 100 mL Mean 236 0.1 2.7 1.9 8.4 8.6
N=4 SD +8.2 +9.7 ±10.4 ±6.9 ±7.2
Albumin, 100 mL Mean 22.2 19.6 17.1 18.1 15.5
N=4 SD ±5.0 ±4.8 ±9.1 +5.1 +6.6
Saline, 200 mL Meái 234 1.8 7.2 9.6 f0T 12.9
N=4 SD ±4.8 ±7.6 ±7.8 ±11.4 ±13.0
Albumin, 200 mL Mean 44.6 36.5 29.4 24.3 27.1
N=4 SD +13.0 +10.7 +7.9 +8.8 +8.6
Table A.3: Change in total plasma albumin content (g) at room temperature.
t = 0 designates the end of infusion.
Patient Surface Remarks HCT General Blood Plasma

# Area (m
)
2 (%) Volume (mL) Volume (mL)
Control 42.4 4422.6 2547.4
1 1.82 l000mL/9.5mins 37.1 50.59.6 3182.5
38 mm. after infusion 40.4 4641.0 2766.0
Control 32.3 4768.0 3227.9
2 1.60 l000mL/llmins 27.6 5568.0 4031.2
Control 37.7 4116.0 2564.3
3 1.68 l000mL/l0mins 31.6 4905.6 3355.4
Control 40.0 4273.5 2564.1
4 1.65 l000mL/llmins 34.3 4983.0 3273.8
Control 34.7 4026.1 2629.0
5 1.63 l000mL/llmins 28.4 4922.6 3524.6
Control 47.5 4537.5 2382.2
6 1.65 l000mL/l3mins 42.4 5082.O 2927.2-
Control 43.9 4086.9 2292.8
7 1.71 l000mL/llmins 37.8 4753.8 2956.9
30 mi after infusion 40.2 4463.1 2668.9
Control 52.3 5635.5 2688.1
8 1.95 950mL/6.5mins 45.2 6396.0 3505.0
Control 44.1 5056.6 2826.6
9 1.93 950mL/7.5mins 38.1 5867.2 3631.8
Control 45.7 5632.0 3058.2
10 1.76 950mL/8.5mins 44.8 5737.6 3167.2
Control 46.9 4907.7 2606.0
11 1.71 900mL/9mins 42.4 5420.7 3122.3
Table A.4: Hemodynamic effect of rapid intravenous infusion of physiologic

saline infusion.
Baseline 1/2 hour post-infusion

HGB (g.100mL’) 12.5+1.7 11.7+1.7
HCT () 38.4±5.2 36.2+5.1
PL (g.lOOmL’)
0 3.4±0.5 3.0+0.5
Table A..5: Mean concentration of hemoglobin and albumin, and mean hemat
ocrits before and after saline infusion,
Patients with Patients with Normal

Heart Failure Anasarca Subjects
PL
11 (mmHg) 26.1+4.2 23.0+2.6 28.6±3.4
Hi (mmHg) 11.5±3.4 9.2+2.6 15.8±2.7
RAPT (mmHg) 11.15 16.29 0
Pct (mmHg) 13.71 16.90 6.8
VPL (mL/cm) 19.2±4.5 21.7±4.4 17.3±1.5
Body Height (cm) 171.9+10.7 171.9±10.7 172.0±9.2
VpL/VI 0.27±0.07 0.28±0.09 0.36±0.06
V/ (mL) 12224±6795 13322±7945 8266± 2536
Table A.6: 11
PL, H and VPL in patients with heart failure (N=13), pa
tients with anasarca (N=7) and n normal subjects. calculated from
H —0.4 x RAP + 15.8; t calculated from Pc = 0.62 x RAP + 6.8; * the cal
culation of SD is the same as that described in APPENDIX B.
Angina pectoris Controls

FL
11 (mmHg) 24.9±2.1 26.8±3.7
1 (mmllg)
U 10.65±2.35 13.15±2.5
RAP (rnmHg) 5.1±1.7 1.5±2.25
Pc (rnmHg) 12.6±2.9 11.15±2.7
VPL (rnL/cm) 18.8±1.8 19.9±1.35
Body Height (cm) 175±6 181±5
VPL/VI 0.37±0.08 0.36±0.08
Vj (mL) 8892±3079 10005+3179
Table A.7: 11 1 and VFL in patients with angina pectoris and in controls.
PL, H *
the calculation of SD is the same as that described in APPENDIX B.
1
I PL (mrnHg) Vi (L)
9.2 19.01
10.7 16.02
11.7 14.40
12.7 12.98
13.7 7.98
13.7 6.71
14.2 10.70
14.2 8.27
18.7 9.94
18.7 9.11
20.7 7.79
20.7 6.73
21.7 6.61
24.7 8.44
25.7 8.34
25.7 7.69
26.7 8.25
26.7 9.38
Table A.8: FL
11 vs. V
1 for patients with nephrotic syndrome.
PL
11 (mmHg) Hi (mmHg) PL
11 (mmHg) 1 (mmHg)
fT
2.3 2.3 15.5 6.4
5.3 5.9 15.5 6.4
5.8 1.9 15.7 3.7
6.6 2.6 17.3 5.9
7.0 3.4 17.4 7.7
7.0 2.9 17.5 5.9
7.8 0.9 17.5 3.9
8.3 2.7 17.9 8.0
8.9 1.7 18.0 8.6
9.0 4.9 18.2 8.2
9.0 4.9 18.4 8.4
9.2 3.2 18.7 5.2
9.5 4.4 18.7 6.7
9.5 3.9 19.0 6.9
9.6 0.7 19.0 9.9
9.9 1.6 19.4 7.7
10.3 29 19.9 I&.7
10.7 5.7 20.7 7.7
11.3 5.4 21.0 10.4
11.5 3.9 21.0 10.9
11.5 3.9 21.7 8.7
11.7 4.7 22.9 14.7
11.9 4.0 23.6 11.7
12.3 1.9 23.6 13.2
12.4 4.5 23.6 14.0
12.9 4.3 24.0 12.2
13.0 3.4 24.4 11.7
13.2 7.0 24.8 12.7
13.7 5.7 24.2 15.2
13.9 7.2 24.4 14.4
14.2 5.7 24.9 13.2
14.2 4.7 26.4 13.7
14.5 4.9 26.9 14.7
Table A.9: ll vs. PL

11 for patients with nephrotic syndrome.
Appendix B
Calculation Of Error Propagation
Calculation of the propagation of experimental error is necessary in the following situa

tions:
1. When the compared quantity is not directly measured in experiment. For example,
blood volume and hemotocrits are measured experimentally, then plasma volume
is calculated from their prodllct. The uncertainty associated with the calculated
plasma volume is estimated on the basis of the standard deviations of blood volume
- and hemotocrits; -
2. When measured quantities are further manipulated, e.g. being converted from
absolute value to percentage change.
The propagation of experimental error is calculated in the following manner.

Assume that the desired quantity U is related to several directly measured quantities
, x
1
x ,
2 •.•, x, by the general equation
,
2
U=f(xi,x (B.1)
Each directly measured quantity has an associated experimental error of Ax, ••,
Ax, respectively. The differential change in U for a differential change in each of the
measured x’s is then given by
dU = —dx +
1
- +... + -‘—dx (B.2)
1
ax 2
ax
144
Appendix B. Calculation Of Error Propagation 145
where -dx is the partial derivative off with respect to x taken with all the remaining
x’s held constant.
When Ax
, Ax
1 ,
2 ..., Ax are sufficiently small that higher order terms of the Taylor
expansion can be neglected, the differentials dU, dx
, dx
1 ,
2 ..., dx can he replaced by
the finite increments AU, Ax
, Ax
1 ,
2 Ax
AU = 1 + 2
LA LA +... + 1
—Ax (B.3)
2
ax
The maximum uncertainty of quantity U is calculated according to Eq. B.3.
Examples
In Mullins’ saline infusion experiment (see Table A.11),
baseline hemoglobin concentration: HGBB = 0.125±0.017 g/mL,
postinfusion hemoglobin concentration: HGBp = 0.117±0.017 g/mL,
Assume hemoglobin remains constant throughout the experiment, baseliiie blood volume
(BVB) is 5195 mL, then post-infusion blood volume (BVp) is
HGBB
BV x BVB
= HGB
Substituting the numbers into the above equation gives
BV = (0.125/0.117) x 5195 = 5550.2 mL
Apply Eq. B.3
ABVP = AHGBB
P
x BVB + HGBB x BVB x AHGBP
P
= 1561.3 mL
Since plasma volume (VPL) equals to BVPL x (1 — HCT), given

baseline hemotocrit: HCTB = 0.384±0.052;
post-infusion hernotocrit: HCT = 0.362±0.051, we get
Appendix B. Calculation Of Error Propagation 146
baseline plasma volume: VPL,B = 3200 mL;

post-infusion plasma volume: VPL,F = 3541±1177 (SD
) mL. Therefore,
1
= [VPLF
VPL% —
1] x 100 = 10.65%
VPL,B
and standard deviation for AVPL% is
= 1
SD
SDVPL% x 100 = 36.78
VPL,B
Since QPL = CPL x VPL, therefore,

baseline albumin content: QPL,B = 34 x 3.2 = 108.8 g. with a standard deviation of
2
SD = /-GPL,B x VPL,B = 16 g;
post-infusion albumin content: QPL,P = 30 x 3.541 = 106.2 g, with a standard deviation
of SD
3 = /CPL,P x VPL,P + CPL,P x 1
SD = 5 x 3.541 + 30 x 1.117 = 53.0 g.
Thus, the percentage change of albumin content is
= [QPLP
QPL% —
1] x 100 = —2.39
Q PL,B
Apply Eq. B.3, the standard deviation for QFL% is
SDQPL% = QPL,B
+ x SD
2
53.0 106.2
—
— 108.8 + 108.82 x 16 —
—
63 07
All these values correspond to those listed in Table 4.7.

Appendix C
Basic Concepts Related To Statistical Analysis
To permit a better understanding of the statistical analysis presented in chapter 5, several

relevant basic concepts will be clarified here.
Covariance Matrix
The covariance matrix is defined as the inverse of the matrix of second partial deriva
tives (i.e. the Hessian matrix) of the objective function, expressed as:
u
{
2 X} a{X,Y}
u{X,Y} a
{
2 Y}
2{
where a } is called the variance operator (read “variance of”); a{ , } is called the
covariance operator (read “covariance of”); X and Y are two random variables. The
variance measures the spread or dispersion of a probability distribution.
The standard deviation of X is the positive square root of the variance of X, i.e.
SD = a{X} = a2{X}
The covariance provides a measure of the association between X and Y. If X and Y are
independent, a{X,Y} = 0, however, the converse is not necessarily so.
Confidence Interval
The probability that a correct interval estimate of an unknown parameter X is

obtained is called the confidence coefficient and is denoted by 1 — c. The interval,
147
Appendix C. Basic Concepts Related To Statistical Analysis 148
L <X < U, within which the value of the parameter in question would be expected to
lie is called a 100(1 — c) percent confidence interval for the parameter X. The interpre
tation of this interval is that, if in repeated random samplings, a large number of such
intervals are constructed, 100(1 — c) percent of them will contain the true value of X.
In the current study, only the 95% confidence interval will be used. When the sample
size is reasonably large, a variable with a sample mean X and a standard deviation SD
has the 95% confidence interval [61]
X—1.96xSD<XX+1.96xSD
Residual Plot
A residual (e) is the difference between an observed value (X) and the corresponding
anticipated value (X), i.e. e = X — X. A staudardized residual (é) is the residual divided
by the standard deviation, i.e. é = e/SD. A residual plot is a plot of standardized
residuals (or residuals) plotted against the fitted value X. It often provides useful clues
for the evaluation of the aptness of the model (see Chapter 5).
Appendix D
Surface Plot And Contour Plot
The objective function (Eq. 4.19) is an unknown function of LS, a, and the intersti
tial compliance relationship. It is determined by the differences between the simulation
results and the experimental data. It is non-linear and can not be expressed as an ana
lytical equation. Therefore, analytical methods can not be applied to find the location of
OBJmin. To allow a visual estimate of the minimum region, surface and contour plots of
the objective function are generated first. Then, starting with an initial point located in
side the minimum region, a numerical optimization program is applied to find the best-fit
parameters.
The surface plot has three dimensions. In this case, the X—axis is a, the Y—axis is
LS, and the Z—axis is OBJ. It is generated by increasing a and LS in incremental
steps (a 20 x 20 grid is chosen) between their lower and upper bounds, and calculating
OBJ at the given values of a, LS, Pc,o and interstitial compliance relationship by using
Eq. 4.14. Figure D.1 shows three surface plots viewed from different angles. The figure
was constructed by using 138 experimental data points.
A contour plot is a projection drawing of the surface plot (Fig. D.1). Contour lines
are drawn by connecting points having the same OBJ value on the projection. From the
contour plot, it is easy to locate the minimum region of the objective function (e.g. the
shaded area on Fig. D.1).
149
Appendix D. Surface Plot And Contour Plot 150
9OD
0’
0
0.5 0.6 0.7 0.8 0.9 1.0

