M.S. Thesis Defense
“A Dynamic Simulator for the
Management of Disorders of the
Body Water Metabolism”
by
……………
………………………….
PROBLEM DESCRIPTION &
BACKGROUND
 Regulation of body water and its appropriate distribution
throughout the body is important in almost every field of
medicine and has been thoroughly investigated in this century.
 This task is accomplished by two control systems that are
interacting in nature:

The systems that control the body water content

The systems that control the body sodium
2
PROBLEM DESCRIPTION &
BACKGROUND

Clinical Abnormalities of Body Fluid Regulation



It is important to differentiate the clinical abnormalities
of sodium content from those of the body water
regulation.
Disorders of sodium metabolism are always manifested
as disorders of volume status, e.g. Circulatory heart
failure, hepatic cirrhosis, nephrotic syndrome.
Disorders of water metabolism are clinically manifested
as disorders of blood sodium
concentration/dysnatremias, since the regulatory
systems controlling water metabolism do so by
maintaining a constant blood sodium concentration.
3
PROBLEM DESCRIPTION &
BACKGROUND
 Disorders of Water Metabolism: Dysnatremias




Under normal conditions, the blood sodium
concentration is maintained between 135-145 mEq/L,
and 105-175 mEq/L are the limits for survival.
Hypernatremia: Loss of water leads to cell shrinkage
and widespread functional disturbances
Hyponatremia/water intoxication: Accumulation of water
leads to hyponatremia, cell swelling and disturbances in
central nervous system.
Hyponatremia is the most common and potentially
serious electrolyte abnormality in hospitalized patients
(Shafiee et al., 2003). It is defined as a blood sodium
concentration of less than 135 mEq/L.
4
PROBLEM DESCRIPTION &
BACKGROUND
 Management of hyponatremia





Although most cases are mild, hyponatremia is clinically important,
and its diagnosis and subsequent management constitutes a
challenging problem, in part due to the complex nature of the body
fluid system.
Severe hyponatremia is associated with substantial mortality and
morbidity.
The main risk with hyponatremia is brain cell swelling, and requires
prompt and vigorous treatment.
Rapid correction of hyponatremia can also lead to severe
neurologic deficits and death.
To date, all the present therapies have significant limitations
improper treatment can aggravate hyponatremia (Verbalis, 2003).
Treatment should weight risks of hyponatremia against risks of
correction.
5
OBJECTIVE
 To develop a system dynamics model which
represents the structure of the body water and
sodium balance for an individual normal adult subject
 To study body water regulation and its disorders by
focusing on the fundamental feedback mechanisms
in the normal and disease physiology
 To develop an interactive simulation model for a
particular body water disorder, i.e. Water intoxication/
hyponatremia
6
METHODOLOGY – SYSTEM
DYNAMICS
 A simulation-based procedure
 Main focus: Identifying internal relations causing system
behavior
 “Predicting” the “dynamic pattern”, instead of predicting
system variables point-by-point
Population
births
 System represented by stock, flow
birth fraction
deaths
death fraction
and auxiliary variables
 Corresponds to a set of difference/differential equation
7
Background Information





Major division of the body water is into Extracellular (EC)
and intracellular compartments (IC).
The main electrolyte of EC is sodium (Na+), and main
electrolyte of IC is potassium (K+).
EC sodium concentration [mEq/L]: Amount of sodium
contained in 1 liter of EC water.
Control of EC sodium concentration is almost the same as
controlling the EC “osmolality”, the number of osmoles per
liter of water.
The concentrations of EC sodium and IC potassium are
always equal.
ECNa = ICK
EC Volume

IC Volume
The “concentration” and “content” of Na is regulated by two
different systems:
8
Control of EC Osmolality & Body
Water
 Hypothalamus controls TBW
via a negative feedback
mechanism: “thirst-ADH”
system”.
 What is the advantage of
maintaining a constant EC
osmolality in terms of water
balance ?
extracellular fluid
volume (ECFV) +
extracellular sodium
concentration
+

drinking
+
1+
filtered sodium
load
blood
volume/pressure
+
+
Antidiuretic
Hormone (ADH)
Total Body Wate r
(TBW)
3-
-
+
5+

