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Research ArticleApplication of Mathematical Modeling for Simulationand Analysis of Hypoplastic Left Heart Syndrome (HLHS) inPre- and Postsurgery Conditions
Ali Jalali,1 Gerard F. Jones,1 Daniel J. Licht,2 and C. Nataraj1
1Department of Mechanical Engineering, Villanova University, Villanova, PA 19085, USA2Neurovascular Imaging Lab, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Correspondence should be addressed to Ali Jalali; ali.jalali@villanova.edu
Received 4 September 2014; Accepted 19 February 2015
Academic Editor: Joakim Sundnes
Copyright ยฉ 2015 Ali Jalali et al.This is an open access article distributed under the Creative Commons Attribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
This paper is concerned with the mathematical modeling of a severe and common congenital defect called hypoplastic left heartsyndrome (HLHS). Surgical approaches are utilized for palliating this heart condition; however, a brain white matter injury calledperiventricular leukomalacia (PVL) occurs with high prevalence at or around the time of surgery, the exact cause of which isnot known presently. Our main goal in this paper is to study the hemodynamic conditions under which HLHS physiology maylead to the occurrence of PVL. A lumped parameter model of the HLHS circulation has been developed integrating diffusionmodeling of oxygen and carbon dioxide concentrations in order to study hemodynamic variables such as pressure, flow, and bloodgas concentration. Results presented include calculations of blood pressures and flow rates in different parts of the circulation.Simulations also show changes in the ratio of pulmonary to systemic blood flow rates when the sizes of the patent ductus arteriosusand atrial septal defect are varied. These changes lead to unbalanced blood circulations and, when combined with low oxygen andcarbondioxide concentrations in arteries, result in poor oxygen delivery to the brain.We stipulate that PVLoccurs as a consequence.
1. Introduction
Hypoplastic left heart syndrome (HLHS) is a congenital heartdefect (CHD) in which the left side of the heart is severelyunderdeveloped. Without early surgical palliation HLHS isuniversally fatal [1]. HLHS results from a failure of the aorticor mitral valve to form. Lack of antegrade flow through thevalves causes insufficient growth of both the left ventricle andthe ascending aortic arch. A typical HLHS heart is comparedwith a normal heart in Figure 1.
Underdevelopment of the left ventricle-aorta complexresulting in critical aortic valve stenosis or aortic valve atresiawith an intact ventricular septum is themost recognized formof HLHS. There are corresponding changes in the right sideof the heart in the case of HLHS. All right sided cardiacstructures are larger than normal including the right atrium,pulmonary artery, and pulmonary valve [2].
As blood returns from the lungs to the left atrium, itmust pass through an atrial septal defect to the right side of
the heart. In cases of HLHS, the right side of the heart mustpump blood to the body through a patent ductus arteriosus(PDA). This maintains fetal parallel circulation where theright ventricle is the only active pump [3]. But, since theductus arteriosus (DA) usually closes within eleven days afterbirth, for an HLHS baby, blood flow is severely compromisedleading to very low circulation and possible death. Hence,the management of neonates with HLHS is very complex.Treatment generally commences with vigorous infusion ofprostaglandin to prevent the PDA from closing. However,reduction in pulmonary resistance after birth results in anunbalanced circulation where most of the blood goes into thepulmonary circulation thereby compromising the systemicoxygen supply. A typical way to treat this disease is shuntsurgery. A shunt is a surgically created connection betweenthe systemic arterial circulation and the pulmonary arteries.Authors in [4] present a good survey of shunt modeling andits application in planning the surgery.
Hindawi Publishing CorporationBioMed Research InternationalVolume 2015, Article ID 987293, 14 pageshttp://dx.doi.org/10.1155/2015/987293
2 BioMed Research International
Normal heart
(a)
Hypoplastic leftheart syndrome
(A)(B)
(C)
(b)
Figure 1: Comparison between normal heart on the left and HLHS heart on the right. (A) is atrial septal defect, (B) is hypoplastic heart, and(C) is patent ductus arteriosus.The left ventricle is very small.The aortic arch is extremely hypoplastic and flow is retrograde. Systemic outputis ductal dependent. Adapted from wikipedia.
The need for a detailed study of the problem of HLHSstems from our recent studies [5โ7] to predict the occurrenceand extent of periventricular leukomalacia (PVL) after Nor-wood surgery in neonates. The PVL is a form of white matterbrain injury, characterized by necrosis (more often coagula-tion) of white matter near the lateral cerebral ventricles. Itcan affect newborns and (less commonly) fetuses; prematureinfants are at the greatest risk of the disorder. Affectedindividuals generally exhibitmotor control problems or otherdevelopmental delays, and they often develop cerebral palsyor epilepsy later in life [8]. Despite being full-term infants,PVL is found in more than 50% of the neonates after cardiacsurgery [1, 9]. As there has been a dramatic reduction inmortality rates following surgery for complex CHDs, therehas been an increasing recognition of adverse neurodevel-opmental sequelae in some survivors. Evaluation of childrenfollowing neonatal repair of CHD demonstrates long termneurodevelopmentalmorbidity and learning disability in sur-vivors of these infant heart surgeries. Management strategiesbefore, during, and after surgery including the type of supportduring operation have been implicated as factors in postoper-ative neurodevelopmental dysfunction. Deficiency in oxygencirculation and low carbon dioxide concentrations (๐CO
2
)have also been considered as important factors affecting themorbidity rates of neurodevelopmental dysfunction [6].
In our previous work in the field of PVL prediction, wehave applied computational intelligence techniques to thedata obtained from 59 patients which were collected at theChildrenโs Hospital of Philadelphia (CHOP). Computationalintelligence (CI) is a set of nature-inspired computational
methodologies, examples of which include Fuzzy Logic sys-tems, Neural Networks, and Evolutionary Computation. Thedecision trees that we have developed suggest some ranges forcritical hemodynamic parameters, such as oxygen concentra-tion and blood pressure, which predict a high probability forthe occurrence of PVL [5, 10, 11]. But since these numbershave been obtained from a retrospective review of limitedset of subjects, they cannot be used as a general applicablecriterion for all neonates. Hence, it is important to carry outphysiological modeling of the cardiovascular system to beginto understand the underlying causal relationships between aparticular set of parameters with the occurrence of PVL.
