M.S. Thesis Defense M.S. Thesis Defense “A Dynamic Simulator for the Management of Disorders of the Body Water Metabolism” by …………… …………………………

M.S. M.S. ThesisThesis Defense Defense

“A Dynamic Simulator for the Management of Disorders of the Body Water Metabolism”

by……………

………………………….

2

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

3

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.

4

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.

5

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.

6

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

7

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

System represented by stock, flow and auxiliary variables

Corresponds to a set of difference/differential equation

Populationbirths deaths

birth fraction death fraction

8

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:

9

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 ?

Control of EC osmolality controls IC volume.

The constancy of the IC volume is important for maintaining optimum function of most cells, and particularly important for the brain.

Total Body Water(TBW)

extracellular fluidvolume (ECFV) +

urine flow

sodium excretedin urine

extracellular sodiumconcentration

-

AntidiureticHormone (ADH)

+

1-

urine sodiumconcentration

drinking

+

2-

+

+

glomerular filtrationrate (GFR)

filtered sodiumload

+

+

4-

+

+

3--

-

-

bloodvolume/pressure

+

+

5+

Causal-loop diagram for body water/osmolality control by renal factors and the ADH-thirst system

10

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:

Mostly it is not possible to control Na balance by regulating intake

Kidneys adjust Na excretion rate against large variations in intake

Na excretion mainly involves three factors:

Filtered load Aldosterone Hormone Atrial Natriuretic Hormone

Simplified causal-loop diagram for sodium and ECFV regulation

extracellular fluidvolume (ECFV)

Extrace llularSodium (ECNa)

ECNa conc

-

AtrialNatriureticHormone(ANH)

eff of ANF

+

6-

+


1-

filtered na load

+

3-

2+

+

bloodvolume/pressure

Aldosterone(ALD)

-

5-

4-

7-

+

eff of ALD

ECNa ratio tototal

+

++

na out in urine-

+

+

-

+

+

Renin

-

+

11

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

12

High-level Representation of the Model

ANH

Sodium (Na)

ADH

Aquaretic (or ADH Antag…

Urinary Na Conc.

Body Water

Renin-ANG-ALD

Diuretic

Saline Inf.

Na Excretion

ALD level

ANH ProductionNa Excretion

ADH Production

Na Infusion

ECNa Concentration,

Filtered Na Load

Drinking, Water Distribution,Urine Flow Rate

Water Infusion

DrinkingADH Production

ADH Production

UNa concentration

Renin Level, ALD Concentration

UNa concentration

Diuretic Concentration

Urine Flow Rate

Aquaretic Concentration

UNa Concentration

13

OVERVIEW OF THE MODEL

Total BodyWater (TBW)


+

urine flow (UFlow)

na out in urine

ExtracellularSodium(ECNa)

extracellularosmolality

-

-

AntidiureticHormone

(ADH)

+


1- -

+

urinaryconcentration

drinking

+

2-

+

+

3-

-

-

+

mean arterialpressure (MAP)

aldosterone(ALD)+

5-

-

-

4-

-

+

-

+

++

+

+

Simplified causal loop diagram of the overall model

14

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.

15

BODY WATER SECTOR

TBW

urine f low

Extracellular Fluid Vol

Extracellular Na \ mEq

IK

~

BV

discontinuous drinking

implied UFlow

~

ef f of ECOsm on drinking

Plasma Volume

min urine f low

Gut

gut to in

water lost

plasma f raction

drinking

insensible loss

pct chg ECOsm

pct change hy dration

~

Glomerular Filtr Rate

time to reach body

Intracellular Fluid Vol

continuous drinking

normal drinking

~

Mean Arter Press

Total Body Water

Daily Water Intake

na out in urine

ECNa ratio to total

Urinary Na conc

Structure simulatesTotal body water and its distribution between the EC and the IC compartments,Drinking and urine flow dynamics ...

Blood volume as a function of EC volume

16

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.

17

SODIUM (Na) SECTOR

ECNa

IK

ICFV

na intake

na out in urinenormal na intake

IK conc

ECNa conc

normal f ract

na out

pct chg ECOsm

ef f of ANH on na excr

set point ECOsm

ANH ratio to normal

na excr ratio

perceiv ed ALD ratio

normal na excr

~

ef f of ANH

ECFV~

GFR

Filtered Na

ECOsm

log ALD ratio

~

ef f of ALD on na excr

Structure simulates ECNa content and ECNa concentrationdynamics which in turn have profound effects on the body water distribution and the EC volume....