a
Figure D.1: Surface plots of the objective function from different angles (a,
b,
and c); d shows the contour plot of the objective function. The shaded area
is the minimum region of OBJ. For compliance relationship
#3.
Appendix E
Simulations At Best-Fit Parameters
151
Appendix E. Simulations At Best-Fit Parameters
152
(A)
30.0-
15.0:
0.0-1
15.0—
—30.0- I I I I I I I
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 1 ‘.0
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0
Time(hrs)
(B)
30.0-
15.0-
G. -rT
0.0-I
liz p
—15.0-
—30.0- I I I I I I I
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 1
60.0
40.0
20.0
0.0
—20.0
—40.0
—1.5 0.0 1.5 3.0 4.5 6.0
Time(hrs)
Figure E.1: (A) Simulation of 100 mL saline infusion; (B)
Simulation of 100
mE albumin infusion; Fluid intake during waking hours (0 13.5
hr) is 1.4 L —
(N=4). For tissue compliance relationship #1.

Appendix E. Simulations At Best-Fit Parameters 153
(A)
30.0-
15.0—
0.0 I—-
—15.0-
—30.C._T I I I I I I I
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 1 . 0
60.C
—-tffEH
-
40.0-
20.0-
—20.0-
—40.C I I I
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0
Time(hrs)
(B)
30.0-
15.0-
—15.0-
30.0- I I I I I I I I
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0
60.0
40.0
20.0
0.0
—20.0
—40.0
—1.5 0.0 1.5 3.0 4.5
Time(hrs)
Figure E.2: (A) Simulation of 100 mL saline infusion; (B)
Simulation of 100
mL albumin infusion; Fluid intake during waking hours (0
13.5 hr) is 1.4 L —

(A)
30.0-
15.0
— III I I I I
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 1
60.0-
40.0
20:0
—20.0
—40.0-
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0
Time(hrs)
(B)
30.0
I I I
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0
60.0-
IL—
—20.0-
-
—40.0— I
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0
Time(hrs)
Figure E.3: (A) Simulation of 200 mL saline infusion; (B) Simulation
of 200
mL albumin infusion; Fluid intake during waking hours (0 13.5
hr) is 1.4 L —

(A)
3 0.0-
15.0
0.0
—15.0
—30.0-
I
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 1
_40.0: I I I I I I I
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0
Time(hrs)
(B)
30.0
15.0
C.
0.0
—15.0
—30.
—1.5 0.0 1.5
6 0.0-
400-
20.0-
0.0-i
—20.0-
—40.0- I I I I I
—1.5 0.0 1.5 3.0 4.5 6.0 7.5 9.0 10.5 12.0
Time(hrs)
Figure E.4: (A) Simulation of 200 mL saline infusion; (B) Simula
tion of 200
mL albumin infusion; Fluid intake during waking hours (0 13.5
hr) is 1.4 L —

Appendix F. Simulations At Best-Fit Parameters 156
Patient #1
30.0
20.0
10.0
0.0
0.0 30.0 60.0 120.0
Patient #2
30.0
0.0 I
0.0 30.0 60.0
Patient #6
30.0
0.0
0.0 30.0 60.0 90.0
Patient
#7
30.0
20.0 -
0.0
0.0 30.0 60.0 90.0 120.0
Patient #11
20.0
10.0
0.0
0.0 30.0 60.0 90.0 120.0
Time(nilns)
Figure E.5: Simulations of acute saline infusion in selected patients. For tissue
compliance relationship #1.

Patient #1
30.0
K 200
I 00
00
30.0 60.0 0.0
Patient #2
30.0
200
10•0-
00
0.0 30.0 60.0 0.0
Patient #6
30 0
20.0
0.0
0.0 30.0 60.0 90.0 0.0
Patient #7
30.0
20.0
10.0
0.0
0.0 30.0 60.0 90.0 120.0
Patient #11
30.0
20.0
10.0
0.0
0.0 30.0 60.0 90.0 120.0
Time(mlns)
Figure E.6: Simulations of acute saline infusion in selected patients. For tissue
158
75.0-
.0 .0 L 5.0
50.0-
25.0-
Time(hrs)
Figure E.7: Transient responses in plasma volume and plasma

albumin con
centration after 2 L of normal saline infusion within 2
hours. For tissue
Appendix F. Simulations At Best-Fit Parameters 159
75.0-
oLo.o.oLo5.o
50.O-
25.0-
0 0 0 0
Time(hrs)
Figure E.8: Transient responses in plasma volume and plasma albumin con
centration after 2 L of normal saline infusion within 2 hours. For tissue
160
25.0
20.0
15.0
i:.:
20.0 22.5 25.0 27.5 30.0

PL mmHg
25.0-
20.0-
15.0-
10.0 -
5.0-
7.5 10.0 12.5 15.0 17.5 20.0
P (mmHg)
Figure E.9: Simulations of steady-state V
1 vs. HPL and V
1 vs. Pc in heart failure
patients. For tissue compliance relationship #1.
25.0
20.0
15.0-
10.0-
5.0- I I
20.0 22.5 25.0 27.5 30.0
PL (mmHg)
25.0-
20.0
15.0
10.0-
5.0 I I I
7.5 10.0 12.5 15.0 17.5 20.0
P(mmHg)
Figure E.1O: Simulations of steady-state Vj vs. IIPL and V
1 vs. Pc in heart
failure patients. For tissue compliance relationship #2.
100.0
80.0
60.0
40.0
20.0
0.0 I— I I I
0.0 5.0 10.0 15.0 20.0 25.0 31
PL (mmHg)
20.0-
16.0-
.
12.0-
S
8.0- I.
1; I
I. a
4.0- . .
. I
•.
•.
0.0 I I I I
0.0 5.0 10.0 15.0 200 25.0 30.0
‘TrP(mmHg)
Figure E.11: Simulations of V

1 vs. IIPL and H vs. ‘IPL in nephrotic syndrome
patients. For the best-fit parameters of tissue compliance relationship
#1.
100.0-
80.0-
60.0-
40.0-
20.0-
0.0 I I
0.0 5.0 10.0 150 20.0 25.0 3 ).0
7rL(mmHg)
20.0
16.0-
.
12.0-
.
8.0- ..
a
4.0-
•
0.0 I I I
0.0 5.0 10.0 15.0 20.0 25.0 30.0
P1. (mmHg)
Figure E.12: Simulations of V

1 vs. 1
IPL and H vs. HPL in nephrotic syndrome
patients. For the best-fit parameters of tissue compliance relatio
nship #2.
164
25.0-
20.0-
S 15.0-
4 10.0-
5.0- I I I
12.0 24.0 36.0 4 I.0
6.0-
5,0 -
4.0
$ -
‘-a 3.0
2.0
1.0-
-
-
.L
0.0 -
12.0 24.0 36.0 48.0
0.0 12.0 24.0 36.0

150.0- 48.0
100.0-
QPL
0
-..--.
-.
50.0- QI
04
C,
0.0-
0.0 12.0 24.0 36.0 48.0
Time(hrs)
Figure E.13: Transient responses of colloid osmotic pressu

res (IIPL and Hi),
plasma volume (Vpjj, and protein contents
(QPL and Qz) after single infusion
of 60 g of human albumin solution. For the best-fit par
ameters of tissue
165
25.0
20.0-
S 15.0-
4 10.0-
5.0 — I I I
0.0 12.0 24.0 36.0 4 [.0
6.0
5.0-
4.0
S 3.0
-
J -
2.0’
1.0-
0.0- I I I
0.0 12.0 24.0 36.0 48.0
4.0-
04
3.5.
3.0-
2.5-
).0 12.0 24.0 36.0 4 I.0
150.0-
100.0-
QPL
:-
0 50.0- QI
0.0 -
0.0 12.0 24.0 36.0 48.0

Time(hrs)
Figure E.14: Transient responses of colloid osmotic pressures

(HPL and Hi),
plasma volume (Vpjj, and protein contents and Qj) after single infusion
(QPL
of 60 g of human albumin solution. For the best-fit para
meters of tissue
Appendix F
List Of Computer Programs
F.1 Parameter List of Steady-State and Transient Simulators
C A list of program variables of all programs listed
C ****************************************************
C Variable key:
C ACC = Accuracy limit
C ALPHA = Scaling factor for ROOT
NV = Number of nonlinearequation - -
C PIPL = Plasma colloid osmotic pressure
C PISKIN Tissue colloid osmotic pressure

C P15 = Tissue colloid osmotic pressure
C PSNRN = Normal tissue hydrostatic pressure

C QPLS = Plasma: albumin content_calculated
C QSS = Tissue: albumin content_calculated
C QPLNRM Plasma: normal albumin content
C QSNRN = Tissue: normal albumin content
C QTNRM = Normal total albumin content

C QTOT = Whole body: albumin content
C RHSF = Nonlinear equations to be solved
C VPLNRN Plasma: normal volume
C VIFNRM Tissue: normal volume
C VTNRN = Normal total extra-cellular volume
C VTOT = Whole body: volume
C VEXS = Tissue excluded volume
C YNEW = Initial solution estimates
C YOLO = Final solution values
C CAVS = Protein concentration in available volume
166
Appendix F. List Of Computer Programs 167
C CPL = Protein concentration in plasma
C CS = Protein concentration in tissue
C iFS = Fluid filtration flowrate
C JLS = Fluid lymph flowrate
C PC = Capillary hydrostatic pressure

C PCNRN = Normal PC
C QPS = Protein flowrate across the capillary wall
C QLS = Lymphatic protein flowrate

C AS = Initial gradient of tissue compliance curve
C BS = Final gradient of tissue compliance curve
C KFS = Tissue filtration transport coefficient
C LSNRM = Tissue basal lymph flowrate
C LSS = Lymph flow sensitivity

C P55 = Permeability-surface area product
C SIGS = Albumin reflection coefficient
C NPS = Number of points on tissue compliance curve
C NPSN1NPS- 1
F.2 Listing of FORTRAN function XDFUNC1

C
FUNCTION XOFUNC(X,N)
C This function is used to calculate the value of the objective

C function at specific values of SIGS, LSS end PCNRM.
IMPLICIT REAL*8CA-H,K,L,3,O-Z)
CONMON/BLKA2/CPLNRM , CSNRM , CASNRM
CONMON/BLKB/JFS , AS
COMMON/ELKO/QPS , QLS
CONMON/BLKG/CPL ,CS, CAVS

COMMON/BLKI/PIPL ,PIS
COMMON/BLKF/PC ,PCNRM,PCGRAD
CONNON/BLKH/LSNRM
CONMON/BLKJ/VTNRN, VIFNRN, VPLNRN
CONNON/BLKK/VEXS
CONNON/ELKL/LSS ,KFS , SIGS , P55

COMMON/BLKT/QTNRM , QSNNM , QPLNRM
COMMON/BLKU/PSNRM ,PS
COMMON/BLKBB/PIPNRN ,PISNRM
COMMON/BLKZB/QTOT, VTOT
COMMON/BLKO/VSP(14) ,PSP(14) ,AS,BS,NPS,NPSM1
COMMON/A/VPINIT , QPINIT , VSINIT , QSINIT
DIMENSION X(N) ,G(6)
LBS = x(i)*40.D0
SIGS = X(2)
PCNRN = X(3)*10.D0
PIPNRM=25 .900
PISNRM=14 .700
CALL SPLINS
CALL COEFF
PLINIT = 25.900
PIINIT = 14.7D0
VIFINT = 8400.000
VPINIT = VPLNRM
QPINIT = VPLNRM * FALB(PLINIT)

C
VSINIT = VIFINT
QSINIT = FALB(PIINIT) * (VIFINT - VEXS)

C
VTINIT = VPINIT + VSINIT

QTINIT = QPINIT + QSINII
C Each data set is progrsned separately so that it can be called
C separately if necessary.
C HUB: Data set A (Data from Hubbard et al.)
C DOYLE: Data set B (Data from DOYLE et al.)
C MULLINS: Data set C (Data from Mullins et al.)