In this paper a lumped parameter model of the HLHScirculation has been developed to study blood pressure andflow in different parts of the cardiopulmonary circulationsystem. The diffusion modeling of oxygen (O
2) and carbon
dioxide (CO2) is also included in themodel. Changes induced
in O2and CO
2concentrations and variation of blood flow
rates in different parts of the body due to changes in someimportant model parameters have also been studied.
2. Pressure Flow Model
Several lumped parameter models of the cardiovascular sys-tem have been developed in past research, for instance, [12โ14].This paper differs frompreviously developed cardiovascu-lar models in that this model is tailored to the uniquephysiology of the HLHS heart in comparison to the abundantliteraturewhich dealswith the simulation of the normal heart.Furthermore, this model combines blood gas modeling with
BioMed Research International 3
PVB
PDA
PABPA
Hypoplastic heart
RV
PV
LA
ASD
RA
Pulmonary circulation
Systemic circulation
DASABSVBSLV
Figure 2: Lumped parameter model of HLHS. Model is made up of three parts: (a) hypoplastic left heart, (b) pulmonary circulation, and (c)systemic circulation. Direction of blood flow is shown by arrows. ASD: atrial septal defect; RA: right atrium; LA: left atrium; TV: tricuspidvalve; RV: right ventricle; PV: pulmonary valve; PA: pulmonary artery; PAB: pulmonary arterial bed; PVB: pulmonary venous bed; PDA:patent ductus arteriosus; DA: descending aorta; SAB: systemic arterial bed; SVB: systemic venous bed; SLV: systemic large veins.
the circulation model to represent a more comprehensivemodel of the HLHS physiology. Moreover, by using para-metric analysis in this study we have been able to track thechanges in the heart for before and after surgery conditions.Like all other lumped parametermodels, thismodel is limitedby simplification assumption that it makes, for example,overlooking solid fluid interactions of arteries and blood flowand Newtonian flow assumption. For this work the lumped-parameter approach used to model the HLHS circulation isshown in Figure 2. Each box represents a lumped parametermodel for a complex system of blood vessels and heartcomponents. This model is built based on methodologiespreviously published for the fetal [15] and neonatal cerebralcirculation [16โ19] and the Norwood procedure [20, 21]. Thecomplete model is composed of threemain parts: a hypoplas-tic left heart, systemic circulation, and pulmonary circulation.Each compartment is made of resistances, capacitances, andinductances. Resistances are used to model the flow in thearteries and veins, and capacitors are used to represent theelasticity of these vessels. Inductors are not typically used formodeling the flow in the veins because veins do not functionprimarily in a contractile manner and so their inductance
values are considered to be negligible in comparisonwith thatof the arteries.
2.1. Hypoplastic Heart. The heart has been assumed to becomposed of three parts: right atrium (RA), left atrium (LA),and right ventricle (RV). Here, as mentioned earlier, we haveconsidered the most severe case of the hypoplastic heartin which the left ventricle is completely blocked (the mostcommon form of HLHS ismitral atresia/aortic atresia; atresiaimplies no flow through the valve). Hence the left ventricle isnot taken into consideration in the model.
The activity of the heart is modeled following the treat-ment in [22]. For both the atria and the ventricle, the totalpressure is expressed as a nonlinear function of the volumeand cycle-time:
๐ (๐ก) = ๐๐ (๐ก) + ๐
๐(๐ก) , (1)
where๐๐ = ๐ผ (๐ก) ๐ธmax (๐ (๐ก) โ ๐
๐ข) ,
๐๐= (1 โ ๐ผ (๐ก)) ๐
0(๐๐พ๐โ ๐(๐ก)
โ 1) .
(2)
4 BioMed Research International
๐ is the pressure, ๐ is volume, ๐๐ขis the unstressed volume,
and ๐ธmax is the maximum elasticity of the heart wall duringthe heart cycle. The activation function ๐ผ is the driving forceof the heart andmodels the release of Ca2+ which initiates thecontraction of the heart muscle [23].
Since the heart muscleโs contraction is different for systoleand diastole cycles, the activity function is defined by differ-ent differential equations in the systole and diastole. Duringdiastole, the activation function is defined by the following:
๐๐ผ
๐๐ก= โ๐พ๐๐ผ, (3)
where ๐พ๐is the relaxation rate. For the systole period it is
defined by the following:
๐2๐ผ
๐2๐ก+ 2๐พ๐
๐๐ผ
๐๐ก+ ๐พ2
๐๐ผ = ๐พ
2
๐๐ผmax, (4)
where ๐พ๐is the excitation rate and ๐ผmax is the limiting value
of the activation function. The solutions to the above lineardifferential equations yield the following:
๐ผ (๐ก) = ๐ผ (๐ก๐) ๐โ๐พ๐(๐กโ๐ก๐),
๐ผ (๐ก) = ๐ผmax โ (๐ผmax โ ๐ผ (๐ก๐ )) (1 + ๐พ
๐(๐ก โ ๐ก๐ ))
โ ๐โ๐พ๐(๐กโ๐ก๐ ),
(5)
where ๐ก๐ is the systole time and ๐ก
๐is the onset of diastolewhich
we set equal to zero assuming the heart cycle starts fromonsetof diastole. This assumption is just for convenience and doesnot impact generalization of themodel.The parameter valuesof ๐ก๐ , ๐พ๐, ๐พ๐, and ๐ผmax are different for ventricles and atria
and are shown in Table 1 [23]. The activation functions arefunctions of time for the ventricle and the atrium and areshown in Figure 3.
The ๐ธmax is a function of volume of the ventricle toaccount for the decreasing elastance with increasing volume[20]. Consider
๐ธmax = ๐ธ1+ ๐ธ2(๐ (๐ก) โ ๐
๐ข) , (6)
where ๐ธ1is constant; ๐ธ
2is a negative-valued constant to
account for decreasing elastance of the ventricle. ๐ธ2is zero
for the atria resulting in a constant ๐ธmax, consistent with theliterature. Again, ๐
๐ขis the unstressed volume of the chamber
which is the volume at zero pressure.This is the ๐ฅ-intercept of the tangent at the end-systolic
point for the pressure-volume (๐-๐) curve. For the diastole,the ventricle and atria fill through an exponential ๐-๐function reflected in the equations below.