2-
+
urine sodium
concentration
-
urine flow
+
Control of EC osmolality
+
+
controls IC volume.
glomerular filtration
sodium excreted
rate (GFR)
in urine
The constancy of the IC
volume is important for
4maintaining optimum function
of most cells, and particularly
Causal-loop diagram for body water/osmolality control
important for the brain.
by renal factors and the ADH-thirst system
9
Control of EC Volume & Body Sodium
 Na is the principal determinant of
ECV.
 Maintenance of normal ECV and
ECNa necessitates a balance
between Na+ intake and Na+
excretion:


7+
ECNa ratio to
total
Atrial
Natriuretic
Hormone
(ANH)
Mostly it is not possible to control
Na balance by regulating intake
Kidneys adjust Na excretion rate
against large variations in intake
2+
+
+
+


blood
volume/pressure
ECNa conc
3-
+
6+
Extrace llular
Sodium (ECNa)
1-
+
eff of ANF
4-
+
+
+
na out in urine +
-
Filtered load
Aldosterone Hormone
Atrial Natriuretic Hormone
glomerular filtration
rate (GFR)
filtered na load
 Na excretion mainly involves three

+
-
-
factors:
extracellular fluid
volume (ECFV)
5-
Renin
eff of ALD
Aldosterone
(ALD)
+
Simplified causal-loop diagram for sodium and ECFV regulation
10
MODEL OVERVIEW
 9 sectors under 5 sector groups
 Body Water Sector
 Sodium (Na) Sector
 Endocrine Sector Group (3 sectors)
 Antidiuretic Hormone (ADH)
 Aldosterone (ALD)
 Atrial Natriuretic Hormone (ANH)
 Urinary sodium concentration sector
 Treatment sector group (3 sectors)
 Diuretic
 Aquaretic (ADH-Antagonists)
 Saline Infusion
11
High-level Representation of the Model
Na Excretion
Sodium (Na)
Renin-ANG-ALD
ALD level
ANH
Renin Level,
ALD
Concentration
Na Excretion
ECNa
Concentration,
Na Infusion
Filtered Na Load
Diuretic
ANH Production
UNa
concentration
ADH
Production
UNa
concentration
ADH
Urinary Na Conc.
Saline Inf .
ADH
Production
Drinking, Water
Distribution,
Urine Flow Rate
Diuretic
Concentration
Water Infusion
Drinking
UNa
Concentration
ADH
Production
Body Water
Urine Flow Rate
Aquaretic (or ADH Antag…
Aquaretic Concentration
12
OVERVIEW OF THE MODEL
+
extracellular fluid
volume (ECFV)
4-
-
+
+
2-
Atrial
Natriuretic
Hormone
(ANH)
extracellular
+ osmolality
-
+ drinking
+
+
1-
+
3-
Total Body
Water (TBW)
Antidiuretic
Hormone
(ADH)
Extracellular
Sodium
(ECNa)
-
+
+
mean arterial
pressure (MAP)
-
urinary
concentration
urine flow (UFlow)
+
-
-
5+
+ na out in urine
+
aldosterone
(ALD)
Simplified causal loop diagram of the overall model
13
BODY WATER SECTOR

Drinking, insensible loss & urine flow are the routes of water
intake and excretion.

Drinking: Considered as a constant or variable rate mechanism
governed by on-off switches and inhibitory feedback. The
supposedly important effects of habit on drinking behavior are
ignored.
Urine flow rate: Directly related to Na excretion, inversely related
to UNa conc, and Na excretion rate.
Insensible loss: Water lost through evaporation.


14
BODY WATER SECTOR
pct chg ECOsm
ef f of ECOsm on drinking
~
normal drinking
Structure simulates
Total body water and its distribution between
the EC and the IC compartments,
Drinking and urine flow dynamics ...
continuous drinking
discontinuous drinking
Daily Water Intake
Gut
drinking
time to reach body
~
Glomerular Filtr Rate
~
Mean Arter Press
gut to in
Total Body Water
Intracellular Fluid Vol
pct change hy dration
~
BV
Plasma Volume
TBW
plasma f raction
insensible loss
Extracellular Fluid Vol
Blood volume as a function of EC volume
Extracellular Na \ mEq
water lost
ECNa ratio to total
urine f low
implied UFlow
IK
Urinary Na conc
min urine f low
na out in urine
15
SODIUM (Na) SECTOR


Total body Na+ and K+ are assumed to be restricted mostly
to the EC & IC compartments, K+ is assumed to be constant.
ECOsm is always proportional to EC sodium concentration and the
ICOsm is proportional to IC potassium concentration.
Only water can move freely between the IC and EC compartments to
equalize their osmolalities.