C HF: Data set 0 (Data from heart failure patients)
C NEPHRO: Data set E (Data from nephrotic patients)
C
SUM = 0.00
CALL HUB(i.D-2,4,SUM1,SUM)
0(1) = SUM
SUM = 0.00
CALL DOYLE(i.D-2,4,SUM)
0(2) = SUM
SUM = 0.00
CALL MULLIMS(i .D-2,4,SUM)
0(3) = SUM
SUM = 0.00
CALL HF(1.D-2,.SD0,i.D-2,4,SUM)
0(4) = SUM
SUM = 0.00
CALL MEPHRO(SUM)
0(5) = SUM
0(6) = 0(1)+G(2)+0(3)+G(4)+0(S)
XDFUMC = 0(6)
C
RETURN
END
SUBROUTINE XDCONS(X,N,M,ME,MMAX,G)
C This subroutine is used to evaluate the constraints imposed on
C the parameters to be estimated.
IMPLICIT REAL*6(A-H,K,L,0-Z)
INTEGER N,M,ME,MMAX
DIMENSION X(N) ,G(MMAX)
COMMON/BLKA2/CPLMRM , CSNRM , CASNRM
COMMON/BLKF/PC,PCNRM,PCGRAD
COMMOM/BLKBB/PIPNRM ,PISNRM
IF(M.LE.0) GO TO 100
0(1) = (x(3)*io.Do - PSNRM)/(PIPNRN — PISMRM) — x(2)/lo.Do

RETURN
100 CONTINUE
JUMP = -M
GO TO (1),JUMP
RETURN
1 0(1) = (X(3)*10.OO — PSNRM)/(PIPNRN - PISNEM) — X(2)/10.OO

RETURN
END
SUBROUTINE HUB (EPS ,NV, SUM1 ,SUM)
C This subroutine is used to evalute the sum of square of the error
C contributed by Hubbard’s data only.
IMPLICIT REAL*8(A-H,K,L,J,O-Z)
INTEGER FLAG
COMMON/BLKI/PIPL,PIS --
COMMON/A/VPINIT , QPINIT ,VSINIT ,QSINIT
COMMON/BLKB/JFS , JLS
COMMON/BLKO/QPS ,QLS
COMMON/SLKG/CPL ,CS, CAVS
COMMON/BLKH/LSNRM
COMMON/BLKL/LSS ,KFS ,SIGS ,PSS
COMMON/BLKZB/QTOT ,VTOT
DIMENSION YOLD(4) ,YNEW(4)
DIMENSION SOLN(6,2),EXP1(6,2,4),T1(6),SD1(6,2,4)
EXTERNAL RHSFB
C Experimental data.
DATA T1/ -1.500,1.D0,3.D0,6.D0,9.O0,12.D0/
DATA EXP1/0.D0,-.033TD0,-.004100,-.O2BSDO,-.040900,-.OT3SDO,
1 0.00, .O1B000, .005900, .035200, .074100, .065600,

2 0.00, .0204D0,—.0041D0,-.024500,-.0164D0,- .045000,

3 0.D0, .1104D0, .103000, .1166D0, .108200, .105200,
4 0.00,— .037300,—.0083D0,-.0166D0, .020700,-.004100,
5 0.00, .050000, .045000, .050000, .033800, .052400,
6 0.D0, .132800, .128600, .062200, .083000, .066400,
7 0.00, .132500, .118800, .078500, .087200, .097400/
DATA SD1/O.ODO, 5.85D—2, 8.430—2, 7.090—2, 6.63D-2,10.16D-2,
1 0.000,38. 1OD-2,38.25D-2,39. 17D—2,39.99D—2,39.35D-2,
3 0.ODO,11.11D-2,10.19D-2, 7.64D—2, 9.73D—2, 6.33D—2,
4 0.ODO,41.82D—2,45.62D-2,45, 100—2,43. 14D—2,43.34D-2,

6 0.ODO,16.94D-2,10.94D-2,11.710-2,19,88D—2,14.71D—2,
7 0.000,19.750—2,17.370-2,16.250—2,18.410-2,17.670—2,
9 0.000, 12.510—2,20.360—2,14.870—2,17.930-2,13,240—2,
1 0.000, 18.41D-2,14.79D—2,15.61D—2,14.84D-2,16,36D—2/
DO 60 IPET1,4
C Set initial conditions.
YNEW(1) = VPINIT
YNEW(2) = QPINIT
YNEW(3) = VSINIT
YNEW(4) = QSIMIT
C Solve differential equations.
DO 30 I = 0,5
IP=I+1
TI = T1(IP)
IF(I,EQ.0) GOTO 10
TIM T1(I)
DT=TI-TIM
TSTART=1 .D-1*DT
TMIN1 . D-4*DT
TMAX=DT
CALL RK4C(RHSFB,NV,TIM,TI,YOLD,EPS,YNEW,NFTJNC,FLAG,IPET)
IF(FLAG.EQ.0) GOTO 70
10 CALL AUXSAM(YNEW)
SOLN(IP,1) PIPL
SOLN(IP,2) = YNEW(1)
DO 20 J = l,NV
YOLO(J) = YNEW(J)
20 CONTINUE
30 CONTINUE
C
C Calculate the sum of square of error.
00 50 .1=1,2
SOLNOSOLN(1,J)
00 40 1=2,6
SOLN(I ,J)=(SOLN(I,J)-SOLN0)/SOLNO
ERROR’SOLNCI , .1) -EXP1 (I, .1, IPET)
SUN SUM +4.00*(ERR0R**2)/(5D1(I,J,IpET)**2)
40 CONTINUE
50 CONTINUE
60 CONTINUE
RETURN
70 WRITE(6,80)
80 FORMAT(1X,’ODE SOLVER FAILS 1 ‘)
STOP
END
SUBROUTINE DOYLE (EPS ,NV,SUM)
C This subroutine is used to evaluate the sum of square of error
C contributed by Doyle’s data only.
INTEGER FLAG
COMMON/B/T2(3,S)
CONNON/BLKI/PIPL ,PIS
COMMON/A/VPINIT,QPINIT,VSINIT,QSINIT
COMMON/BLKB/JFS ,J1S
COMMON/BLKD/QPS ,QLS
COMMON/BLKG/CPL ,CS, CAVS
COMMON/SLKF/PC ,PCNRM,PCGRAD
COMMON/BLKH/LSNRM
COMNON/BLKL/LSS ,KFS , 5105 ,PSS
COMMON/BLKI3/PSNRN ,PS
COMMON/8LKZ8/QTOT ,VTOT
DIMENSION YOLO(4) ,YNEW(4)
DIMENSION SOLN(3,S) ,EXP2(3,S) ,502(3,S)
EXTERNAL RHSFC
DATA EXP2/O.000, .249300, .085800,
+ 0.000, .248900, .154600,
+ 0.000, .228800, .138100,
+ 0.000, .289600, .164000,
+ 0.000, .198100, .081000/
DATA S02/ .07i500,.078000,.073900,
+ .066300, .070900, .069300,
+ .069600, .076400, .073900,

+ .077300, .085700, .082400,
+ .064400, .069800, .066800/
00 60 IPET1,S
YNEW(1) = VPINIT
YNEW(2) = QPINIT
YNEW(3) = VSINIT
YNEW(4) = QSINIT
C
C Solve the differential equations.
DO 30 I 0,2
1P1+1
TI = T2(IP,IPET)/60.D0
IF(I.EQ.0) GOTO 10
TIM = T2(I,IPET)/60.D0
DTTI-TIM
TSTART1 .O-1*DT
TMIN1 .D-4*DT
ThAXDT
CALL RK4C(RHSFC,NV,TIM,TI,YOLD,EPS,YNEW,NFUNC,FLAG,IPET)
IF(FLAG,EQ.O) GOTO 70
SOLN(IP,IPET) = YNEW(1)
DO 20 .3 = 1,NV
YOLO(J) = YNEWCJ)
20 CONTINUE
30 CONTINUE
C
SOLNOSOLN(1 ,IPET)
DO 50 1=2,3
SOLN(I , IPET)(SOLN(I ,IPET)-SOLNO)/SOLNO
ERROR=SOLN(I ,IPET)-EXP2(I,IPET)
sUMsUM+(ERROR*ERR0R)/(5D2C.I ,IPET)*SD2(I,IPET))
50 CONTINUE
60 CONTINUE
RETURN
C
70 WRITE(6,80)
80 FORMAT(1X,’ODE SOLVER FAILS 2’)
STOP
END
SUBROUTINE MULLINSCEPS ,NV,SUM)
C contributed by Mullins’ data only.