Effect of Aldosterone on Na+ excretion

18

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).

The kidney is the common site of action of body water & sodium hormones.

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 10-20 liters per day!).

ADH Pool ADH in plasmaactual ADH release ADH clear

pct decrease in cap

desired ADH conc

ADH clear del

ADH conc in plasma

desired ADH in plasma

ADH ratio to normal

pct chg BV

normal ADH conc

ADH adj time

ADH production

pool cap

normal BV

normal PV

desired ADH release

~

ef f of ADH av ail

max pool cap

~

BV

pct chg ECOsm

~

ef f of BV on ADH ~

ef f of ECOsm on ADH

normal ADH prod

~

ef f of cap on ADH prod

Stock-flow diagram of ADH sector

19

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

20

UNa CONCENTRATION SECTOR Why does the kidney play with urine

concentration?

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.

implied UNa conc

Normal UNa conc

GFRo

~

ef f of ADH

min UNa conc

ADH ratio to normal

max att UNa conc

~

Glomerular Filtr Rate

max UNa conc

prc chg GFR

~

ef f of aquaretic on UNa

ExtracellularNa conc

~

potential escape

~

ef f of max att UNa on UNaUrinary Na conc

implied UNa conc by ADH ~

ef f of GFR on UNa

escape

ADH ratio to normal

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

21

Integrated Body Water & Sodium Regulation

Overall regulation of body fluids by integrated control of body water & body sodium regulators

Total BodyWater (TBW)


+

urine flow (UFlow)

na out in urine

ExtracellularSodium(ECNa)

ECNa conc

-

-

AntidiureticHormone(ADH)

+


- -

+

UNa conc

drinking

+

-

+

+


-filtered na load

+

+

intracellular fluidvolume (ICFV)

+

-

-

ECNa ratio tototal

+

-

+

+

+

mean arterialpressure (MAP)

aldosterone(ALD)

+

-

--

-

-

-

-

+

-

+

+

+

22

BASE BEHAVIOR –continuous version

key variables in the equilibrium run..

hormonal variables in the equilibrium run..

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BASE BEHAVIOR– discontinuous version

Equilibria of key variables with discontinuous drinking...

Equilibria of drinking and urinary excretion...

Main change in the dynamics of the urine flow, drinking, and the UNa concentration

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BASE BEHAVIOR– discontinuous version

Equilibria of hormonal dynamics with discontinuous drinking..

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•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

25

BASE BEHAVIOR – Water Loading

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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)

26

BASE BEHAVIOR – Water Loading

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Base dynamics of body water & body sodium following ingestion of 1 L of water (TBW in ml)

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4Increasing urine volume

•Due to decrease in urine concentration induced by ADH

Decreasing ECNa concentration

•Due to EC volume expansion

27

BASE BEHAVIOR

Urine osmolality proportional to plasma ADH levels, Urine volume is

inversely related to urine osmolality.

Normal physiologic relationships among EC osmolality, AVP (or ADH) concentration, urine osmolality, and urine volume in man (from Verbalis, 2003)

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0

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300

UNa conc v . urine f low : 1 -

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urine f low 0 375 750

0

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UNa conc v . urine f low : 1 -

Simulated relationships among urine flow and UNa concentration

28

Experiments with Changes in Daily Water Intake- Increased water intake

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Daily water intake increasedfrom 2,2 L. to 4,4 L.

03:09 25 Ey l 2005 Paz

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1: drinking 2: urine f low 3: na out in urine 4: UNa conc

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Almost no change in TBW, MAP, and the ECNa

A slight fall in ECNa concentration 142 to 141 mEq/L

Main effect: great fall in the UNa conc. & consequent rise in urine flow...

29

Sensitivity of Blood Volume to Different Levels of Daily Water Intake

Approximate and simulated effectsof 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

30

Experiments with Changes in Sodium Intake- Increased daily Sodium Intake:

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Daily sodium intake elevated: from 180mEq/d to 235 mEq/d.

Increased ECNa conc. stimulates thirst & drinking, urine flow increases to match the elevated intake,Urine is concentrated.

Increased blood pressure..