Initial states and parameters are standard values which are quoted
frequently in the major medical textbooks and in earlier models.
16
SODIUM (Na) SECTOR
Structure simulates
ECNa content and ECNa concentration
dynamics which in turn have
profound effects
on the body water distribution
and the EC volume....
ECFV
~
set point ECOsm
GFR
pct chg ECOsm
ECOsm
ECNa conc
Filtered Na
perceiv ed ALD ratio
na out in urine
normal na intake
ECNa
na intake
normal f ract
log ALD ratio
~
ef f of ALD on na excr
na out
IK
na excr ratio
IK conc
Effect of Aldosterone on Na+ excretion
~
ef f of ANH
ef f of ANH on na excr
normal na excr
ICFV
ANH ratio to normal
17
HORMONAL SECTOR GROUP
 The functions of the body are
regulated by two major
physiological systems: 1-Nervous
system and 2-Endocrine (or
hormonal) system (Guyton, 2000).
pct decrease in cap
max pool cap
pool cap
ADH clear del
ef f of ADH av ail
~
~
ef f of cap on ADH prod
ADH Pool
ADH production
actual ADH release
ADH in plasma
ADH clear
 The kidney is the common site of
action of body water & sodium
hormones.
ADH ratio to normal
ADH conc in plasma
normal ADH prod
ADH adj time
desired ADH release
normal PV
 Antidiuretic Hormone (ADH)


Regulates the EC osmolality and
the body water by changing urine
concentration.
Promotes concentration of urine
can control the reabsorption of up to
10% of the filtered water (up to 1020 liters per day!).
normal ADH conc
desired ADH in plasma
desired ADH conc
~
~
BV
ef f of BV on ADH
~
ef f of ECOsm on ADH
pct chg BV
pct chg ECOsm
normal BV
Stock-flow diagram of ADH sector
18
HORMONAL SECTOR GROUP
 Renin-Angiotensin-
Aldosterone System

Regulates EC volume by
responding changes in
blood pressure
 Atrial Natriuretic Hormone
 Regulates EC volume and
sodium by responding
changes in EC volume &
sodium distribution
19
UNa CONCENTRATION SECTOR
 Why does the kidney play with urine
concentration?
ADH ratio to normal
~
Glomerular Filtr Rate



Conservation of water and elimination of body
wastes is essential for the relative constancy of
our internal environment, since water is
continuously lost from the body .
Forming a small and concentrated urine will
minimize the required water intake to match
the continuous loss.
When there is excess water, a dilute, watery
urine is formed; otherwise urine will be
concentrated to compensate the loss of water.
ef f of ADH
~
GFRo
~
ef f of aquaretic on UNa
prc chg GFR
ExtracellularNa conc
~
implied UNa conc by ADH
ef f of GFR on UNa
implied UNa conc
~
potential escape
Normal UNa conc
max UNa conc
escape
max att UNa conc
ADH ratio to normal
Urinary Na conc
~
ef f of max att UNa on UNa
min UNa conc
 What are the factors affecting urine concentration?