C
INTEGER FLAG
COMMON/BLKI/PIPL , PIS
COMMON/A/VPINIT , QPINIT ,VSINIT , QSINIT
COMMON/BLKD/QPS , QLS
COMMON/BLKG/CPL ,Cs, CAVS
COMMON/BLKH/LSNRM
COMMON/BLKL/LSS , KFS , SIGS , PSS
COMMON/BLKU/PSNRN ,PS
DIMENSION YOLD(4) ,YNEW(4)
DIMENSION SOLN(2,2) ,EXP4(2,2) ,T4(2) ,SD4(2,2)
EXTERNAL RHSFE
DATA T4/ O.000,2.SDO/
DATA EXP4/O.ODO, .106500,O.ODO,-.117600/
DATA SO4/O.ODO,49.31D-2, O.000,27.68D-2/
YNEW(1) = VPINIT
YNEW(2) QPINIT
YNEW(3) VSINIT
YNEW(4) QSINIT
C
IPET2
DO 30 I = 0,1
IP=I+1
TI = T4(IP)
IF(I.EQ.0) GOTO 10
TIM = T4(I)
DT=TI-TIM
TSTART=l .D-1*DT
Appendix F. List Of Computer Pro,gTams 176
TMIN=1 .D-4*DT
TMAX=DT
CALL RK4C(RHSFE,NV,TIM,TI,YOLD,EPS,YNEW,NFUNC,FLAG,IPET)
IF(FLAG.EQ.0) GOTO 70
SOLN(IP,i) = YNEW(1)
SOLN(IP,2) = CPL
DO 20 3 = 1,NV
YOLD(J) = YNEW(3)
20 CONTINUE
30 CONTINUE
DO 60 3=1,2
SOLNOSOLN(1 ,J)
DO 50 1=2,2
SOLN(I , J)’(SOLN(I ,J)—SDLND)/SOLNO
ERROR”SOLN(I !4U ,3)
SUM=SUM+i ii. D0* (ERROR*ERRDR) / (SD4(I, 3) **2)
50 CONTINUE
60 CONTINUE
RETURN
70 WRITE(6,80)
80 FORMAT(iX,’DDE SOLVER FAILS 3’)
STOP
END
C *************************************
SUBROUTINE HF(ACC,ALPHA,EPS,NV,SUM)
C *************************************
C This subroutine is used to evaluate the sum of square of eorror
C contributed by the data from heart failure patients.
IMPLICIT REAL*8(A-N,K,L,J,D-Z)
INTEGER FLAG,FLAGG
C
COMMON/BLKA2/CPLNRM , CSNRM , CASNRM
COMMON/BLKG/CPL ,Cs, CAVS
COMMON/BLKH/LSNRJ4
COMM0N/BLKJ/VTNR4 ,VIFNRM,VPLNRN
COMMON/ELKK/VEXS
COMMON/BLKL/LSS , KFS ,SIGS ,PSS
COMMONJBLKT/QTNRM , QSNRN , PLNRM
COMMON/BLKU/PSNRM ,P5
COMMON/BLKBB/PIPNRN ,PISNRM
COMMON/BLKDD/ALBSTO
COMNON/BLKZB/QTOT ,VTOT
COMMON/VQPL/VPL ,QPL
DIMENSION YOLD(4),YNEW(4),YOLDA(2),YNEWA(2),YFINAL(2)
DIMENSION A(4) ,B(4) ,C(4) ,XPVI(3),XPVPL(3),SD3(3) ,POINT(3)
DIMENSION Y1(4),Y2(4),Y3(4),Y4(4)
EXTERNAL RHSFA
DATA A/20.3,23.4,24.0,25.9/
DATA B/8.1,1O.4,12.2,14.7/
DATA C/20. 1,16.91,11.45,10.0/
DATA XPVI/O.562000,0.433200,—O.113500/
DATA SD3/2 .064400,1.836100,0.803900/
DATA POINT/7,00,13.D0,22.D0/
TSTART1 . 0-1*0 .00500
TMIN1 .0-4*0.00500
TMAX=0 .0100
VSG = VIFNRN+3000.D0
DO 40 IPET2,3
PIPL = A(IPET)
P15 = B(IPET)
PC = C(IPET)
CPL = FALB(PIPL)
PCC = PC
VPL = FVPL(PCC)
QPL = VPL*FALB(PIPL)
QSG = VSG*FALB(PIS)*3.DO/4.OO
YOLD(1) = VSG
C Solve the differential equation.
CALL ROOT(RHSFA,l,O.DO,YOLD,ACC,ALPHA,YNEW,FLAG)
IF(FLAG.EQ,O) THEN
PRINT*,’----ROOT FAILED----’
STOP
ENDIF
IF(VSG.LE.O.OO.OR.QSG.LE.O.OO) THEN
PRINT*, ‘----NEGATIVE VOL/Q GENERATED----’
STOP
ENDIF
VSG = YNEW(1)
CIS = FALB(PIS)
QS = YNEW(l)*FALB(PIS)
QTOT = QS + QPL
PS = FCOMPS(YNEW(1))
Y1CIPET) = YNEW(1)/1000.DO
CHANGE = (YNEW(l)-vIFNRM)/VIFNRN
ERROR = CHANGE-XPVI(IPET)
= SUN + p0INT(IPET)*ERR0R**2/SD3(IPET)**2
40 CONTINUE
RETURN
END
C ************************
SUBROUTINE NEPHRO (SUM)

C contributed by the data from nephrotic patients.
IMPLICIT REAL*8(A-H,K,L,J,O-2)
INTEGER FLAG
COMMON/BLKA2/CPLNRM , CSNRM , CASNRM
COMMON/BLKB/JFS JLS
COMNON/BLKG/CPL ,CS,CAVS
COMMONIBLKI/PIPL ,PIS
COMMON/BLKF/PC , PCNRM , PCGRAD
COMMON/BLKH/LSNRM
COMMON/BLKJ/VTNRM ,VIFNRM,VPLNRM
COMMON/BLKK/VEXS
COMMON/BLKL/LSS ,KFS,SIGS,PSS
çoMMoN/T0T/vToT , QTOT
COMNON/BLKU/PSNRM ,PS
COMMON/BLKY/PIPPS(100) ,PISKIN (100) • NA ,NAM1
COMMON/BLKBB/PIPNRM , PISNRM
COMNON/BLKDD/ALBSTO
COMMON/BLKZ/DIFV(19) ,DPIPL(19) ,NN
COMMON/BLKHH/PIPLPI (66) ,PII (66)
DIMENSION YOLD(2),YNEW(2),EXP6(66),SD6(66),EXP7(19) ,SD7(19)
EXTERNAL RHSF
DATA ACC,ALPHA,NV/1.D-2,0.5D0,2/
DATA EXP6/-0 .84354D+0,-0.59864D+0,—0.87075D+0,-0.82313D1-0,
+ -0.76871D+0,-0.80272D+0,-0.93878D+O,-0.81633D+0,
+ -0.884350+0,-0.66667D+0,—0.66667D+0,—0.78231D+0,
+ -0.70068D+O,—0.73469D+0,—0.962380—0,—0.89116D+0,
+ -0,80272D+0,-0.6l224D+0—0.63265D+0,—0.73469D+0,
+ -0.73469D+0,—0.68027D+0,—0.72789D+0,—0.87075D+0,
+ -0.69388D+0,—0.70748D+0,—0.76871D+0,-0.52381D+0,
+ —0.61224D+0,—0.51020D+0,—0.61224D+0,-0.68027D+0,
+ -0.66667D+0,—0.56463D+0,—0,56463D+0,-0.74830D+0,
+ —0.598640+0,-0.47619D+0,—0.59864D+0,--0.73469D+0,
+ —0.45578D+0,—0.41497D+0,-0.44218D+0,-0.42857D+0,
+ -0.64626D+0,--0.54422D+0,—0.53061D+0,-0.32653D+0,
+ —0,47619D+0,-0.272110+0,-0.47619D+0,—0.29252D+0,
+ -o .258500+0,-0.40816D+0, 0 .000000+0,-0.20408D+0,
+ —0. 10204D+O,-0.47619D—1,--0. 170070+0,—0.20408D+0,
+ —0.136060+0, 0.34014D—l,-0.20408D-1,—0,10204D+0,
+ -0.680270—1, 0.000000+0/
DATA SD6/0.1103D0,0.130300,0.108100,0.111900,0.1164D0,
+ 0.113600,0.109700,0.119700,0.114200,0.1319D0,0.131900,0.1225D0,
+ O.129200,0.126400,0.1086D0,0.1136D0,0.120800,0.1364D0,
+ O.134700,0.1264D0,0.126400,O.130800,O.126900,O.115300,
+ 0.108000,0.106900,0.101900,0.121900,0.114700,0.123000,
+ O.114700,O.109100,0.110200,0.118500,O.118500,0.103500,
+ 0.115800,0.172600,O.162600,0.151500,0,174300,0.177600,
+ 0.175400,0.176500,0.158800,0.167100,0.168200,0.184900,
+ 0.172600,0.189300,0.172600,0.187600,0.190400,0.178200,
+ 0.163200,0.146600,0.154900,0.159300,0.149300,0.146600,
+ 0.152100,0.166000,0. 161500,0. 154900,0.157700,0.163200/
DATA EXP7/ 0.126310+1, 0.907140+0, 0.714290+0, 0.545240+0,
+ -0.500000-1,—0.20119D+0, 0.27381D+0,-0,15476D-1,
+ 0.000000+0, 0.183810+0, 0.84524D—1,-0.72619D—1,
+ -0. 19881D+0,—0.213100+0, 0.47619D-2,—0.71429D-2,
+ —0,84524D—1,—0. 178570—1, 0.116670+0/
DATA S07/0.362900,0.337100,0.323000,0.310800,0.267500,
+ 0.256500,0,291000,0.270000,1. 111100,0.156200,0.149000,
+ 0.144700,0.135500,0.134500,0.145700,0.144800,0.139200,
+ 0.144000,0.153800/
NA = 97
NAM1 = NA - 1
PIPLUL = 28.00
C GUESS THE INITIAL VALUES OF QPL, QS, VPL, VS
QPLG = VPLNRM * FALB(PIPNRM)

QSGO= (VIFNRN — 400.00) * FALB(PISNRM) * 3.00/4.00
VPLG = VPLNRM
VSG0 = VIFNRM - 400.00
DIV = 0.2500
C
SUMPIO .00
VSG=VSG0
QSGQSGO
00 20 IN = 1,66
PIPP = PIPLPI(IN)
CPL = FALB(PIPP)
YOLD(1) = VSG
YOLD(2) = QSG
CALL ROOT(RHSF,NV,0.O0,YOLO,ACC,ALPHA,YNEW,FLAG)
IF(FLAG.EQ.0)THEN
PRINT*, ‘*****RQQT FAILED! ****‘
STOP
ENOIF
VSG = YNEW(1)
QSG = YNEW(2)
IF(VSG.LE.O.O0.OR.QSG.LE.D.O0)ThEN
PRINT*,’ IN = ‘,IN,’VSG = ‘,VSG,’QSG = ‘,QSG

PRINT*,’** NEGATIVE VOL/Q GENERATED *****‘
STOP
ENOIF
C
C Calculate the sum of square of error contributed by PISKIN.

C
VPLG = VTOT - VSG
QPLG = QTOT - QSG
CAVS = QSG / (VSG - VEXS)
PISKIN(IN) = FPI(CAVS)
CHANGE = (PISKIN(IN) -PISNRM) /PISNRH
ERROR CHANGE-EXP6 (IN)
SUMPISUNPI+ERROR**2/506 (IN) **2
20 CONTINUE
SUMIFV = 0.00
VSGVSG0
QSG=QSGO
DO 40 1=1,19
PIPPD?IPL(I)
CPL=FALB (PIPP)
YOLO(i)VSG
YOLO (2) =QSG
CALL ROOT(RHSF,NV,0.O0,YOLD,ACC,ALPHA,YNEW,FLAG)
IF(FLAG.EQ.0) THEN
PRINT*, ‘*****ROOT FAILEIH*****’
STOP
ENOIF
VSG = YNEW(1)
QSG = YNEW(2)
IFQVSG.LE.O.O0.OR.QSG.LE.0.O0) THEN
PRINT*,’ I = ‘,I,’VSG= ‘,VSG,’QSG= ‘,QSG
PRINT*, ‘*****NEGATIVE VOL/Q GENERATED
STOP
ENOIF
C Calculate the sum of square of error contributed by VIF.
IF(PIPP.EQ. 17.400) THEN
ERROR = 0.00
GO TO 35
END IF
CHANGE= (YNEW (1) -VIFNRN) /VIFNRN
ERROR= CHANGE-EXP7 (I)
35 SUNIFVSUNIFV+ERROR**2/5O7 (I) **2
50 FORNAT(IX,SF1O.4)
40 CONTINUE
SUN = SUN+SIJNPI+SUNIFV
RETURN
END
C
SUBROUTINE COEFF
C This subroutine is used to calculate the values of the transport
C parameters: LSNRN, P55, KFS.
IMPLICIT REAL*8(A-H,J,K,L,0-Z)
COMMON/BLKA2/CPLNRN , CSNRM , CASNRM
COMMON/BLKT/QTNRM QSNRM , QPLNRM
COMMON/ELKDO/ALBSTO
COMMON/BLKH/LSNRM
COMMON/ELKF/PC , PCNRM , PCGRAD
COMMON/BLKK/VEXS
COMMON/BLKBS/PIPNRM ,PISNRM
COMMON/BLKL/LSS , KFS ,SIGS ,PSS
COMMON/BLKJ/VTNRN,VIFNRM , VPLNRN
C Set the normal steady-state conditions.
PIPNRM = 25.900
PISNRM = 14.700
PSNRM = FCOMPS(VIFNRM)
CPLNRM = FALB(PIPNRM)
CASNEM = FALB(PISNRM)
CSNRM = CASNEM * (1.00 - VEXS / VIFNRM)