Due to: shift of H2O between the EC and the IC compartments Untitled

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Sensitivity of ECNa concentration to Different Daily Sodium Intakes

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ECNa conc: 1 - 2 - 3 - 4 - 5 - 6 - 7 -

Sodium intake varied between 0.2 of normal salt intake and 5 times normal intake,a range of 25- fold

ECNa concentration is kept within 1% control limits when all feedbacks are intact

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

32

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

100

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0.2 0.4 0.6 0.8 1 1.3 1.6 1.9 2.3

sodium intake (times normal)

Normal

ADH-thirstblocked

each one of ADH & thirst systems can control the ECNa conc. with reasonable effectiveness

if both of them are blocked simultaneously, ECNa conc. changes tremendously

33

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

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0.3 0.5 0.8 1 1.2 1.5 2 2.5 3

Sodium intake (times normal)

Normal

ALDblocked

ECNa concentration almost equally well controlled with or without ALD feedback control

34

Sustained Aldosterone Loading

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1: TBW 2: ECFV 3: Mean Arter Press

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Open circles indicate experimental data of Relman and Schwartz (1952); solid circles indicate experimental data of Davis and Howell (1953);

Taken from (Uttamsingh, 1985)

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Model generated outputs

35

Sustained Aldosterone Loading- cont.

ALD escape prevents excessive volume increases in patients who have excess amounts of ALD

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.

36

Absence of ADH production- Diabetes Insipidus

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TBW can no longer be conserved

ECNa conc. is kept at an elevated level

Hypernatremia

Blood pressure is kept constant

Drinking behavior & urinary excretion ....

.....periods became very frequent &UNa concentration is very low

Increased water turnover:From 2-3 L/d up to 10-20 L/d

37

Water Deprivation

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Water intake decreased to 0

Urine flow is minimized by maximally concentrating urine,

but continuous loss of water cannot be compensated without an external source of water

ECNa conc. increases &TBW decreases continuously...

nonlethal range of ECNa conc.is 115 to 175 mEq/L.

38

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

39

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.

40

THE INTERACTIVE DYNAMIC SIMULATOR (BWATERGAME)

Main effects of Diuretics: increase in Na excretion

and blocking the ability

of ADH Main effect of Aquaretics:

decrease urine concentration

Saline Infusion: Hypertonic, isotonic, hypotonic

Side effects..

~

ef f of diuretic on na excr

Diuretic in Blood

intrav enous diuretic

clear diuretic

diuretic clear del

diuretic blood conc

diuretic absorptionPerceiv ed Diuretic conc

correct diuretic conc

diuretic del

DOSE DIURETIC

~

ef f of diuretic on UNa

Diuretic in Stomach

oral diuretic

diuretic abs const

stomach v olume

oral

diuretic stomach conc

intrav enous

~

BV

Oral Dose Diuretic

Intrav enous Dose Diuretic

41

Verification and validation of newly added structures

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Cumulativ e Urine Volume: 1 - 2 - 3 - 4 - 5 - 6 -

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....

42

Development of hyponatremia

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1: TBW 2: ECNa 3: ECNa conc 4: ECFV 5: MAP

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Dynamics of key indicators when only ADHor thirst is dysregulated..

Appearance of hyponatremia when both ADH & thirst are dysregulated

43

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

44

ADH-Induced Hyponatremia (SIADH)

The most common causes of hyponatremia are:

The SIADH (38%), Incorrect hydration (19%), Diuretic treatment (30%)

(Halperin and Bohn, 2002).

45

THE INTERACTIVE DYNAMIC SIMULATOR (BWATERGAME)

46

Results of the Game Tests by Players

Total body water

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1: Total Body Water 2: Normal Body Water

1

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1: HYPERTONIC 3% SALINE 2: ISOTONIC SALINE 3: HYPOTONIC SALINE

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ECNa concentration

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Blood pressure

Saline infusion decisions

47


110

115

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145

0 16 32 48 64 80 96 112

128

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hours

EC

Na

co

nc

player1

player2

player3

player4

player5

normal

Dynamics of ECNa concentrationfor five players...

39

40

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Bo

dy

Wa

ter

player1

player2

player3

player4

player5

normalDynamics of total body water...

48


Dynamics of hourly correction rate..

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MA

P

player1

player2

player3

player4

player5

normal

Dynamics of mean arterial pressurefor five players..

49


Dynamics of total water intake..

Dynamics of Na+ intake resulting from decisions.for five players..

0

50

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Na

inta

ke

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player2

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player4

player5

0.5

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3

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8 24 40 56 72 88 104

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wat

er in

take

player1

player2

player3

player4

player5

50

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.

51

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

52

Questions and Comments...

Documents

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