ADH is the main determinant of urine osmolality
Glomerular filtration rate can influence urine osmolality by varying rate of fluid
 Main Assumptions
 Urine osmolality is assumed to be the same as UNa conc, urea is excluded
20
Integrated Body Water & Sodium
Regulation
+ extracellular fluid
volume (ECFV)
ECNa ratio to
total
+
intracellular fluid
volume (ICFV)
-
+
-
-
+
Atrial
Natriuretic
Hormone
(ANH)
ECNa conc
+
+
-
+
-
+
Total Body
Water (TBW)
Antidiuretic
Hormone
(ADH)
Extracellular
Sodium
(ECNa)
-
filtered na load
+
mean arterial
pressure (MAP)
-
-
+
-
+
+ drinking
+
urine flow (UFlow)
+
UNa conc
-
+
glomerular filtration
rate (GFR)
-
+
+
na out in urine
-
+
aldosterone
(ALD)
Overall regulation of body fluids by integrated control of body water &
body sodium regulators
21
BASE BEHAVIOR –continuous version
1: TBW
1:
2:
3:
4:
2: ECNa
1
1
2
1:
2:
3:
4:
4: MAP
1
2
4
1
2
4
4
3
4
3
key variables in the
equilibrium run..
2
4
3
3
37000
2000
138
90
0.00
Page 1
1
2
39000
2100
144
100
3
1:
2:
3:
4:
3: ECNa conc
41000
2200
150
110
9.60
19.20
28.80
38.40
48.00
Hours
Untitled
1: ALD ratio to normal
1:
2:
3:
4:
hormonal variables in
the equilibrium run..
1:
2:
3:
4:
1:
2:
3:
4:
1.00
1
3: ADH ratio to normal
4: Renin ratio
2
3
4
1
2
3
4
1
2
3
4
1
2
3
4
1
0.00
0.00
Page 1
2: ANH ratio to normal
2.00
9.60
19.20
28.80
Hours
Untitled
38.40
2
3
22
4
48.00
BASE BEHAVIOR– discontinuous version
1:
2:
3:
4:
1: TBW
40350
2134
144
110
2: ECNa
3: ECNa conc
4: MAP
1
2
1:
2:
3:
4:
40000
2132
143
100
3
1
4
3
2
4
4
Equilibria of key variables
with discontinuous
drinking...
4
1
2
1
1:
2:
3:
4:
3
2
39650
2130
141
90
3
0.00
6.00
12.00
Hours
18.00
24.00
Untitled
1: urine f low
Equilibria of drinking and
urinary excretion...
Main change in the
dynamics of the urine flow,
drinking, and the UNa
concentration
1:
2:
3:
2: UNa conc
3: drinking
150
250
4000
2
1:
2:
3:
1
75
150
2000
2
1
2
1
2
1:
2:
3:
0
50
0
3
0.00
3
6.00
1
3
12.00
Hours
Untitled
3
18.00
2324.00
BASE BEHAVIOR– discontinuous version
1: Renin ratio to normal
1:
2:
3:
4:
2: ALD ratio to normal
3: ANH ratio to normal
4: ADH ratio to normal
1.5
4
3
4
1:
2:
3:
4:
1:
2:
3:
4:
1
3
1.0
1
2
2
3
3
Equilibria of hormonal
dynamics with
discontinuous drinking..
2
4
1
2
1
4
0.5
0.00
6.00
12.00
Hours
18.00
24.00
Untitled
•ADH is the most variable hormone under normal conditions. The variation
in ADH prevents higher fluctuations in the ECNa concentration in the case
of varying fluid intake
•Almost no variation in ALD, responsible for the long term dynamics for EC
volume and sodium control.
•Medium fluctuation in ANH during the day
24
BASE BEHAVIOR – Water Loading
Base dynamics of urinary
excretion following ingestion of
1 L of water...
(a) data from Baldes and Smirk, (1934),
(b) data for eight subjects
(c) data for one subject
(taken from Uttamsingh, 1985)
1:
2:
1: urine f low rate ml\min
12.0
5.0
1:
2:
6.5
3.0
1:
2:
1.0
1.0
2: na excr ratio
1
1
1
0.00
2
2
1.00
2
2.00
Hours
1
2
3.00
4.00
Untitled
25
BASE BEHAVIOR – Water Loading
1:
2:
3:
1: TBW
41000
1.0
200
2: ADH ratio to normal
3: UNa conc
2
2
1:
2:
3:
2
1
40500
0.6
100
Base dynamics of
body water & body sodium
following ingestion of 1 L of water
(TBW in ml)
3
3
3
1
1:
2:
3:
40000
0.3
0
1
0.00
2
1.00
3
1
2.00
Hours
3.00
4.00
Untitled
Increasing urine volume
•Due to decrease in urine
concentration induced by ADH
1:
2:
3:
4:
1: ECNa
2131
2.0
1.5
143
2: ANH ratio to normal
4: ECNa conc
1
4
1
1:
2:
3:
4:
2128
1.5
1.0
141
4
4
3
Decreasing ECNa concentration
3
2
3
3
•Due to EC volume expansion
3: ALD ratio to normal
1
2