QPLNRN = VPLNRM * CPLNRM
QSNRM = VIFNRM * CSNRM
QTNRM = QPLNRM + QSNRM
VPLNRM = VPLNRM
VSNRM = VIFNRM
VTNRM = VPLNRM + VSNRM
C Calculate LSNRM.
EPNRM = (CSNRM-(1 .00-SIGS)*CPLNRM)/(CSNRM-(1 .D0-SIGS)*CASNRM)
Ml = VIFNRM - VEXS
IF(ABS(1.00-SIGS) .LT.1.0-8) THEN
LSNRM = ALBSTO/ (CSNRM/ (CPLNRM-CASNRN) /W1+i . 00/VIFNRM)
ELSE
LSNRM = ALBSTO/((i .OO-SIGS)*EPNRM/ (1 .OO-EPNRM)/W1+1 .OO/VIFNRM)
ENDIF
C Calculate P55.
IF(ABS(i.DO-SIGS).LT.l.O-8) THEN
PSS=CSNRM*LSNRM/ (CPLNRN-CASNRM)
ELSE
P55 = Ci .DO-SIGS)*LSNRM/OLOGC1 .DO/EPNRM)
ENDIF
C Calculate KFS.
KFS = LSNRM / (PCNRM - PSNRM - 5105 * CPIPNRM - PISNRM))

PE = -DLOGCEPNRM)
RETURN
END
SUBROUTINE AUXSAMCY)
C **********************
C This subroutine is used to calculate all system variable values at
C given compartmental protein and fluid contents.
INPLICIT REAL*8(A-H,J,K,L,O—Z)
COMMON/BLKB/JFS , AS
COMNON/BLKO/QPS , QLS
CONNON/BLKF/PC,PCNRM,PCGRAD
COMNON/BLKG/CPL ,CS, CAVS
CONNON/BLKH/JLSNRM
COMMON/BLKK/VEXS
COMNON/BLKL/LSS ,KFS, SIGS, P55
COMMON/BLKT/QTNRM , QSNRN , QPLNRM
COMMON/BLKU/PSNRN ,PS
CONNON/BLKZA/PRESLO
COMNON/BLKZB/QTOT ,VTOT
DIMENSION Y(4)
CPL = Y(2) I Y(1)

PC = FCOMPC(Y(1))
Cs = Y(4)/ Y(3)
CAVS = Y(4)/ (Y(3) - VEXS)
PIPL = FPI(CPL)
PIS = FPI(CAVS)
PS = FCOMPS(Y(3))
JFS = KFS * (PC — PS — SIGS* (PIPL - PIS))
JLS = .JLSNRM + LSS * (PS - PSNRM)
IF(JLS .LT. JLSNRM) JLS=JLSNRM*(PS-PRESLO)/(PSNRM-PRESLO)
ULJLS1O .OO*JLSNRM
IF(JLS . GT.ULJLS) JLSUL.JLS
EP= (1.00 — SIGS) * JFS / P55

IF(EP.GT.5O.00) THEN
QPS=JFS* (1 DO-SIGS) *CPL
.
ELSEIF(EP.LT.-5O.OO) THEN
QPSJFS*(1.OO—SIGS)*CAVS
ELSEIF(ABS(O.D0-EP) .LT.1.D-8) THEN

QPS=PSS* (CPL-CAVS)
ELSE
QPS = JFS *(1.oo-sIG5)*(CpL-CAv5*Exp(-Ep))/(1.oo-Exp(-Ep))
ENDIF
QLS = JLS*CS
RETURN
END
SUBROUTINE AUXNEP (Y)
C
C
IMPLICIT REAL*B(A-H,J,K,L,O—Z)
C
,QLS
,PCNRM , PCGRAD
COMMON/BLKG/CPL ,CS, CAVS

COMMON/BLKH/JLSNRM
COMMON/BLKI/PIPL,PIS
COMMON/BLKK/VEXS
COMMON/BLKL/LSS , KFS , SIGS ,PSS
COMMON/TOT/VTOT , QTOT
COMMON/ELKU/PSNRM ,PS
COMMON/BLKZA/PRESLO
DIMENSION Y(2)
VDLPLA = 3200.00
VTOT = VOLPLA + Y(1)
QPLAS = VOLPLA * CPL
QTDT = QPLAS + Y(2)

PC = PCNRM
CS = Y(2) / Y(1)
CAVS = Y(2) / (Y(i) — VEXS)
PIPL = FPI(CPL)
PIS = FPI(CAVS)
PS = FCDMPS(Y(1))
JFS = KFS * (PC — PS — SIGS * (PIPL - PIS))
JLS = JLSNRN + LSS * (PS - PSNRM)
IF(JLS .LT. JLSNRM) JLSJLSNRM*(PS-PRESLO)/(PSNRM-PRESLD)
ULJLS=10 D0*JLSNRM .
IF(JLS.GT.ULJLS) .JLS=ULJLS
EP= (1.00 - SIGS) * iFS / p55
IF(EP.GT.50.DC) THEN
QPS=JFS* (1. DO—SIGS) *CPL
ELSEIF(EP.LT.-50.DD) THEN
QPS=—JFS* (1.00-5105) *CAV5
ELSEIF(ABS(0.D0-EP).LT.1.D-8) THEN
Qp5=PSS* (CPL-CAVS)
ELSE
QPS = iFS *(1.DQ-5I05)*(CPL—CAV5*EXP(—Ep))/(1.DQ-EXp(—EP))
ENDIF
QLS = .JLS * CS
RETURN
END
C ******************************
SUBROUTINE TOMACA,B,C,O,X,N)
C ******************************
C This subroutine uses the Thomas algorithm to find the solution

C of a tridiagonal matrix.
IMPLICIT REAL*8CA-H,O-Z)
C Thomas algorithm
DIMENSION ACN),B(N),C(N),O(N),X(N),PC1OI),QCiD1)
NM = N - 1
PU) = —CU) / BU)
QC1) = OC1) / BC.)

00 10 I = 2,N
IM = I—i
DEN = AU) * PCIM) + B(I)
PCI) = -CCI) / OEN
QCI) = COCI) — ACI) * QCIM)) / OEN

10 CONTINUE
XCN) = QCN)
DO 20 II = 1,NM
I = N - II
XCI) = PCI) * XCI+1) + QCI)

20 CONTINUE
RETURN
END
C ************************************
DOUBLE PRECISION PUNCTION FALBCPI)
C ************************************
C This function calculates Albumin concentration - using a fitted

C CAlb) vs. C.0.Ppl relationship.
C
IMPLICIT REAL*8CA-H,O-Z)
C
CONMON/BLKCC/CALB1 ,CALB2
FALB = (CALB1 + CALB2 * P1) / 1.0+3
RETURN
END
C **********************************
DOUBLE PRECISION FUNCTION FPI(C)
C This function calculates colloid osmotic pressure - using a

C fitted C.O.P vs. (Alb) relationship.
IMPLICIT REAL*8(A-H,O-Z)
COMMON/BLKN/CPI1 ,CPI2
R = C * 1.0+3
FPI = CPI1 + CPI2 * R

RETURN
END
C ****************************************
DOUBLE PRECISION FUNCTION RHSFA(IJX,Y)
C ****************************************
C This function evaluates the non-linear equations for a given
C set of Y values. Same as RHSFB,RHSFC,RBSFD,RHSFE,RHSFF.
IMPLICIT REAL*8(A—H,J,K,L,O—2)
C
CDMMON/BLKD/QPS , QLS
DIMENSION Y(i)
CALL AUXALT(Y)
RHSF3 = JFS — JLS
RHSF4 = QPS - QLS
GOTO(1O,20),I
10 RI-ISFA = RHSF3
RETURN
20 RHSFA = RHSF4
RETURN
END
DOUBLE PRECISION FUNCTION RHSFB(I,T,Y,IPET)
IMPLICIT REAL*8(A-H,.J,K,L,O-Z)
CONMON/BLKB/JFS , JLS
CONMON/BLKD/QPS , QLS
DIMENSION Y(4) ,SAL1(4) ,PRO(4)
DATA SAL1/100.DD,100.OD,200.DD,200.DD/
DATA PRO? 0.00, 25.00, 0.00, 50.00?
CALL AUXSAM(Y)
IF(T.LT.0.000)THEN
RHSFI = .JLS — iFS + SAL1(IPETV1.500

RHSF2 = QLS - QPS + PRO(IPET)*.6SDO/1.SDO
RHSF3 = iFS — AS
RHSF4 QPS — QLS
ELSEIF(T.GT.D.DDO.AND.T.LT. 13.SDD)TNEN
RNSFI. = AS — iFS + 1400.DD?13.SDO

RHSF2 = QLS — QPS
RHSF3 = iFS — AS
RHSF4 = QPS — QLS
ELSE
RHSF1 = JLS - iFS
RHSF2 = QLS — QPS
RHSF3 = iFS - JLS
RHSF4 = QPS - QLS
ENDIF
GDTO(10,2D,3D,40) ,I
10 RHSFB = RUSF1
RETURN
20 RHSFB = RHSF2
RETURN
30 RHSFB = RHSF3
RETURN
40 RHSFB = RHSF4
RETURN
END
DOUBLE PRECISION FUNCTION RHSFCCI,T,Y,IPET)

C
IMPLICIT REAL*8(A-H,J,K,L,0—Z)
COMMON/BLKB/JFS,JLS
COMMON/BLKD/QPS QLS
COMMON/B/T2(3,S)
DIMENSION Y(4) ,SAL2(5)
DATA SAL2/4*1000.D0,900.D0/
C
CALL AUXSAM(Y)
IF(T.LE.T2(2,IPET)/60.D0)THEN
RHSF1 itS — JFS + SAL2(IPET)/T2(2,IPET)*60.O0
RHSF2 = QLS — QPS
RHSF3 = IFS — ES
RHSF4 = QPS - QLS
ELSE
RHSF1 = itS - JFS
RHSF2 = QLS — QPS
RHSF3 = .TFS — JLS

RHSF4 = QPS - QLS
ENOIF
GDTO(10,20,30,40),I
10 RHSFC = RHSF1
RETURN
20 RHSFC = RHSF2
RETURN
30 RHSFC = RHSF3
RETURN
40 RHSFC = RHSF4
RETURN
END
C *********************************************
DOUBLE PRECISION FUNCTION RHSFO(I,T,Y,IPET)
C *********************************************
IMPLICIT REAL*8(A-H,J,K,L,O-Z)
COMMON/BLKB/JFS ,JLS
COMMON/BLKO/QPS, QLS
COMMON/B/T2(3,5)
DIMENSION Y(4) ,SAL3(2) ,PRO3(2)
DATA SAL3/4420 .0500,5996. 83D0/
DATA PRO3/29.3500,9.6500/
CALL AUXSAM(Y)
IF(T.LT.1:soo) THEN
RHSF1 = .JLS - JFS + SAL3(IPET)/1.SDO

RHSF2 = QLS - QPS + PRO3(IPET)*.6500/1.SDO
RHSF3 = JFS — JLS
RHSF4 = QPS - QLS

ELSE
RHSF1 = JLS — JFS

RHSF2 = QLS - QPS
RHSF3 = JFS - JLS
RHSF4 = QPS - QLS
ENDIF
GOTO(10,20,30,40),I
10 RHSFD = RHSF1
RETURN
20 RHSFD = RHSF2
RETURN
30 RHSFD = RHSF3
RETURN
40 RHSFD = RHSF4
RETURN
END
C *********************************************
DOUBLE PRECISION FUNCTION RHSFE(I,T,Y,IPET)
INPLICIT REAL*8(A—H,J,K,L,O-Z)
COMNON/BLKB/JFS , JLS
COMMON/BLKO/QPS, QLS
DIMENSION Y(4) ,SAL4(2) ,URI(2)
DATA SAL4/-2800 .00,2000.00/
OATA URI/O .000,1500.00/

C
CALL AUXSAN(Y)
IF(T.LT.2,000)THEN
RHSF1 = ES — .JFS + SAL4(IPET)/2.OO

RBSF2 = QLS - QPS
RRSF3=JFS— JLS
RHSF4 = QPS - QLS
ELSEIF(T.GE.2,000.ANO.T.LT.24.000)THEN
RHSF1 = JLS — JFS - URI(IPET)/22.DO