Hence, for maximum isometric pressure, we have [22]
๐isomax,RA (๐ก) = ๐ผ๐RA (๐ก) ๐ธ1,RA (๐RA (๐ก) โ ๐
๐ข,RA)
+ (1 โ ๐ผ๐RA (๐ก)) ๐0,RA (๐
๐พ๐โ ๐RA(๐ก) โ 1) ,
๐isomax,LA (๐ก) = ๐ผ๐LA (๐ก) ๐ธ1,LA (๐LA (๐ก) โ ๐
๐ข,LA)
+ (1 โ ๐ผ๐LA (๐ก)) ๐0,LA (๐
๐พ๐โ ๐LA(๐ก) โ 1) ,
Table 1: Heart model parameters.
Parameters ValuesRight atrium
๐ธ1, RA 7.35mmHg/mL
๐0, RA 0.17mmHg
๐พ๐, RA 0.484mLโ1
๐๐ข, RA 1mL
Left atrium๐ธ1, LA 7.35mmHg/mL
๐0, LA 0.17mmHg
๐พ๐, LA 0.484mLโ1
๐๐ข, LA 1mL
Right ventricle๐ธ1, RV 8.5mmHg/mL
๐ธ2, RV โ0.042mmHg/mL2
๐0, RV 0.9mmHg
๐พ๐, RV 0.062mLโ1
๐๐ข, RV 4mL
ASD๐ ASD 0.1mmHgโ sโ mLโ1
Tricuspid valve๐พTric 0.0006mmHgโ s2โ mLโ1
Pulmonary valve๐พPV 0.0008mmHgโ s2โ mLโ1
Activation function๐พ๐(ventricle) 51
๐พ๐(atrium) 75
๐พ๐
55๐ก๐ (ventricle) 0.193 s
๐ก๐ (atrium) 0.173 s
๐ผmax (ventricle) 150๐ผmax (atrium) 130
๐isomax,RV (๐ก) = ๐ผ๐RV (๐ก) (๐ธ1,RV + ๐ธ
2,RV (๐RV (๐ก) โ ๐๐ข,RV))
โ (๐RV (๐ก) โ ๐๐ข,RV) + (1 โ ๐ผ
๐RV (๐ก)) ๐0,RV
โ (๐๐พ๐โ ๐RV(๐ก) โ 1) ,
(7)
where ๐ผ๐is normalized ๐ผ. The atria and ventricles are
modeled with variable capacitors to account for the time-dependent relationship of pressure with volume and alsoviscous losses. A flow resistance has been introduced betweenthe right and left atria to account for the defect in the wallsof the heart permitting a mixing of blood flow between theatria. In the present work, this mixing has been modeledas an orifice unlike [24] where it was modeled as a simpleresistor.The reason for modeling ASD as a variable nonlinearresistor instead of as a simple linear resistor is because of itsvery small diameter in comparison with other compartmentswhich leads to a nonnegligible nonlinearity. A nonlinear
BioMed Research International 5
0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 0.45 0.5โ1
0
1
2
3
4
5
Time (s)
Heart muscle activation function
VentricleAtrium
๐ผ(t
)
Figure 3: Ventricular and atrial activation functions.
pressure flow relationship (Darcy-Weisbach equation) is usedas follows:
ฮ๐ (๐ก) = ๐พASD โ ๐ (๐ก)2. (8)
The tricuspid and the pulmonary valves are also modeledas unidirectional orifices (diodes) and a similar pressure flowrelationship has been used for them. This model representsan idealized situation since, in reality, the tricuspid valve doesleak sometimes and the flow is not completely unidirectional.
2.2. Pulmonary Circulation. The pulmonary circulation isdivided into three compartments: proximal pulmonary arter-ies (PA), pulmonary arterial bed (PAB), and pulmonaryvenous bed (PVB). The PA and PAB are modeled using ๐ ๐ฟ๐ถand PVB by ๐ ๐ถ circuits. All these circuit elements haveconstant values. Flow enters into the PA from the pulmonaryvalve and the blood flows out to the left atrium (LA). Itshould be noted that the PDA is present in the newbornwhichnormally closes after 5โ10 days. To model it, a nonlinearresistor is added between the pulmonary artery and theaorta. The addition of the PDA to the model is anothermajor difference between this model and other previouslydeveloped models; this is especially important in the currentstudy because of our focus on HLHS.
2.3. Systemic Circulation. The systemic circulation is dividedinto four compartments: descending aorta (DA), systemicarterial bed (SAB), systemic venous bed (SVB), and systemiclarge veins (SLV). The DA and SAB are modeled by ๐ ๐ฟ๐ถ andSVB and SLV are modeled by ๐ ๐ถ circuits. Blood comes infrom the PDA and flows to the right atrium.
2.4. Fluid Flow. For each compartment, time-dependentvariables, such as pressure in the capacitance, are expressedas differential equations and since these equations cannot
RL
C
QoutQin P1 P2
Figure 4: Simple RLC compartment to describe model. ๐ ispressure; ๐ฟ (inductance) accounts for blood inertance;๐ (resistance)accounts for resistance to blood flow; ๐ถ (capacitance) accounts forcompliance.
be solved analytically, numerical integration is used. Thisapproach calculates solutions with variable time steps toavoid mathematical instability that would lead to divergenceof the solution. For every RLC compartment shown inFigure 4, analysis has been carried out as shown.
The relationship between pressure and volume in thecapacitor leg in Figure 4 can be calculated using the following:
๐๐ (๐ก) =๐๐ (๐ก)
๐ถ, (9)
where ๐๐(๐ก) is the change in the compartment volumecalculated from the pressure differential.The pressure change๐1โ ๐2in Figure 4 is given by the following:
๐1(๐ก) โ ๐
2(๐ก) = ๐ ร ๐out + ๐ฟ
๐๐out๐๐ก
. (10)
Hence, for every compartment, the change in the output flowrate is expressed using the following equation:
๐๐out๐๐ก
=๐1(๐ก) โ ๐
2(๐ก) โ ๐out ร ๐
๐ฟ. (11)
ASD is assumed to be a variable nonlinear resistor; therefore,we can write the relationship between๐ and pressure changethrough Darcy-Weisbach equation:
๐ASD =
{{{{{{
{{{{{{
{
โ๐RA โ ๐LA๐พASD
๐RA > ๐LA
โ๐LA โ ๐RA๐พASD
๐LA > ๐RA,
(12)
where ๐RA and ๐LA are the right and left atrial pressures,respectively. By assuming realistic initial values, numericalintegration is carried out for a sufficient number of heartcycles to achieve steady-periodic values for every parameter.The PDA flow rate is estimated from the following:
๐PDA =๐PA โ ๐Aorta
๐ PDA, (13)
where ๐PA and ๐Aorta are the pulmonary artery and descend-ing aorta pressures, respectively.