1:
2:
3:
4:
2126
1.0
0.5
140
2
1
4
2
0.00
1.00
2.00
Hours
3.00
4.00
Untitled
26
UNa conc v . urine f low : 1 300
BASE BEHAVIOR
150
0
0
200
urine f low
400
Untitled
UNa conc v . urine f low : 1 200
100
0
0
375
750
Normal physiologic relationships among EC osmolality,
urine f low
Untitled
AVP (or ADH) concentration, urine osmolality,
Simulated relationships
and urine volume in man (from Verbalis, 2003)
among urine flow and UNa concentration
Urine osmolality proportional to plasma ADH levels, Urine volume is
inversely related to urine osmolality.
27
Experiments with Changes in Daily
Water Intake- Increased water intake
1:
2:
3:
4:
1: ECNa
2130.00
142.50
103
40300
2: ECNa conc
3: MAP
Daily water intake increased
from 2,2 L. to 4,4 L.
4
4
1:
2:
3:
4:
4: TBW
1
4
4
4
3
2120.00
141.50
101
40150
Almost no change
in TBW, MAP, and the ECNa
1
3
2
1
2
1:
2:
3:
4:
2110.00
140.50
100
40000
0.00
14.40
3
2
28.80
1
43.20
2
3
1
2
57.60
3
72.00
Hours
A slight fall in ECNa concentration
142 to 141 mEq/L
Untitled
Main effect:
great fall in the UNa conc.
& consequent rise in urine flow...
1:
2:
3:
4:
1: drinking
191
250
9.00
135
2: urine f low
3: na out in urine
4: UNa conc
3
1:
2:
3:
4:
190
150
8.00
90
1
2
1
2
1
2
1
2
3
3
1:
2:
3:
4:
189
50
7.00
45
4
0.00
4
18.00
3
4
36.00
Hours
4
54.00
03:09
72.00
25 Ey l 2005 Paz
Untitled
28
Sensitivity of Blood Volume to Different
Levels of Daily Water Intake
Approximate and simulated effects
of changes in daily water intake
on blood volume (from Guyton, 2000).
Under normal conditions,
blood pressure (or blood volume)
is not affected
by changes in water intake
29
Experiments with Changes in Sodium
Intake- Increased daily Sodium Intake:
Increased ECNa conc.
stimulates thirst & drinking, urine flow
increases to match the elevated intake,
Urine is concentrated.
1:
2:
3:
4:
5:
1: water lost
165
170
130
35.00
300
2: drinking
3: urine f low
3
2
125
130
90
20.00
200
1
5
2: MAP
1
1:
2:
3:
4:
2200.00
105
144.0
40100
1:
2:
3:
4:
2100.00
95
142.0
39950
2
3
1
4
2
1
4
2
2
4
2
3
3
3
4
1
3
4
5
0.00
5
7.20
14.40
21.60
28.80
36.00
Hours
Untitled
4
1: TBW
85
90
50
5.00
100
4: TBW
3
1:
2:
3:
2
1:
2:
3:
4:
5:
3: ECNa conc
4
1
2
4
4
1: ECNa
2300.00
115
146.0
40250
5: UNa conc
1
2
3
5
1:
2:
3:
4:
5:
4: na out in urine
1
1:
2:
3:
4:
3
2: ECFV
41000
15.8
25.1
3: ICFV
2
2
2
1
0.00
9.00
18.00
Hours
27.00
36.00
Untitled
1:
2:
3:
Increased blood pressure..
Due to: shift of H2O between the
EC and the IC compartments
Daily sodium intake elevated:
from 180mEq/d to 235 mEq/d.
40500
15.4
24.8
2
3
1:
2:
3:
40000
15.0
24.4
1
1
3
3
1
0.00
12.00
1
24.00
Hours
3
36.00
48.00
Untitled
30
Sensitivity of ECNa concentration to
Different Daily Sodium Intakes
ECNa conc: 1 - 2 - 3 - 4 - 5 - 6 - 7 1:
146.50
1:
Sodium intake varied between
0.2 of normal salt intake
and 5 times normal intake,
a range of 25- fold
143.50
1:
140.50
0.00
Page 2
18.00
36.00
Hours
54.00
72.00
ECNa concentration is kept
within 1% control limits
when all feedbacks are intact
Untitled
Simulated levels of ECNa concentration with different daily sodium intakes
ECNa concentration is controlled with reasonable effectiveness
even with large changes in sodium intake,
as long as water intake is enough to balance the losses
31
Effect of ADH-thirst feedback system
on ECNa concentration
Effect of changes in sodium intake
on ECNa conc - from (Guyton, 2000)
(1) under normal conditions
(2) after the ADH-thirst feedback has been blocked
200
190
180
170
Normal
160
each one of ADH & thirst systems
can control the ECNa conc.
with reasonable effectiveness