RHSF2 = QLS — QPS
RHSF3 = JFS - JLS
RHSF4 = QPS - QLS

ELSE
RHSF1 = JLS - JFS
RNSF2 = QLS - QPS
RHSF3 = iTS - AS
RHSF4 = QPS - QLS
ENOIF
GOTO(1O,20,30,40) ,I
10 RUSFE = RHSF1
RETURN
20 RESFE = RHSF2
RETURN
30 RHSFE = RHSF3
RETURN
40 RHSFE = RHSF4
RETURN
END
C ****************************************
DOUBLE PRECISION FUNCTION RHSFFCI,T,Y)
IMPLICIT REAL*8(A-H,J,K,L,O-Z)
CDMMON/BLKB/JFS , AS
DIMENSION Y(4)
CALL AUXSAM(Y)
RHSF1 = JLS - JFS + 1750.D0/2,SDO
RHSF2 = QLS - QPS

RHSF3 = JFS - AS
RHSF4 = QPS - QLS

GO-TD(10,2&,30,40),I
10 RHSFF = RHSF1
RETURN
20 RHSFF = RHSF2
RETURN
30 RHSFF = RHSF3
RETURN
40 RHSFF = RHSF4
RETURN
END
C ****************************************
DOUBLE PRECISION FUNCTION RHSF(I,X,Y)
C ****************************************
IMPLICIT REAL*8(A-H,J,K,L,D—Z)
DIMENSION Y(2)
C
CALL AUXNEP(Y)
RHSF3 = JFS - JLS
RHSF4 = QPS - QLS
GOTO(10,20),I
10 RHSF = RHSF3
RETURN
20 RHSF = RHSF4
RETURN
END
BLOCK DATA
IMPLICIT REAL*8(A-H,K,L,O-Z)
COMMON/B/T2(3,S)
COMNON/BLKF/PC ,PCNRM,PCGRAD
CONNON/BLKJ/VTNRN,VIFNRN,VPLNR14
COMMON/BLKK/VEXS
COMMON/BLKN/CPI 1, CPI2
CONNON/BLKO/VSP(14) ,PSP(14) ,AS,BS,NPS,NPSN1
CONNON/BLKZ/DIFV(19) ,DPIPL(19) ,NN
COMMON/BLKHH/PIPLPI (66) ,PII (66)
CONNDN/BLKCC/CALB1 , CALB2
COMMON/BLKDD/ALBSTO
COMMDN/BLKZA/PRESLO
C
DATA VEXS/2.1D+3/
DATA PCGRAD/0 . 00965BD0/
DATA PRESLO/ 13.057700/
DATA VTNRN,VIFNRM,VPLNRN/11 .60+3,8.40+3,3.20+3/
DATA CPu ,CPI2/1 .754900—4,0.65684000/
DATA CALB1 ,CALB2/-0.2671730-3,0 .1522440+1/
DATA NPS,NPSN1/14,13/
DATA VSP/B.4D+3,8.92D+3,9.45D+3,9.970+3,10.500+3,1j.02D+3,
+ 11.550+3,12.07D+3,12.600+3,13.65D+3,14.700+3,16.80D÷3,
+ 21.000+3,25.230+3/
DATA PSP/-0.7000,0.3200,0.8600,1,15D0,1.37D0,1.5600,
+ 1.69D0,1.80D0,1.8800,1.99D0,2.O1DO,2.04D0,2.1200,
+ 2.20D0/
DATA DPIPL/9.2D0,1O.7D0,11.7D0,12.7D0,13.7D0,13.7D0,
+ 14.2DO,14.2DO,17.4DO18.7DO,18.7DO,2Q.7DQ,2O.7DQ,
+ 21.7D0,24.7D0,25.7D0,25.7D0,26.7D0,26.7D0/
DATA DIFV/19.O1D+3,16.02D+3,14.40D+3,12.98D+3,7.98D+3,6.71D+3,
+ 1O.7OD+3,8.27D+3,O.ODO,9.944D+3,9.11D+3,7.79D+3,6.73D+3
+ 6.61D+3,8.44D+3,8.34D+3,7.69D+3,8.25D+3,9.35D+3/
DATA P11/ 2.3130, 5.9D0, 1.9D0, 2.6D0, 3.4D0, 2.9D0,
+ 0.9D0, 2.7D0, i.7D0, 4.9D0, 4.9130, 3.2D0,
+ 4.4D0, 3.9D0, 0.7D0, 1.6D0, 2.9D0, 5.7D0,
+ 5.4D0, 3.9D0, 3.9D0, 4.7D0, 4.0130, 1.9D0,
+ 4.5D0, 4.3D0, 3.4D0, 7.ODO, 5.7D0, 7.2D0,
+ S.7D0, 4.7D0, 4.9D0, 6.4D0, 6.4D0, 3.7D0,
+ 5,9D0, 7.7D0, 5.9D0, 3.9D0, 8.ODO, 8,6D0,
+ 8.2D0, 8.4D0, 5.2D0, 6.7D0, 6.9D0, 9,9D0,
+ 7.7D0,10.7D0, 7.7D0,10.4D0,1O.9D0, 8.7D0,
+ 14.7D0, i1.7D0,13.2D0,14,ODO,12.2130,j1.7D0,
+ 12.7D0,15.2DD,14.4D0,13.2D0,13.7D0,14.7130/
DATA PIPLPI/ 2.3D0, 5.3D0, 6.8D0, 6.6D0, 7.ODO, 7.ODO,
+ 7.8130, 8.31)0, 8.9D0, 9.0130, 9.ODO, 9.2D0,
+ 9.5D0, 9.5D0, 9.6D0, 9.9D0,10.3D0,10.7D0,
+ 11.3D0,i1.5D0,11.5D0,11.7130,11.9130,12.3130,
+ 12.4D0,12.9D0,13.ODO, 13.2D0, 13.7D0,13.9D0,
+ 14.2D0,14.2D0,14.5D0,15.5D0,15.5D0,15.7D0,
+ 17.3D0,17.4D0,17.5D0,17.5D0,17.9130,18.oDo,
+ 18.2D0,18.4D0,18.7D0,18.7D0,19.ODQ,19.oDa,
+ 19.4D0,19,9D0,20.7D0,21 .ODO,21 .0D0,21.7D0,
+ 22.9D0,23.6D0,23.6130,23.6D0,24.QDQ,24.4D0,
+ 24.8D0,24,2D0,24.4D0,24.9D0,26.4D0,26.9D0/
C DATA AS,BS/1.96154D-3,1 .81347D—5/
C DATA AS,BS/1 . 96154D—3,5.0000D-5/
DATA AS,BS/1.96154D-3,1 .05D-4/
DATA ALBSTO/0 . 020539D0/
DATA T2/ 0.D0, 9.5D0,47.5D0,
+ 0.D0,11.ODO,71.ODO,
+ 0.D0,13.0D0,28.0D0,
+ 0.DO,11.DDO,41.ODO,
+ 0.D0, 9.0D0,49.0D0/
END
C *************************************
DOUBLE PRECISION FUNCTION FCOMPS(V)
C *************************************
C
C This function calculates the skin
C compartments hydrostatic pressure.
COMMON/BLKO/VSP(i4),PSP(14),AS,BS,NPS,NPSM1
IF(V.LE.VSP(1)) GO TO 10
IF(V.GE.VSP(9)) GO TO 20
FCOMPS = FS(V)
RETURN
iO FCONPS = PSP(i) + AS * C V — VSPC1))

RETURN
20 FGOMPS PSPCP) + BS * KV — VSPC9))

RETURN
END
C *******************
SUBROUTINE SPLINS
C This subroutine SPLINES the experimently
C obtained PS vs. VS data set.
IMPLICIT REAL*B(A-H,O-Z)
COMMON/BLKO/XCi4) ,YC14) ,A1,BN,N,NM
COMMON/BLKQ/QC1Oi) ,RC1O1) ,S(100)
DIMENSION HC100) ,AC1O1) ,BC10I) ,C(101) ,OC1O1)
DO 10 I = 1,NM
H) = XCI+i) — XCI)
10 CONTINUE
AC1) = 0,00
BU) = 2.00 * HO)
CU) = MCi)
0(1) = 3.00 * CCYC2) — Y(1)) / MU) — Al)

DO 20 I = 2,NM
IP = 1+1
IM = I-i
AU) = MCDI)
BCI) = 2.00 * (MCDI) + MCI))

CCI) = MCI)
DCI) = 3.00 * CCYCIP) — YCI)) / MCI) — CYCI) — Y(IM))/MCIM))
20 CONTINUE
ACN) = MCNM)
BCN) = 2.00 * MCNM)
CCN) = 0.00
OCN) = -3.00 * CCYCN) - YCNM)) / MCNM) - BN)
CALL TOMACA,B,C,O,R,N)
00 30 I = l,NM
IP = I + 1
QCI) = CYCIP) — YCI)) / MCI) — MCI) * (2.00 *RCI)+R(IP))/3.00

SCI) = CRCIP) — RCI)) / C3.00 * MCI))
30 CONTINUE
RETURN
END
C **************************+******
DOUBLE PRECISION FUNCTION FSCZ)
C *********************************
C This function evaluates skin compartment hydrostatic pressure

C - using a splined set of data.
IMPLICIT REAL*BCA-M,O-Z)
C
COMMON/BLKO/X(14) ,Y(l4) ,A1,BN,N,NM
COMMON/BLI{Q/QClOl) ,R(101) ,S000)

C
11
IF(Z.LT.X(1)) GO TO 30
IF(Z.GE.X(NM)) GO TO 20
3 = NM
10 K(I+J)/2
IF(Z.LT.X(K)) 3 = K
IF(Z.GE.X(K)) I = K
IF(J.EQ.I+1) GO TO 30
GO TO 10
20 INM
30 OX=Z—x(I)
FS = Y(I) + OX * (Q(I) + OX * (RU) + ox * 5(I)))

RETURN
ENO
C *************************************
DOUBLE PRECISION FUNCTION FCOMPC(V)

C *************************************
C This function is used to calculate capillary hydrostatic
C pressure at given volume.
C-
IMPLICIT REAL*B(A-H,O-Z)
COMMON/BLKF/PC,PCNRM , PCGRAO
COMMON/BLKJ/VTNRM ,VIFNRM,VPLNRM
FCOMPC = PCNRN + PCGRAO * (V - VPLNRM)

IF(FCOMPC.LT.2.O0) FCOMPC = 2.00
RETURN
END
C ***************************************************
SUBROUTINE RK4C(F,M,A,B ,YA,EPS,YB ,NFUN,FLAG, IPET)
C ***************************************************
IMPLICIT REAL*B(A-H,K,O-Z)
INTEGER FLAG
DIMENSION YA(M) ,YI(lO),YB(N),YBOLO(iO),YARG1(10),yARG2(10)
DIMENSION K1(1G) ,K2(10) ,K3(iO) ,K4(10)
FLAG1
NINT=1
NFUN=0
10 NFUN=NFUN+4*NINT*M
Dfl (B-A) /NINT
XIA
DO 20 11,M
20 YI(I)=YA(I)
00 70 INT1,NINT
00 30 11,M
K1(I)=Dx*Fa ,XI ,YI,IPET)
30 YARG1(I)=YI(I)+K1(I)/2.O0
XARG=XI+0X/2 .00
00 40 11,M
K2(I)=DX*F(I ,XARG,YARG1 ,IPET)
40 YARG2(I)=YI(I)+K2(I)/2.D0
00 80 11,M
K3 (I) 0X*F (I ,XARG,YARG2 ,IPET)
50 YARG1(I)=YI(I)+K3(I)
xI=xI+0x
0060 11,M
K4w=ox*Fa ,XI ,YARG1 ,IPET)
60 YI(I)YI(I)+(K1(I)+2.O0*(K2(I)+K3(I+K4(I))/6.oo
70 CONTINUE
00 80 11,M
80 YB(I)=YI(I)
IF(NINT.EQ.1) GO TO 100
YBOIFM=0 .00
00 90 1=1,11
90 YBOIFM=OMAX1(DABS((YB(I)—YBOJ.D(I))/YB(I)),yBDIfl4)
IF (YNOIFM . LT EPS) RETURN
.
IF(NINT.GT.10000) GO TO 120
100 DO 110 I=1,M
110 YBOLO(I)=YB(I)
NINT2*NINT
GO TO 10
120 FLAG=0
RETURN
ENO
C **********************************************
SUBROUTINE GAUSS(A,N,NOR,NOC,X,RNORM, IERROR)
C Purpose:
C Uses Gauss elimination with partial pivot selection to
C solve simultaneous linear equations of form JA(*;X:;C:.