6 BioMed Research International
2.5. Oxygen and Carbon Dioxide Diffusion Modeling in theVascular System. Theoxygen diffusion takes place from lungsto the alveolar capillaries and then from the blood capillariesto the body tissues. At steady state, the oxygen release anduptake will be equal, and hence we need to model only onediffusion process to find the partial pressures. The processof oxygen diffusion modeling is the same as what has beendone in [20] but carbon dioxide calculation is added inour model. The reason for including CO
2diffusion to the
model is that our previous findings have suggested bloodCO2
concentration to be an important parameter in prediction ofthe PVL occurrence.
On the whole, the oxygen uptake and release equationscan be written as was done in [25]. Consider
๐๐(๐ถpvO
2
โ ๐ถ๐O2
) = SVO2,
๐๐ (๐ถ๐O2
โ ๐ถVO2
) = CVO2,
SVO2= CVO
2,
(14)
where SVO2is the oxygen uptake rate in the lungs expressed
in mL/min, and it is specified as an input to the system,CVO2is the whole body oxygen consumption, ๐ถpvO
2
isoxygen concentration in the pulmonary vein, ๐ถ
๐O2
is oxygenconcentration in the aorta, and ๐ถVO
2
is oxygen concentrationin the veins. Since the PDA concentration of oxygen in aortaand pulmonary artery is equal, we simply replace oxygencontent in the pulmonary artery with its value in the aorta inthe second equation. It should be noted that this assumptionis only true for the MA (atresia) patients.
The term ๐๐is the average pulmonary flow obtained by
taking an average of ๐ASD (atrial septal defect flows) overmultiple cardiac cycles. There are two reasons. Firstly, understeady state conditions, all the pulmonary venous return flowpasses through the ASD and pulmonary venous flow is equalto pulmonary flow. Hence, on average atrial septal defect flowand pulmonary flow are equal. Secondly, a large fraction of(ideally half) the pulmonary artery flow goes to aorta, andhence, to find the average pulmonary flow, it is more reliableto calculate ๐ASD. Similarly, ๐
๐is the average systemic flow
obtained by taking an average of PDA over the heart cycles.Oxygen exchange in alveoli can be modeled using Hillโs
approach [26]. Oxygen in the blood is determined by theamount of oxygenated hemoglobin (98%) and the oxygendissolved in blood (2%). So, the total volume of blood oxygenconcentration (๐ถ
๐O2
) depends on the saturated blood oxygen(๐๐O2
) and the partial pressure of blood oxygen (๐๐O2
) bythe model from [16]; this is shown in (15). The term ๐ฝ isthe concentration of O
2in the blood hemoglobin at 100%
saturation and the term ๐พ is concentration of dissolved O2.
๐ฝ and ๐พ have units of mLโ mLโ1mmHgโ1 and the unit ofconcentration is mL/mL. One has
๐ถ๐O2
= ๐ฝ โ ๐๐O2
+ ๐พ โ ๐๐O2
. (15)
Differentiating (15), we get the following:๐๐ถ๐O2
๐๐ก= ๐ฝ โ
๐๐๐O2
๐๐ก+ ๐พ โ
๐๐๐O2
๐๐ก. (16)
The relationship between oxygenized hemoglobin anddissolved oxygen is given by the oxygen dissociation curve:
HbO2= ๐๐O2
=
(๐๐O2
/๐50)๐
1 + (๐๐O2
/๐50)๐, (17)
where HbO2is the oxygenized hemoglobin, ๐50 is the partial
pressure of oxygen at 50% saturation (๐๐O2
= 0.5), and ๐
is a constant. Differentiating the above equation, we get thefollowing:
๐๐๐O2
๐๐ก= (
๐๐๐O2
๐๐๐O2
)(
๐๐๐O2
๐๐ก) , (18)
where
(
๐๐๐O2
๐๐๐O2
) =1
๐50
๐ ร (๐๐O2
/๐50)๐โ1
(1 + (๐๐O2
/๐50)๐
)2. (19)
By combining the above equations, we have the following:
๐๐ถ๐O2
๐๐ก=
๐๐๐O2
๐๐ก(๐พ + ๐ฝ(
๐๐๐O2
๐๐๐O2
)) . (20)
Assuming that oxygen in the capillaries of the lungs is at aconstant partial pressure of 150mmHg and that there is acontinuous oxygen transfer from the lungs to the pulmonaryblood capillaries, if we take the volume in the capillaries asa single unit with a volume ๐cap, then the time available forthe transfer of oxygen to blood capillaries can be assumed tobe the time taken for the pulmonary flow to fill the capillaryvolume, ๐cap. One has
๐ก = (
๐cap
๐๐
) , (21)
where๐๐is the pulmonary flow rate. At any point of time, the
diffusion flux from the lungs to the blood capillaries is givenby the following:
๐ทO2
= ๐ท๐ฟO2
(๐alv๐2
โ ๐๐๐2
) , (22)
where ๐ท๐ฟO2
is the total lung diffusion capacity for oxygen.The diffusion flux of oxygen ๐ทO
2
will lead to a change inthe concentration of the volume in the blood capillaries, andhence we could write
๐ทO2
= ๐cap๐๐ถ๐O2
๐๐ก. (23)
Thus, we have the following:
๐cap๐๐ถ๐O2
๐๐ก= ๐ท๐ฟO2
(๐alvO2
โ ๐๐O2
) . (24)
Substituting for ๐๐ถ๐O2
/๐๐ก we get
๐cap๐๐๐O2
๐๐ก(๐พ + ๐ฝ(
๐๐๐O2
๐๐๐O2
)) = ๐ท๐ฟO2
(๐alvO2
โ ๐๐O2
) . (25)
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Hence, at any instant, the change in the partial pressureof oxygen in blood capillaries by diffusion is given by thefollowing:
๐๐๐O2
๐๐ก=
๐ท๐ฟO2
(๐alvO2
โ ๐๐O2
)
๐cap (๐พ + ๐ฝ (๐๐๐O2
/๐๐๐O2
))
. (26)
Integrating this equation over the limits, by using the numer-ical trapezoidal integration method with a time step of 0.01 s,
โซ
๐pvO2
๐๐O2
(๐พ + ๐ฝ (๐๐๐O2
/๐๐๐O2
))
(๐alvO2
โ ๐๐O2
)
๐๐๐O2
=
๐ท๐ฟO2
๐capโซ
๐cap/๐๐
0
๐๐ก,
(27)
where๐pvO2
is the partial pressure of oxygen in the pulmonaryveins. Since this is a complex function of ๐
๐๐2
, integration iscarried out numerically. An estimated value of ๐
๐๐2
is usedas an initial guess and the value of ๐pvO
2
is calculated fromthe integral. If (27) is not satisfied, an improved value of๐๐O2
is chosen and integration is repeated. This procedureis continued until (27) is satisfied to the required level ofaccuracy. The values of ๐
๐O2
and ๐pvO2
are checked to satisfythe integral equation and if the left hand side of (27) turnsout to be less (or more) than the right hand side, then theintegration is carried out again with a lower (or higher) value.This process is repeated until the equation is satisfied to therequired level of accuracy. Using the final value of ๐
๐O2
andoxygen release equation, the value of ๐VO
2
is calculated.The exchange modeling for CO
2has been implemented
using the same approach as we used for oxygen. The onlydifference is that the CO
2is released in the lungs and it is
taken up by the blood from the body tissues. Hence, we have
๐๐(๐ถ๐CO2
โ ๐ถpvCO2
) = SVCO2,
๐๐ (๐ถVCO
2
โ ๐ถ๐CO2
) = CVCO2,
SVCO2= CVCO
2,
(28)
where SVCO2is the CO
2release rate in the lungs expressed in
mL/min, and it is specified as an input to the system, CVCO2
is the whole body CO2release rate, ๐ถpvCO
2
is CO2con-
centration in the pulmonary vein, ๐ถ๐CO2
is CO2concentra-
tion in the aorta, and๐ถVCO2
is CO2concentration in the veins.