150
ADH-thirst
blocked
140
130
120
110
if both of them are blocked
simultaneously,
ECNa conc. changes tremendously
100
0.2
0.4
0.6
0.8
1
1.3
1.6
1.9
2.3
sodium intake (times normal)
32
Effect of ALD feedback system
on ECNa concentration
Effect of changes in sodium intake
on ECNa conc - from Guyton (2000).
(1) under normal conditions
(2) after the ALD feedback has been blocked
150
148
146
144
142
ECNa concentration
almost equally well controlled
with or without ALD feedback control
Normal
140
138
ALD
blocked
136
134
132
130
0.3
0.5
0.8
1
1.2
1.5
2
2.5
3
Sodium intake (times normal)
33
Sustained Aldosterone Loading
1: TBW
1:
2:
3:
2: ECFV
3: Mean Arter Press
42000
18.0
140
1
1
1
1:
2:
3:
41000
16.5
120
1
3
3
3
3
2
2
2
2
3
2
1:
2:
3:
40000
15.0
100
1
0.00
40.00
80.00
Page 1
120.00
160.00
200.00
Hours
Untitled
1: ALD ratio to normal
1:
2:
3:
2: na excr ratio
3: ECNa conc
5
1.00
145.0
2
2
2
3
3
1:
2:
3:
4
0.60
142.5
3
1
1
1
1
50.00
100.00
Hours
150.00
3
2
1:
2:
3:
3
0.20
140.0
0.00
Page 1
Open circles indicate experimental data
of Relman and Schwartz (1952);
solid circles indicate experimental data of Davis and Howell (1953);
Taken from (Uttamsingh, 1985)
200.00
Untitled
Model generated outputs
34
Sustained Aldosterone Loading- cont.
 ALD conc. is increased to 4 times its normal and then maintained
at this elevated level
 Initial sodium retention and volume expansion due to decreased na
excretion rate
 Increase in TBW, ECFV, and MAP are limited due to “aldosterone
escape” accomplished by combined increase in the GFR, Filtered
sodium, and ANH
 ECNa concentration hardly changes from 142 mEq/L to 143 mEq/L.
ALD escape prevents excessive volume
increases in patients who have excess
amounts of ALD
35
Absence of ADH productionDiabetes Insipidus
1: TBW
1:
2:
3:
40050
147.5
101
2: ECNa conc
3: MAP
1
2
2
2
TBW can no longer be conserved
3
Blood pressure is kept constant
2
1:
2:
3:
39550
144.5
100
3
3
1
3
ECNa conc. is kept at an elevated level
3
1:
2:
3:
2
39050
141.5
98
0.00
24.00
1
1
1
48.00
72.00
96.00
Hypernatremia
120.00
Hours
Untitled
1: urine f low
Drinking behavior &
urinary excretion ....
1:
2:
3:
600.00
100.00
4000.00
1:
2:
3:
425.00
50.00
2000.00
2: UNa conc
3: drinking
1
.....periods became very frequent &
UNa concentration is very low
1
1
1
2
2
Increased water turnover:
From 2-3 L/d
up to 10-20 L/d
1:
2:
3:
250.00
0.00
0.00
3
0.00
3
6.00
2
2
3
12.00
Hours
3
18.00
24.00
Untitled
36
Water Deprivation
1: TBW
1:
2:
3:
4:
40000
170
15.0
101
2: ECNa conc
3: ECFV
4: MAP
1
Water intake decreased to 0
1
3
1:
2:
3:
4:
2
2
3
4
2
3
1
4
3
2
4
1:
2:
3:
4:
36000
140
14.5
96
1
3
2
4
0.00
Page 1
Urine flow is minimized
by maximally concentrating urine,
1
4
38000
155
14.8
98
14.40
28.80
43.20
57.60
72.00
Hours
Untitled
but continuous loss of water
cannot be compensated
without an external source of water
1: GFR
ECNa conc. increases &
TBW decreases continuously...
nonlethal range of ECNa conc.
is 115 to 175 mEq/L.
1:
2:
3:
4:
2: ADH ratio to normal
125
7
500
65
3: UNa conc
4: urine f low
1
2
3
3
3
2
1:
2:
3:
4:
124
4
313
40
1
3
1
2
1
1:
2:
3:
4:
122
1
125
15
2
0.00
Page 2
4
4
18.00
4
36.00
Hours
Untitled
4
54.00
72.00
37
Other Experiments
 Experiments with changes in daily sodium
intake
 Experiments with changes in daily water
intake
 Loss of Aldosterone (Addison’s disease)
 Test of the drinking behavior
38
THE INTERACTIVE DYNAMIC
SIMULATOR (BWATERGAME)
 Designed to allow users explore the possible effects
of therapeutic interventions for water intoxication
 Major modifications of the game:


Some sectors/structures are added to the original model for
representing the treatment options (Diuretic, Aquaretic and
Saline Infusion sectors), and the variables for game related
measurements,
Some equations and graphical functions of the original
model are modified to incorporate the effects of treatment
options or the effects of a disease process: Set-level of ADH
increased fourfold & the thirst function of the potential patient
is modified.
39
THE INTERACTIVE DYNAMIC
SIMULATOR (BWATERGAME)
 Main effects of Diuretics:
stomach v olume
~
BV
diuretic stomach conc
increase in Na excretion
and blocking the ability
of ADH
 Main effect of Aquaretics:
 decrease urine
concentration
 Saline Infusion: Hypertonic,
isotonic, hypotonic

diuretic blood conc
diuretic del
Diuretic in Blood
Diuretic in Stomach
diuretic clear del
Perceiv ed Diuretic conc
oral diuretic
clear diuretic
diuretic absorption
correct diuretic conc
diuretic abs const
oral
intrav enous diuretic
intrav enous
DOSE DIURETIC
~
Oral Dose Diuretic
ef f of diuretic on na excr
~
Intrav enous Dose Diuretic
ef f of diuretic on UNa
 Side effects..
40
Verification and validation of
newly added structures
Cumulativ e Urine Volume: 1 - 2 - 3 - 4 - 5 - 6 1:
2000
1:
1000
1:
0
0.00
Page 1
6.00
12.00
Hours
18.00
24.00
Untitled
Cumulative volume-time relationship of a series of doses of Aquaretic
in comparison to placebo (dotted lines) (Modified from Yamamura et al., 1993)
vs. Model behavior....
41
Development of hyponatremia
1: TBW
Dynamics of key indicators
when only ADH
or thirst is dysregulated..
1: TBW
1:
2:
3:
4:
5:
2: ECNa
42000
2135
142
15
103
2: ECNa
40300
2130
143
15
103
3: ECNa conc
1
4: ECFV
1:
2:
3:
4:
5:
5: MAP
5
40150
2120
142
15
101
4
5
1
1
1
1:
2:
3:
4:
5:
40000
2110
141
15
100
1
2
4
3
1
3
2
5
4
5
2
3
4
12.00
24.00
5
3
4
2
5
3
4
36.00
Page 1
5
1
5
0.00
1
5: MAP
1
5
41000
2085
139
15
101
4: ECFV
2
2
3
1:
2:
3:
4:
5:
3: ECNa conc
1:
2:
3:
4:
5:
4
48.00
60.00
Hours
Untitled
5
2
4
3
1:
2:
3:
4:
5:
40000
2035
135
15
100
2
40.00
80.00
3
120.00
1: TBW
4
3
1
0.00
Page 1
4
2
2
160.00
3
200.00
1:
2:
3:
4:
5:
2: ECNa
45000
2200
145.0
15
107
4
3: ECNa conc
5
1
4
3
Untitled
42500
2000
130.0
15
103
2
4
1
5
4
1
1:
2:
3:
4:
5:
5: MAP
2
Hours
Appearance of hyponatremia
when both ADH & thirst
are dysregulated
4: ECFV
4
5
5
5
3
1
2
3
3
2
1:
2:
3:
4:
5:
40000
1800
115.0
15
100
1
0.00
Page 1
3
2
24.00
48.00
72.00
96.00
120.00
Hours
Untitled
42
Development of hyponatremia
 Hyponatremia can be
classified into 3 basic
types depending on the
EC volume status of the
patient:

Normovolemic
(euvolemic): clinically
normal EC volume

Hypervolemic: elevated
EC volume

Hypovolemic: decreased
EC volume
43
ADH-Induced Hyponatremia (SIADH)
The most common causes of
hyponatremia are:



The SIADH (38%),
Incorrect hydration (19%),
Diuretic treatment (30%)
(Halperin and Bohn, 2002).
44
THE INTERACTIVE DYNAMIC
SIMULATOR (BWATERGAME)
45
Results of the Game Tests by Players
1: Total Body Water
1:
2:
2: Normal Body Water
47.5
1
1
ECNa concentration
1
1
1:
2:
1:
2:
Total body water
43.8
2
40.0
0.00
Page 1
1
2
32.00
2
2
64.00
96.00
2
128.00
160.00
Hours
Total body water
1: HY PERTONIC 3% SALINE
1:
2:
3:
1:
2:
3:
2: ISOTONIC SALINE
3: HY POTONIC SALINE
2000
Saline infusion
decisions
1000
1
1:
2:
3:
Page 4
Blood pressure
2
1
0
1
0.00
2
3
1
40.00
2
3
2
80.00
Hours
3
3
120.00
160.00
Untitled
46
Results of the Game Tests by Players
145
140
player1
player2
130
player3
player4
125
Dynamics of
ECNa concentration
for five players...
player5
normal
120
115
48
110
16
0
14
4
12
8
11
2
96
80
64
48
32
16
47
0
46
hours
player1
45
player3
43
player4
player5
42
normal
41
40
hours
16
0
14
4
12
8
11
2
96
80
64
48
32
39
16
Dynamics of total body water...
player2
44
0
Body Water
ECNa conc
135
47
Results of the Game Tests by Players
130
125
120
player1
MAP
115
player2
player3
110
Dynamics of mean arterial pressure
for five players..
player4
player5
105
normal
100
95
16
0
14
4
12
8
11
2
96
80
64
48
32
16
0
90
hours
Dynamics of hourly correction
rate..
48
Results of the Game Tests by Players
450
400
Na intake
350
300
player1
250
player2
Dynamics of Na+ intake
resulting from decisions.
for five players..
player3
200
player4
150
player5
100
50
0
15
2
13
6
12
0
10
4
88
72
56
40
24
8
3.5
3
hours
player1
player2
2
player3
player4
player5
1.5
1
hours
15
2
13
6
12
0
10
4
88
72
56
40
24
0.5
8
Dynamics of total water intake..
water intake
2.5
49
CONCLUSION








ADH is extremely important for control of Na concentration, yet it has a relatively
mild effect on the control of blood volume/pressure.
Arterial pressure is mainly determined by “Na intake”, rather than water intake,
which at first seems paradoxical, since arterial pressure is in fact determined by
the “water volume” of the EC compartment
Excessive secretion of either ADH or ALD does not increase body fluid volumes
infinitely, since the effects known as ‘ADH escape’ and ‘ALD escape’ protect the
body from retention of high levels of water
Effective correction of the SIADH can only be attained if a negative water
balance can be maintained. Replacing the sodium deficits alone is worthless
since blood volume/pressure conserving mechanisms cause an increased
sodium excretion rate following the intake
Graded doses of hypertonic saline infusion is the most useful solution for the
treatment, when administreded carefully to prevent an overcorrection, and
concurrently with drugs that increase the urine flow
ADH-Antagonists are superior over diuretics in SIADH in preventing edema.
The model and the game version constitute an experimental laboratory for a
closed-loop therapy approach to hyponatremia.
The game version can be used as a learning and teaching environment for the
renal physiology, and especially for the differentiation between the concepts of
“Na content” and “Na concentration”, and related disorders.
50
FURTHER RESEARCH
 Conversion of current game model for treatment of severe
hyponatremia in an intensive care unit setting

Changing the initial conditions of the modified model and the
treatment options
 Model may be extended to incorporate K+ dynamics
 Na+ and K+ regulation is coupled with levels of aldosterone
 Incorporation of urea
 Urea contributes to 40 percent of the urine osmolality
 Urea is used for the therapy of SIADH; oral urea is efficient
in producing a high osmotic diuresis in patients with the
SIADH (Decaux, 1981).
 Improved structures for drinking, e.g. short term gastric
inhibition
51
Questions and
Comments...
52