C
C Arguments:
C A Augmented coefficient matrix containing all coefficients
C and R.H.S. constants of equations to be solved.

C N Number of equations to be solved.
C NOR First (row) dimension of A in calling program.
C NOC Second (column) dimension of A in calling program.
C X Solution vector.
C RNORM Measure of size of residual vector ;C:-]A(*;X:.
C IERROR Error flag.
C 1 Successful Gauss elimination.
C =2 Zero diagonal entry after pivot selection. - -
IMPLICIT REAL*B(A-H ,O-Z)
OIMENSION A(NDR,NOC) ,x(N) ,B(SO,51)

C
NM = N - 1
NP = N + i
C Set up working matrix B
00 20 I = 1,N
00 10 .3 = 1,NP
B(I.3) = A(I,J)
10 CONTINUE
20 CONTINUE
C Carry out elimination process N-i times
00 80 IC = i,NN
KP = K + 1
C
C Search for largest coefficient in column K, rows K through N
C IPIVOT is the row index of the largest coefficient
BIG = 0.00
DO 30 I = K,N
SF = OABS(B(I,K))
DO 26 3 = KP,NP
SF = OMAX1(SF,OABS(BCJ,K)))
26 CONTINUE
AB = OABS(B(I,K) / SF)
IF(AB.LE.BIG) GOTO 30
BIG = AB
IPIVOT = I
30 CONTINUE
C
C INTERCHANGE ROWS K AND IPIVOT IF IPIVOT.NE.K
IF(IPIVOT.EQ.K) GOTO 50
00 40 3 = K,NP
TEMP = B(IPIVOT,J)
B(IPIVOT,J) = B(K,J)
B(K,J) = TEMP
40 CONTINUE
SO IF(B(K,K).EQ.O.DO) GOTO 130
C Eliminate BCI,K) from rows K+i through N
00 70 I = KP,N
QUOT = B(I,K) / B(K,K)
B(I,K) = 0.00
DO 60 3 = KP,NP
8(1,3) = 6(1,3) — QUOT * B(K,J)

60 CONTINUE
70 CONTINUE
80 CONTINUE
IF(B(N,N).EQ.0.O0) GOTO 130
C Back substitute to find solution vector

C
XCN) = BCN,NP) / B(N,N)
DO 100 II = 1,NM
SUM = 0.00
I = N - II
IP = I + 1
DO 90 3 = IP,N
SUM = SUM + B(I,J) * XCJ)
90 CONTINUE
XCI) = (B(I,NP) — SUM) / BCI,I)

100 CONTINUE
C Calculate norm of residual vector, C-A*X
C Normal return with IERROR = 1

C
RSQ = 0.00
00 120 I = l,N
SUN = 0.00
DO 110 .1 = 1,N
SUM = SUM + ACI,J) * XCJ)

110 dONTIUE
RSQ = RSQ + CDABS(ACI,NP) - SUM)) ** 2

120 CONTINUE
RNORM = OSQRTCRSQ)
IERROR = 1
RETURN
C Abnormal return because of zero entry on diagonal, IERROR2
130 IERROR = 2
C
C
C find the solution of a set of simultaneous RETURN RETURN
END
C **********************************************
SUBROUTINE ROOTCF,M,X,YOLD,EPS,ALPHA,Y,FLAG)
C **********************************************
C This subroutine uses Newton’s method to

C find the solution of a set of simultaneous
C non-linear equations.
INTEGER FLAG
DIMENSION YOLD(M) ,Y(M),DY(1O),DELY(10),A(lo,11)
NP = N + 1
DO 10 I 1,M
Y(I) = YOLD(I)
DELY(I) = 1.0—6 * YOLO(I)

10 CONTINUE
DO 60 ITER = 1,100
FLAG = 0
DO 40 I 1,M
DO 30 J = iMP
IF(J.EQ.MP) GOTO 20
y(J) = y(j) + DELY(3)

FUP = F(I,X,Y)
Y(J) = Y(J) - 2.00 * DELY(J)
FDOWN = F(I,X,Y)
y(j) = y(3) + DELY(J)
A(I,J) = (FUP — FDOWN) / (2.00 * DELY(J))

GOTO 30
20 A(I,J) = —F(I,X,Y)
30 CONTINUE
40 CONTINUE
CALL GAUSS(A,M,10,11,DY,RNORM,IERROR)
FLAG 1
DO 50 I = 1,M
Y(I) = YCI) + ALPHA * DY(I)

IF(DABS(DY(I)).GT.EPS) FLAG = 0
50 CONTINUE
IF(FLAG.EQ,1) RETURN
60 CONTINUE
RETURN
END
C **********************
SUBROUTINE AUXALT(Y)
C This subroutine is used to calculate the system variables from
C compartmental fluid and protein contents.
IMPLICIT REAL*8(A-H,J ,K,L,O-Z)
COMMON/BLKB/JFS , .315
COMMON/BLKO/QPS , QLS
COMMON/BLKF/PC , PCNRM,PCGRAO
COMMON/B LKG/CPL ,CS, CAVS
COMNON/BLKH/JLSNRM
COMMON/BLKK/VEXS
COMMON/BLKL/LSS ,KFS ,SIGS ,PSS
COMMON/BLKZA/PRESLO
COMMON/VQPL/VPL , QPL
DIMENSION Y(i)
qis = Y(l)*FALB(PIS)
CS = QIS / Y(i)
CAVS = QIS / (Y(i) - vExS)
PS = FCOMPS(Y(Ij)
JFS = KFS * (PC — PS - SIGS * (PIPL - PIS))

JLS = JLSNRM + LSS * (PS — PSNRM)
IF (.315. LT. JLSNRM) THEN
JLSJLSNBN* (P5-PRESLO) / (PSNRM—PRESLO)
ENOIF
ULJLS1O .OO*JLSNRM
IF(JLS GT.ULJLS) JLSULJLS

.
EP= (1.00 — SIGS) * iFS / P55

IF(EP.OT.SO.DO) THEN
QPS.TFS* Ci .00—5105) *CPL
ELSEIF (EP LT. -50.00) THEN

.
QPS=JFS*(1 .D0-SIGS)*CAVS
ELSEIF(ABS(0.D0-EP).LT.l.O-B) THEN
QPSPSS* (CPL-CAVS)
ELSE
QPS = JFS *(1.O0—SIGS)*(CPL—CAVS*EXP(—Ep))/(j.D0-EXP(-Ep))
ENDIF
QLS = .JLS * CS
RETURN
END
C *****************************************************************
SUBROUTINE OESOLV(F,M,A,B,YO,EPS,HSTART,HMIN,HMAX,YB,FLAG,IPET)
IMPLICIT REAL*B (A-H, O-Z)
DIMENSION YO(M) ,YA(10) ,YB(M)
EXTERNAL F
INTEGER FLAG
BNAB-A
HOLD=HSTART
DO 10 I=1,M
10 YA(I)=Y0(I)
20 CALL RKF(F,M,X,YA,HOLD,YB,YOIF,IPET)
GAZIMM BD0* (EPS*HOLD/ (BMA*YDIF) ) **O .2500

.
HNEW=GAMMA*MOLD
IF(GAMMA.GE.1.D0) GO TO 30
IF(HNEW.LT.HOLD/10.OO) HNEW=HOLD/10.
IF(BNEW.LT.HMIN) GO TO 50
HOLDHNEW
GO TO 20
30 IF (HNEW GT .5. D0*HOLO) HNEW5 O0*HOLD
. .
IF(NNEW GT .HMAX) HNEWHMAX

.
IF(X+HOLD.GE.B) GO TO 70
XX+H OLD
HOLDHNEW
DO 40 11,M
40 YA(I)=YB(I)
GO TO 20
50 FLAG=0
BX
DO 60 11,M
60 YB(I)YA(I)
RETURN
70 FLAG=1
HSTART=HNEW
HDLDB-X
CALL RKF(F,M,X,YA,HOLD,YB,YDIF,IPET)
RETURN
END
SUBROUTINE RKF(F,M,X,YOLD,H,YNEW,YDIFM,IPET)
IMPLICIT REAL*8(A-H,D-Z)
DIMENSION YOLD(N) ,YNEW(M) ,YARG1(10) ,YARG2(10)
REAL*8 K1(1D),K2(10),K3(10),K4(10),KS(10),K6(10)
DATA C21,C31,C32,C33/.2500, .375D0, .0937500, .2612500/
DATA C41,C42/.92307692307692307300, .87938097405553025700/
DATA C43,C44/-3 .2771961766044606100,3.32089212S62S8532300/
DATA C51 ,C52/2 . 03240740740740722D0, -B. 00/
DATA C53,CS4/7. 1734892787524364700,-.2058966B61598440SD0/
DATA C61 C62/ SDO

, . ,— . 29629629629629629400/
DATA C63,C64/2.D0,-1 .3816764132S5360500/
DATA C6S,C66/ .4529727095S1656916D0,—.275D0/
DATA C71,C72/ . 118518518518518509D0, .51898635477582845400/
DATA 3,C74/ .506131490342016654D0, —. 1800/
DATA C75,CB1/.0363636363636363636D0, .00277777777777777778D0/
DATA C82 C83/— .0299415204678362568D0,

, — .029199893673577883800/
DATA CB4,C85/.O200, .036363636363636363600/
DO 10 11,M
K1(I)3*F(I,X,YDLD,IPET)
10 YARG1(I)YDLD(I)+C21*K1(I)
XARG=X+C21*H
DO 20 I=1,N
K2(I)=H*F(I,XARG,YARG1 IPET) ,
20 YARG2 (I) YDLD(I)+C32*K1 CI)+C33*K2 (I)

XARG=X+C31*H
00 30 11,M
K3(I)H*F(I,XARG,YARG2,IPET)
30 YARG1(I)Y0L0(I)+C42*Ki(I)+C43*K2(I)+C44*K3(I)
XARGX+C41*H
00 40 I=1,M
K4(I)H*F(I ,XARG,YARG1, IPET)
40 YARG2(I)=YOLO(I)+C51*K1(I)+C62*K2(I)+C53*I{3(I)+C54*J{4(I)
XARG=X+H
00 50 11,M
K5(I)=H*F(I ,XARG,YARG2,IPET)
50 YARG1(I)=YOLD(I)+C62*K1(I)tC63*K2(I)+C64icK3(I)+C65*K4(I)
1 +C66*I{5(I)
XARGX+C61*H
00 60 11,M
60 K6(I)=H*F(I,XARG,YARG1,IPET)
YDIFMO .00
00 70 11,M
YNEW(I)Y0L0(I)+C7i*Ki(I)÷C72*K3(I)+C73*J(4(I)÷C74*K5(I)+
1 C75*K6(I)
YDIFOABS(C81*Ki(I)+C82*K3(I)+C83*K4(I)÷C84*K5(I)+C55*K6(ifl)
70 IF(YDIF.GT.YOIFM) YDIFM=YDIF
RETURN
END
C *************************************
DOUBLE PRECISION FUNCTION FVPL(PCC)

C *************************************
C This function is used to calculate the plasma volume at given
C capillary hydrostatic pressure.
COMMON/BLKF/PC,PCNRM,PCGRAD
COMMON/BLKJ/VTNRN , VIFNRM, VPLNRM