Referring to [17, 18] for the relationship of concentrationof CO
2to its partial pressure at a temperature of 37โC and
pH =7.4 andneglecting the effect of oxygen saturation (whichis reasonable), we get
๐ถ๐CO2
= 0.009083๐๐CO2
, (29)
๐๐ถ๐CO2
๐๐ก= 0.009083
๐๐๐CO2
๐๐ก, (30)
where ๐ถ๐CO2
is the blood CO2concentration in mL/mL. The
diffusion equation for CO2becomes
๐cap๐๐ถ๐CO2
๐๐ก= ๐ท๐ฟCO2
(๐alvCO2
โ ๐๐CO2
) , (31)
where ๐ท๐ฟCO2
is diffusion capacity of lung for CO2which is
known and ๐alvCO2
is alveolar pressure of CO2, which is set to
41mmHg. Using (30) and (31), and after integration, we have
โซ
๐pvCO2
๐๐CO2
0.009083
(๐alvCO2
โ ๐๐CO2
)
๐๐๐O2
=
๐ท๐ฟCO2
๐capโซ
๐cap/๐๐
0
๐๐ก. (32)
Equation (32) is numerically integrated with an initial valueof ๐๐CO2
such that the value of ๐pvCO2
satisfies carbon dioxiderelease equation in the lungs. It is iterated until the equationis satisfied with a certain level of accuracy. Again, using thevalue of๐
๐CO2
and using the equation of carbon dioxide takenup by the blood, we get a solution for ๐pvCO
2
.
2.6. Parameter Values. The parameter values for the caseof a newborn HLHS patient were taken from a child afterstage 1 circulation with a neoaorta and a Blalock-Taussigshunt replacing the PDA [20]. Since the first step Norwoodprocedure is applied for a child in his/her early few weeks,the parameter values for these infants would be comparable;these values are listed in Tables 1โ3. It should be noted that๐ ASD,๐ PDA, and๐ PA are the only variableswhich change post-operatively; we performan analysis by varying the parametersto include a wide range of patients.
The value of the resistance for the pulmonary arteries isalmost a hundred times that which is used in [20]. This isan estimated value to show very severe conditions. This isbecause, for a newborn baby, it is well known that pulmonaryresistance is very high, falls precipitously after the first breath,and continues to fall over the first few weeks of his life.The average body surface area (BSA) for an adult male isaround 1.5m2 and the average surface area for a newbornchild is 0.30m2. Hence a scaling factor of five can be assumedwhile estimating some of the parameters for a child fromthe parameters of an adult. Although this method is widelyused by clinicians in estimating the parameters, it brings someuncertainty to the model; hence, a parametric analysis hasbeen carried out in order to understand the effect of thosevariables on the outputs.
The oxygen consumption rate in an average adult is300mL/min [24] and hence the average oxygen consump-tion rate in a child can be assumed to be approximately60mL/min. The total lung diffusion capacities for O
2and
CO2are 62mL/min (mmHg)โ1 and 478mL/min (mmHg)โ1,
respectively, for an adult. Considering the scaling factor of 5and the fact that the diffusion capacity is inversely propor-tional to the square of the surface area, we have a diffusioncapacity for a child for O
2and CO
2as 2.5mL/min (mmHg)โ1
and 19mL/min (mmHg)โ1, respectively. Average CO2release
rate by an average adult is 400mL/min, and hence the averagerelease rate for a child is 80mL/min.
2.7. Numerical Methods and Algorithms. The simulations andmodeling presented in this paper have been done usingMatlab. We used the trapezoidal integration method with atime step of 0.01 s for numerical integration. The numericaldifferentiation for solving ordinary differential equationspresenting the HLHS model has been done using explicit
8 BioMed Research International
Table 2: Circulation parameters.
Parameters ValuesPulmonary circulation
PA๐ 2mmHgโ sโ mLโ1
๐ฟ 0.00412mmHgโ s2โ mLโ1
๐ถ 0.27410mL/mmHgPAB
๐ 0.41688mmHgโ sโ mLโ1
๐ถ 0.04078mL/mmHgPVB
๐ 0.01097mmHgโ sโ mLโ1
๐ฟ 0.00218mmHgโ s2โ mLโ1
๐ถ 0.88750mL/mmHgSystemic circulation
DA๐ 0.19883mmHgโ sโ mLโ1
๐ฟ 0.00287mmHgโ s2โ mLโ1
๐ถ 0.06118mL/mmHgSAB
๐ 3.51120mmHgโ sโ mLโ1
๐ฟ 0.00535mmHgโ s2โ mLโ1
๐ถ 0.44296mL/mmHgSVB
๐ 0.32255mmHgโ sโ mLโ1
๐ถ 0.31030mL/mmHgSLV
๐ 0.08265mmHgโ sโ mLโ1
๐ถ 4.07890mL/mmHgPatent ductus arteriosus
๐ 1mmHgโ sโ mLโ1
Table 3: Blood gas diffusion parameters.
Parameters ValuesOxygen
๐ท๐ฟO2
180mL/minฮ 0.00003 (mLโ mLโ1mmHgโ1)๐ต 0.2213 (mLโ mLโ1mmHgโ1)๐ 2.7๐avO2
100mmHgCarbon dioxide
๐ท๐ฟCO2
450mL/min๐cap 3.5mL๐avCO2
41mmHg
fourth-order Runge-Kutta method [27]. In our simulationswe have set the time step and time span to 0.01 s and 10 s,respectively. We have then ignored the first few cycles todrop the transients and to achieve steady-state solution. Theinitial condition has been set to 0.1 of the respective unitsfor the pressures and flows. The computer used to run thesimulations has a 32GB of RAM and an Intel Xeon X5680
2.6 2.7 2.8 2.9 3 3.1 3.2 3.3 3.4 3.50
20
40
60
80
100
120
Time (s)
Pres
sure
(mm
Hg)
PRAPPAB
PPVB
Figure 5: Pressures in right atrium, pulmonary artery, and pul-monary venous bed. As it is expected in the case of HLHS babies,since blood is pumped from right ventricle to the whole body,pressures in pulmonary arterial bed for the HLHS babies are higherthan those for normal babies.
2.6 2.7 2.8 2.9 3 3.1 3.2 3.3 3.4 3.50
20
40
60
80
100
120
140
160
180
Time (s)
Pres
sure
(mm
Hg)
PDAPPA
PRV
Figure 6: Pressures in right ventricle, descending aorta, andpulmonary artery. The heart rate is assumed to be 160 bpm basedon the average HLHS patient data.
processor. The computation time to run the simulations for10 s was 6.19 s.
3. Results
Numerical results were obtained using the parameter valuesas discussed above. Typical important pressure curves forvarious points of the body are shown in Figures 5 and 6.The pressures depicted by the model in Figures 5 and 6
BioMed Research International 9
2.6 2.7 2.8 2.9 3 3.1 3.2 3.3 3.4 3.5โ50
0
50
100
150
200
250
Time (s)
Flow
rate
(mL/
s)
QAQPA
Figure 7: Flow rates in aorta and pulmonary artery. The plots areshown for ๐ ASD and ๐ PDA equal to 1mmHgโ sโ mLโ1. The neonatalsituation shown in this figure is dangerous, because most of the flowgoes to the pulmonary artery and there is not enough flow going tothe vital organs.
10 15 20 25 30 35 40 45 50 55 600
20
40
60
80
100
120
140
160
Pres
sure
(mm
Hg)
Volume (cm3)
Figure 8: Pressure-volume loop. ๐ ASD and ๐ PDA are set to0.1mmHgโ sโ mLโ1 and HR is 160 bpm.
are consistent with the atrial, ventricular, and pulmonarypressures of the HLHS heart. The pressure values of thedifferent sections of the heart through the two contractioncycles are consistent with a heart that has a blockage/defectof the left ventricle as in patients with hypoplastic leftheart syndrome, where the right ventricle is responsible forcirculating blood to the lungs as well as throughout the body.
The variations of flow rate in the aorta and the pulmonaryartery are shown in Figure 7. Another very important curveis the ๐-๐ loop for the right ventricle, which is shown inFigure 8. There are no discontinuities or nonsmoothness
2.6 2.7 2.8 2.9 3 3.1 3.2 3.3 3.4 3.50
5
10
15
20
25
30
Time (s)
Flow
(cm
3 /s)
Figure 9: Flow rate in PDA for ๐ PDA is equal to 10mmHgโ sโ mLโ1.
in the figure since all the relationships that are used forcalculating the pressures and the volumes are exponential.Note that the heart rate in this paper is assumed to be 160 bpmwhich is calculated from the mean values of patient data.Theend-diastolic and systolic volumes for the right ventricle are49.9 and 18.2 cm3, respectively, with an ejection fraction of63.5%.
Figure 9 displays the PDA flow rate. Increasing theresistance decreases the flow rate as might be expected.
3.1. Parametric Analysis. Weperformed a parametric analysisto investigate the effect of some clinically important param-eters on the model performance and also to provide a wayto compare different stages in the HLHS babyโs life. Whena baby is born, the PDA is fully open; hence ๐ PDA is low.When the baby takes his first breath, pulmonary resistancefalls sharply in the first few hours but still remains at a highvalue for the first few days of life as it slowly drops down tonormal. To model this phenomenon, we assume ๐ PDA = 0.1
and ๐ PA = 2mmHgโ sโ mLโ1; the resulting pressure curves forthe different parts are as shown in Figure 10.
As can be seen in Figure 10, aortic pressures are in thenormal range of 75โ115mmHg and the pulmonary pressuresare also normal. But as the baby ages by 5โ10 days, the PDAbegins to close and hence ๐ PDA increases.
As the pulmonary resistance further drops to ๐ PA =
0.2mmHgโ sโ mLโ1, less flow crosses PDA to aorta. In thissituation, since the pulmonary pressure is higher than theaortic pressure, there would be more systemic flow thanpulmonary flow. The pressure curves for this stage areshown in Figure 11. In this situation, the condition becomesextremely dangerous. All the flow goes to the lungs and thereis a reverse pressure gradient across the PDA such that thepressure in the PA is less than the pressure in the aortic archand there is no flow going to the vital organs. Pressure buildsin the RA because of the extra small pulmonary flow anddeath ensues.
Norwood procedure is performed to create a neoaortafrom the common pulmonary artery as the cardiac outflow
10 BioMed Research International
2.6 2.7 2.8 2.9 3 3.1 3.2 3.3 3.4 3.50
20
40
60
80
100
120
140
160
Time (s)
Pres
sure
(mm
Hg)
PAOPPA
PRV
Figure 10: Pulmonary artery and aorta pressure just after birth inHLHS baby with ๐ PDA = 0.1 and ๐ PA = 2mmHgโ sโ mLโ1.
2.6 2.7 2.8 2.9 3 3.1 3.2 3.3 3.4 3.50
20
40
60
80
100
120
140
160
Time (s)
Pres
sure
(mm
Hg)
PPAPAO
PRV
Figure 11: Pulmonary artery and aorta and right ventricle pressurebefore Norwood circulation procedure.
track. A synthetic shunt of constant diameter is placed tostabilize the pulmonary blood flow and the PDA is legated.