C
FVPL = VPLNRM + (PCC - PCNRM)/PCGRAO
IF(FVPL.LT.2372.O0) FVPL = 2372.00

RETURN
END
F.3 Listing of program PATDYN

C Filename: PATDYN
C This progam is used to simulate the transient responses of the
C microvascular exchsnge system after a single intravenous infusion
C of human albumin. Unless specify, subroutines and functions called
C in this program are the same as those listed in Section F.2 with
C the same names.
IMPLICIT REAL*8(A-H,K,L,J,O—Z)
INTEGER FLAG,FLAG6,FLAG7,FLAGG
COMMON/BLKA2/CPLNRM ,CSNRM , CASNRM
CCMMON/BLKD/QPS ,QLS
COMMON/3LKG/CPL,CS,CAVS
COMMON/5LKI/PIPL ,PIS
COMMON/BLKH/LSNRN
COMMON/BLKJ/VTNRN ,VIFNRM , VPLNRM
COMMON/BLKK/VEXS
COMMON/BLKL/LSS , KFS , SIGS ,PSS
COMMON/BLKT/QTNRM, QSNRM , QPLNRM
COMMON/BLKBB/PIPNRM ,PISNRM
COMMON/BLKDD/ALBSTO
COMMON/BLKZB/QTOT , VTOT
COMMON/BLKZJ/EXPLVL (4) ,EXCPL(4) ,EXDLPI (3) ,EXDLCA(3)
COMMON/BLKZK/EXPIPL(4) ,EXPII(3) ,EXCAV(3)
DIMENSION SOLN(16,769),T(lOOl),SOL(iOOi) ,SOLF(16)
DIMENSION YOLO(4),YNEW(4),YOLOA(2),YNEWA(2),YFINAL(2)
DIMENSION YEX1(4),YEX9(4),YEX3(4) ,YEX2(3),YEX11(3),
+ YEX1T(3) ,YEX18(3)
EXTERNAL RHSF,RHSFA
DATA ACC,ALPHA,EPS,DT,NP,NV/i,O-6,.500,i.000,O.OSOO,769,4/
FLAG7 = 0
FLAGS = 0
TSTART1 .0-1*0 .00500
TMIN=l .0-4*0.00500
TMAXDT
C Set LSS, SIGS, and PCNRM paremeter values.
LSS = 43.08086800
SIGS = 0.9887763700
PCNRM = 11.000
CALL SPLINS
CALL COEFF
C Set initial fluid volumes end protein contents.
PLINIT = 10.57400
PIINIT = 3.30400
VIFINT = 18250.00
VPINIT = VPLNRM
QPINIT = VPLNRM * FALB(PLINIT)
VSINIT = VIFINT
QSINIT = FALB(PIINIT) * (VIFINT — VEXS)

VTINIT = VPINIT + VSINIT
QTINIT = QPINIT + QSINIT
YNEW(1) = VPINIT
YNEW(2) = QPINIT
YNEW(3) = VSINIT
YNEW(4) = QSINIT
C
C Solve differential balances.
00 30 I = 1,1940
TIM = (I-1)*OT
TI = I * DT
IF(I.EQ,1) GOTO 14
CALL DESOLV(RHSF,NV,TIM,TI,YOL0,Ep5,TSTP.RT,TMIN,TMAX,
+ YNEW,FLAG)
IF(FLAG.EQ,0) GOTO 33
CALL AUXSAM(YNEW)
C Store results at select time intervals.

C
14 IF(TI.LT.3.DO.OR.TI.EQ.3.000)THEN
IK=(I—1)/4 +1
REALI = I
RI = (REALI — 1.00)14.00 + 1.00

RIK 1K
CHK = RI - RIK
ELSE
IK=(I-i)120+ 13
REALI = I
RI = (REALI—l.O0)/20.O0 + 13,00
RIK = 1K
CHK = RI - RIK
ENOIF
IF(CHK.NE.0.O0) GOTO 56
15 CALL AUXSAN(YNEW)
T(IK)0T*(I—1)
SOLN(1,IK) = YNEW(1)
SDLN(3,IK) = PC -
SOLN(4,IK) = PIPL
SOLN(5,IK) = CPL
SOLN(6,IK) = PIS
SOLN(T,IK) = CS
SOLN(8,IK) = CAVS
SOLN(9,IK) = PS
SOLN(1O,IK) = .TFS
SOLN(11,IK) = JLS
SOLN(12,IK) = QPS
SOLN(14,IK) = QLS
56 DO 20 J = 1,NV
YOLO(J) = YNEW(J)
20 CONTINUE
30 CONTINUE
C Calculate final steady-state variable values and store them.

VTOT = YNEW(1) + YNEW(3)
QTOT = YNEW(2) + YNEW(4)
YOLOA(1) = YNEW(3)
YOLDA(2) = YNEW(4)
CALL ROOT(RHSFA,2,1000.0O,YOLOA,ACC,ALPHA,YFINAL,FLAGG)
CALL AUXALT(YFINAL)
SOLF(1) = VTOT - YFINAL(1)

SOLF(2) = QTOT - YFINAL(2)
SOLF(3) = PC
SCLF(4) = PIPL
SOLF(S) = CPL
SOLF(6) = PIS
SCLF(7) = CS
SOLF(8) = CAVS
SOLF(9) PS
SOLF(10) = JFS
SOLF(11) = .TLS
SOLF(12) = QPS
SOLF(14) = QLS
SOLF(1S) = YFINAL(1)
SCLF(16) = YFINAL(2)
C Output variables stored and associated times.
00 112 1=1,109
WRITE(6,91)T(I) ,SOLN(4,I),SOLN(6,I) ,SOLNC3,I) ,SOLNC9,I)
91 FORMAT(6X,F6.3,SX,F7.4,5X,F7.4,SX,F7.4,5X,F7.4)
112 CONTINUE
WRITE(6,4i)SOLF(4),SOLF(6),SOLF(3),SOLF(9)
41 FORMAT(17X,F7.4,5X,F7.4,5X,F7.4,5X,F7.4)
00 lii 1=1,109
WRITE(6,95)T(I),SOLN(15,I),SOLN(1,I),SOLN(16,I),SOLN(2,I)
95 FORMAT(6X,F6.3,SX,F10.3,SX,F7.2,SX,F7.3,5X,F7.3)
111 CONTINUE
WRITE(6,45)SOLF(15) ,SOLF(1) ,SOLF(16) ,SOLF(2)

45 FORNAT(17X,F10.3,5X,F7.2,SX,F7.3,5X,F7,3)
00 113 1=1,109
WRITE(6,99)T(I),SOLN(10,I),SOLN(11,I) ,SOLN(12,I),SOLNC14,I)
99 FORMAT(6X,F6.3,5X,F8.2,5X,F8.2,5X,F8.3,5X,F8.3,SX,F8.3)
113 CONTINUE
WRITE(6,49)SOLF(1O) ,SOLF(11) ,SOLFC12) ,SOLF(14)
49 FORNAT(17X,F8.2,5X,F8.2,5x,F8.3,5x,F8.3,5x,FB.3)
00 117 1=1,109
WRITE(6,58)T(I),SOLN(5,I),SOLN(5,I),5OLN(7,I)
68 FORMAT(6X,F6.3,5X,F7.S,5X,F7.5,5X,F7.5)
117 CONTINUE
WRITE(6,24)SOLF(6) ,SOLF(8) ,SOLF(7)
24 FORMAT(17X,F7.5,5X,F7.5,6X,F7.5)
STOP
33 WRITE(6,40)
40 FORNAT(1X,’OOE SOLVER FAILS! ‘)
STOP
END
C ***************************************
DOUBLE PRECISION FUNCTION RHSF(I,T,Y)
C ***************************************
C - - -
C This function evaluates the non-linear
C equations for a given set of Y values.
IMPLICIT REAL*8CA-H,J,K,L,O-Z)
CONMON/BLKB/JFS ,AS
COMNON/BLKO/QPS , QLS
DIMENSION YC4)
C
CALL AUXSAN(Y)
IF(T.LT. 1.600)THEN
RHSF1 = JLS - .JFS + 200.00
RHSF2 = QLS - QPS + 40.00*0.6500
RHSF3 = JFS — JLS

RHSF4 = QPS - QLS
ELSEIFCT.GE. 1.500.AND.T.LE.26.500)THEN
RHSF1 = JLS — JFS - (300.00/24.00)

RHSF2 = QLS - QPS - (15.aoo/24.Do)*o.65D0
RHSF3 = JFS - JLS
RHSF4 = QPS - QLS
ELSEIF(T.GT.25.500.AND.T.LE.92.639D0)THEN
RHSF1 = JLS — iTS

RUSF2 = QLS — QPS — (15.8D0/24.D0)*o.e500
RHSF3 JFS — JLS
RHSF4 = QPS — QLS
ELSE
RHSF1 = AS - JFS
RHSF2 = QLS - QPS
RHSF3 = IFS - AS
RHSF4 = QPS - QLS
ENDIF
GOTO(10,20,30,40),I
10 RHSF = RHSF1
RETURN
20 RBSF = RHSF2
RETURN
30 RHSF = RHSF3
RETURN
40 RHSF = RHSF4
RETURN -
END

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A COMPARTMENTAL MODEL OF HUMAN MICROVASCULAR

A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF

THE REQUIREMENTS FOR THE DEGREE OF

MASTER OF APPLIED SCIENCE

We accept this thesis as conforming

THE UNIVERSITY OF BRITISH COLUMBIA

© Shuling Xie, 1992

Department of b1-’.9 e4M’1,

Date Qc-evbc-’r /3 / 992

to the interstitium by filtration according to the Starling’s hypothesis, while albumin

List of Tables viii

2 Physiological Principles Of The Microvascular Exchange System 5

3.4.3 Colloid Osmotic Pressure Relationship

3.5 Normal Steady-State Conditions

4 Parameter Estimation And Data Analysis 55

5 Results And Discussion 82

7 Future Work 123

A Raw Experimental Data 137

B Calculation Of Error Propagation 144

D Surface Plot And Contour Plot 149

E Simulations At Best-Fit Parameters 151

F List Of Computer Programs 166

2.1 Chemical composition of plasma in the human 11

3.1 Mathematical descriptions of the interstitial compliance relationship . 47

4.1 Unknowns in the coupled Starling model . . 56

5.1 Best-fit parameters corresponding to three tissue compliance relationships 84

A.1 Raw experimental data from Hubbard et al. (1984) 138

2.1 Schematic of the circulatory system in human body 7

3.1 Schematic diagram of the compartmental model of the MVES 34

4.1 Experimental data for patients with nephrotic syndrome 75

during waking hours 92

change variables 119

D.1 Surface and contour plots of the objective function 150

E.1 Simulations of a 100 mL saline or albumin infusion using compliance rela

change variables using compliance relationship #2 165

ciousness when I became a new mother.

in a very narrow range and the body functions normally.

The objectives of the current study are:

1. to formulate a coupled Starling model for describing the microvasdillar exchanges

3. to design a reliable parameter estimation procedure;

5. to validate the mathematical model.

If a reliable model of microvascular exchange system in the human can be developed,

Physiological Principles Of The Microvascular Exchange System

entire circulatory system is illustrated in Fig. 2.1.

2.1.1 Arrangement of the Capillaries

Arlercs to head and

Figure 2.1: Schematic of the circulation systems in human body [17].

2.1.2 The Composition and Properties of the Blood

40% of the total blood volume, a state of shock will be induced.

2.1.3 Structure of the Transport Barrier and the Transport Mechanisms

2.1.3.1 Capillary Wall

Constituent Concentration (g/100 mL)

Albumin 3.4 5.0

Total globulin 2.2 4.0

Hemopexin 0.05 0.1-

Ceruloplasmin 0.03 0.05

Ferritin 0.015 0.3 -

Glucose 0.07 0.11

Urea nitrogen < 0.02

Table 2.1: Chemical compositions of plasma in the human [74].

bone marrow and spleen.

2.1.3.2 Basement Membrane

The basement membrane is composed of several matrix-specific components, including