The constant diameter of the shunt limits the amount offlow to the low resistance PA, thereby stabilizing ๐๐/๐๐ , amodel which has been presented in [20].
Three parameters,๐ ASD, ๐ PA, and ๐ PDA, were chosen andwere varied over a range of physiological resistance, and theresulting changes in the hemodynamic parameters were ana-lyzed. Varying ASD resistance (๐ ASD) corresponds to varyingmagnitudes of the septal defect. Varying the pulmonaryartery resistance (๐ PA) corresponds to the increasing age ofthe baby. Finally, the last parameter varied is the resistance
0 1 2 3 4 5 6 7 8 9 101
1.5
2
2.5
3
3.5
RPDA (mmHg/(mL/s))RASD = 0.01RASD = 4
RASD = 10
O2
deliv
ery
(mL/
(cyc
leยท
m2 ))
Figure 12: Systemic oxygen delivery. Oxygen delivery is calculatedby multiplication of system flow and arterial oxygen concentration.The results are consistent with what is presented in [20].
within the PDA (๐ PDA). This parameter can be controlled byan infusion of prostaglandin to prevent PDA closure.
Two parameters are varied in each plot to study the effectsof the parametric variation on systemic hemodynamics.The graphs of important hemodynamic parameters such ascardiac output, pulmonary to systemic flow ratio, and oxygenand carbon dioxide partial pressures are presented (Figures12โ15). Systemic oxygen delivery as a function of increasing๐ PDA is shown in Figure 12.We can observe from this plot thatoxygen delivery will decrease with increase of both ๐ ASD and๐ PDA.Although this is a fairly obvious fact, the interesting find-ing is that in the case of very high ๐ ASD the oxygen deliveryis not monotonically decreasing, and it has a maximum forsome intermediate values of ๐ PDA. We can infer that in thecase of neonates with very high ๐ ASD an increase in ๐ PDA tosome extent could be helpful.
As can be observed from Figures 13(a) and 13(b), thepulmonary-to-systemic flow ratio (๐๐/๐๐ ) changes with thechange in the model parameters. As ๐ ASD increases, this ratiodecreases because the pulmonary flow keeps on decreasing;this is because, at steady state, all the pulmonary flow passesthrough the ASD, and an increase of ๐ ASD leads to a decreasein the flow. As ๐ PDA increases, the systemic flow decreasessince all the systemic flow passes through ductus arteriosuswhich leads to an increase in the ๐๐/๐๐ ratio.
A ๐๐/๐๐ ratio around one is optimal for the body [28]and hence a suitable area for the flow can be selected fromthese graphs accordingly. Considering the parameters thathave to be changed, such a point can be reached.Thedirectionof blood flow depends upon the resistance, and hence, in thecase of HLHS, blood follows the path of least resistance. Inhigh ๐ PA resistances in constant ๐ PDA, the ratio decreasesbecause, due to high pulmonary resistance, the amountof pulmonary flow decreases and systemic flow increases
BioMed Research International 11
0 1 2 3 4 5 6 7 8 9 101
2
3
4
5
6
7
8
RPDA (mmHg/(mL/s))
Qp/
Qs r
atio
RPA = 0.1RPA = 0.5
RPA = 1RPA = 2
(a)
0 1 2 3 4 5 6 7 8 9 100
1
2
3
4
5
6
Qp/
Qs r
atio
RPDA (mmHg/(mL/s))
RASD = 0.1
RASD = 1
RASD = 2
RASD = 10
(b)
Figure 13: Variation of ๐๐/๐๐ by changing the most important model parameters. Values around one are normal.
0 1 2 3 4 5 6 7 8 9 1079
80
81
82
83
84
85
86
87
88
89
Satu
ratio
n (%
)
RPA = 2RPA = 0.1RPA = 0.5
RPDA (mmHg/(mL/s))
(a)
0 1 2 3 4 5 6 7 8 9 1030
40
50
60
70
80
90
Satu
ratio
n (%
)
RASD = 0.1RASD = 1
RASD = 10
RPDA (mmHg/(mL/s))
(b)
Figure 14: Variation of arterial oxygen saturation by changing the most important model parameters.
leading to a decrease in the ๐๐/๐๐ ratio. Plots show thatin some combination of PA, ASD, and PDA resistances theoptimal ๐๐/๐๐ can never be achieved. For example, if ๐ PA =
0.1mmHgโ sโ mLโ1, the optimal ๐๐/๐๐ ratio is unreachable.As shown in Figures 14(a) and 14(b), as ๐ PDA increases,
the arterial O2saturation also increases and becomes nearly
constant at high values of the resistance; however, it decreasesmonotonously with ๐ ASD. The decrease with ๐ ASD becomesmore profound at lower values of ๐ PDA. This trend is alsoobserved with ๐ PA. For constant ๐ PA, systemic arterial O
2
concentration increases with increasing ๐ PDA.
As๐ PDA increases, cardiac output (sumof pulmonary andsystemic flows) decreases slowly as the systemic flow keepson decreasing and this counters the effect of the increasingpulmonary flow as shown in Figures 15(a) and 15(b). As ๐ ASDincreases, cardiac output decreases significantly due to a rapidreduction in the pulmonary flow. Hence, it can be deducedthat the sensitivity of the pulmonary flow to๐ ASD is very high.A similar trend can be observed with ๐ PA playing the samerole as that of ๐ ASD.
Figure 16 shows a plot of ๐CO2
(partial pressure of carbondioxide) for constant ๐ PA = 0.1mmHgโ sโ mLโ1 and varying
12 BioMed Research International
0 1 2 3 4 5 6 7 8 9 1025
30
35
40
45
50CO
(mL/
s)
RPDA (mmHg/(mL/s))
RPA = 0.1RPA = 2
RPA = 8
(a)
0 1 2 3 4 5 6 7 8 9 1020
25
30
35
40
45
50
CO (m
L/s)
RPDA (mmHg/(mL/s))
RASD = 0.1RASD = 1
RASD = 10
(b)
Figure 15: Variation of cardiac output by changing the ๐ ASD, ๐ PA, and ๐ PDA.
0 1 2 3 4 5 6 7 8 9 1010
20
30
40
50
60
70
RPDA (mmHg/(mL/s))
Veno
us C
O2
part
ial p
ress
ure (
mm
Hg)
RASD = 0.1RASD = 1
RASD = 4RASD = 10
Figure 16: Variation of ๐CO2 for constant ๐ PA = 0.1mmHgโ sโ mLโ1and changing ๐ PDA and ๐ ASD. Previous finding underlined theimportance of ๐CO2 as a risk factor for the occurrence of PVL.
values of๐ PDA and๐ ASD.We focus on๐CO2
since our previousstudies based on computational intelligence (CI) techniqueshave shown that 43mmHg๐CO
2
is an important threshold forpredicting PVL. By inclusion of๐CO
2
in ourmodel we attemptto find a reason for this interesting but somewhat inexplicableresult of the CI technique. Our results show that all values of๐CO2
are less than 43mmHg for ๐ PA = 0.1mmHgโ sโ mLโ1 and๐ ASD โฅ 4mmHgโ sโ mLโ1. Considering the fact that ๐CO
2
tosome extent is measureable and controllable post- and pre-operatively, this finding could well lead to a valuable insight.
4. Conclusion
The goal of this paper has been to develop a lumpedparameter model of HLHS, a fairly common congenital heartdisease. The need for this physical modeling comes from ourultimate goal to predict and prevent one of the consequencesof this abnormal circulation, namely, a form of brain injurycalled periventricular leukomalacia (PVL).
The exact causes of PVL are not well understood and inthis paper our focus has been on understanding how somecritical parameters such as flow resistances at the atrial septaldefect or patent ductus arteriosus might alter systemic flowand systemic oxygen delivery, which could be reasonablyexpected to have a causal relationship to PVL occurrence.
In this paper, we have compared the results of HLHScirculation (preoperative condition) to Norwood circulation(postoperative condition). Results show the manner andextent of changes in the pressure and blood flow in differentparts of the body. In reporting the modeling results, we havemostly focused on the pulmonary to systemic flow ratio(๐๐/๐๐ ), O
2delivery, and O
2saturation because we believe
that these parameters are important risk parameters of thePVL occurrence. By use of the model, the following pointswere demonstrated or confirmed.
Different sizes of the PDA and the ASD and differentresistances of the PDA and the ASD will result in changingthe regulation of pulmonary and systemic flow and hencethese resistances play a critical part in our goal to predict theoccurrence of the PVL.
The direction of blood flow depends upon the PA resis-tance and that of the PDA resistance. Increase in the PDAresistance leads to blood flowing where the resistance isthe least. This results in an increased ๐๐/๐๐ ratio. Withan increase in the PDA resistance a greater portion of thecardiac output goes into the lungs.This will lead to a systemic
BioMed Research International 13
hypoperfusion and poor O2delivery. This result is consistent
with the results presented in [29].By comparing the slope in cardiac output and pulmonary
to systemic flow variation plots, one could observe that therates of change (slopes) are higher for variation of PA resist-ance in comparisonwith the variation of ASD resistance.Thismeans that the PA resistance is more influential on the COand pulmonary to systemic flow ratio than the ASD resist-ance. This suggests that the PA resistance is more directlyinvolved in the determination of the ๐๐/๐๐ ratio and thecardiac output.
The optimal O2delivery is achieved when balanced
pulmonary and systemic perfusion is established, namely,when ๐๐/๐๐ is around 1. Our results show that, for somevalues of ๐ PA and ๐ ASD, the optimal ๐๐/๐๐ can never beachieved. Since insufficient O
2delivery is considered to be a
potential cause for PVL, it seems reasonable to infer that thesevalues of ๐ ASD and ๐ PA lead to high risks of PVL.
It is known that the correlation between venous O2
saturation and O2delivery is better than the correlation
between arterial O2saturation and O
2delivery. However,
since measurement of the mixed venous saturation in clinicalpractice remains difficult, we just considered the case ofarterial oxygen saturation [30] in this study.
The developed model also has some other interestingapplications. For example, with some minor modificationsto cover the partly underdeveloped left heart, the proposedmodel could form a good foundation for the analysis ofnewborns with underdeveloped left ventricles and modelbased design of left ventricular assist devices.
Given that the exact causes of PVL are still not clearlyunderstood, the main goal of this paper has been to developa sound mathematical model to investigate HLHS, a severecongenital deformation which has the highest correlationwith the occurrence of PVL as suggested by preliminarypostoperative data collected from Childrenโs Hospital ofPhiladelphia (CHOP). Also, the paper aims to provide atool to better understand the main factors that drive theHLHS physiology by a suitable variation of physiologicalparameters.
Our previous computational intelligence based findings[5, 7, 10] suggest some important factors in the occurrenceof PVL; however, since the exact physiological reasons andcauses of those findings are not clear, the current model hasbeen developed to discover cases that will lead to the PVLsituation and to analyze them. We hope that the developedmodel could open the door for further investigation of theHLHS syndrome and also to its connection with PVL. Thepostoperative results are consistent with what is reported in[20] which makes this model potentially valuable for clinicaluse.
Some of the limitations of the current work are as follows.
(i) The effect of respiration and regulatory mechanismssuch as HR baroreflex and total peripheral resistancebaroreflex on the cardiopulmonary performance isnot considered in building the model.
(ii) The values of the components of the analog electricalcircuit are estimated and there is still no direct,
reliable, and safe way to measure them with highconfidence.
(iii) The results of themodel should be validated clinically.A parameter adaptation algorithm for patient specificmodeling should be developed and implemented onthe patient specific data. The correlation between thePVL occurrence and different values for ASD, PA, andPDA resistances should be calculated for the aim ofPVL occurrence prediction.
To improve the model further and to add more verisimil-itude with reality, it is important to include other factors intothe system such as autoregulation and to investigate its effects.Our current work is continuing on this important problemand will focus on addressing some of the above limitations.
Finally we would like to comment about the generalutility of the procedures developed in this paper. Withall the obvious limitations, the method of constructing amathematical model pursued in this paper is still appealingbecause it permits the change of parameters very easily tounderstand their influence on the usual key clinical outputssuch as ๐๐/๐๐ . Such models exist for other conditionsbut none exist for PVL based on preoperative conditions.By use of a parametric analysis on computer models westart to acquire the very useful ability to predict pre- andpostoperative conditions for specific patients and also todevelop patient specific models to investigate physiologicalstates of individual patients. That said, we would like toreiterate the limitations of the current model and hope todevelop and inspire development of improved models withappropriate corroboration.
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper.
Acknowledgment
The research reported in this paper is supported by a grantfrom National Institute of Health (no. 1 R01 NS 72338 01A1).
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