modeling the inflammatory-cardiovascular response during
TRANSCRIPT
Kristen Windoloski & Mette OlufsenNorth Carolina State University
Collaborator: Ronan BergRigshospitalet, Copenhagen, Denmark
June 2021
Modeling the inflammatory-cardiovascular response during sepsis
Sepsis Background
Bacteria enters the body and causes an infection
The infection spreads and enters the bloodstream, allowing it to travel to different parts of the body
Uncontrolled inflammation can result in major organ dysfunction and even death
Immune cells and cytokines work to fight the infection throughout the body, leading to unregulated inflammation
Neurological System
Respiratory System
Hematological System
Cardiovascular System
Renal System
Hepatic System
Macrophages
Granulocyte
Fibroblast
Endothelial Cells
Mast Cell
Lymphocyte
Sepsis Symptoms
Low blood pressure
High heart rate
๐๐ธ๐๐ก = โ๐'๐ธ
๐๐)
๐๐ก = ๐พ+)๐) 1 โ๐)
๐-โ ๐ป+/ ๐ธ ๐+ + ๐+123๐ป+/ ๐๐๐น ๐ป+7 ๐ผ๐ฟ10 ๐)
๐๐;๐๐ก
= ๐ป+/ ๐ธ ๐+ + ๐+123๐ป+/ ๐๐๐น ๐ป+7 ๐ผ๐ฟ10 ๐) โ ๐พ+;๐;
๐๐๐๐น๐๐ก
= ๐123+๐ป1237 ๐ผ๐ฟ6 ๐ป1237 ๐ผ๐ฟ10 ๐; โ ๐123 ๐๐๐น โ ๐ค123
๐๐ผ๐ฟ6๐๐ก
= ๐>+ + ๐>123๐ป?@>/ ๐๐๐น ๐ป?@>7 ๐ผ๐ฟ6 ๐ป?@>7 ๐ผ๐ฟ10 ๐; โ ๐> ๐ผ๐ฟ6 โ ๐ค?@>
๐๐ผ๐ฟ8๐๐ก = ๐B+ + ๐B123๐ป?@B/ ๐๐๐น ๐ป?@B7 ๐ผ๐ฟ10 ๐; โ ๐B ๐ผ๐ฟ8 โ ๐ค?@B
๐๐ผ๐ฟ10๐๐ก
= ๐CD+ + ๐CD>๐ป?@CD/ ๐ผ๐ฟ6 ๐; โ ๐CD ๐ผ๐ฟ10 โ ๐ค?@CD
Bolus Dose Inflammation Model
Monocytes
Cytokines
Endotoxin
E1EF= C
GH(โ๐ + ๐J + ๐1 ๐+ โ ๐J (๐123๐ป/ TNF โ ๐123 + ๐1>๐ป/ IL6 โ ๐?@> )โ๐1CD(1 โ ๐ป7 IL10 โ ๐?@CD )Temperature
๐๐1๐๐ก = โ๐S1S ๐ธ ๐1 + ๐S1 ๐1,+ โ ๐1Pain
๐๐๐๐ก
=๐2+๐;)TNF(t โ ฮบ WX,YZ[
)TNF(t โ ฮบ WX,YZ[ + ๐2,]^_WX,YZ[
๐2CDWXH`
)IL10(t โ ฮบ WXH` + ๐2CDWXH`
โ ๐2๐Nitric Oxide
Blood Flow & Volume
๐ โ ๐ป๐dFe = ๐ป(๐f7 โ ๐fg)
๐๐h๐๐ก = ๐hi โ ๐jkF
๐h=๐jkF โ ๐hi
๐ h
Peripheral Vascular Resistance & Heart Rate
๐๐ d๐๐ก
= ๐)S1๐คo
๐คo + ๐o)S1โ ๐)2๐ โ ๐) ๐ d โ ๐ p , ๐ค =
๐๐1๐๐ก
๐๐ป๐๐ก
=โ๐ป + ๐q ๐ป+ โ ๐ปp ๐ปq/ ๐ โ ๐p ๐ ๐ต๐, ๐ต๐p + ๐ปp
๐o
Cardiovascular-Pain-Thermal Model
Inflammatory-Cardiovascular-Pain-Thermal Model
Mean Bolus Data & Model
Source: Dobreva, A., Brady-Nicholls, R., Larripa, K., Puelz, C., Mehlsen, J., & Olufsen, M. S. (2021). A physiological model of the inflammatory-thermal-pain-cardiovascular interactions during an endotoxin challenge. The Journal of Physiology, 599(5), 1459-1485.
Patient Specific Bolus Data & Model
0
400
800
TNF-
(p
g/m
L)
0
500
1000
1500
IL-6
(pg/
mL)
Time (hr)
36
38
40
Tem
p (o
C)
Time (hr)
840
880
920
PP
T (k
Pa)
Time (hr)
115
120
125
130
BP (m
mH
g)
0
40
80
0
200
400
0
20
40
0
400
800
37
38
39
40
600
700
800
110
120
130
60
80
100
0
20
40
60
IL-1
0 (p
g/m
L)
Time (hr)
60
80
100
HR
(bpm
)
200
600
1000
IL-8
(pg/
mL)
0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8
0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8
A
B
Patient 6
Patient 19
Time (hr) Time (hr) Time (hr)0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8
Time (hr)
TNF-
(p
g/m
L)Te
mp
(o C
)
IL-6
(pg/
mL)
PP
T (k
Pa)
BP (m
mH
g)IL
-10
(pg/
mL)
HR
(bpm
)IL
-8 (p
g/m
L)
R = 0.962
R = 0.972 R = 1.002
R = 0.992 R = 0.802
R = 0.832 R = 0.932
R = 0.932
R = 0.972
R = 0.962 R = 1.002
R = 0.862 R = 0.902
R = 0.902 R = 0.972
R = 0.972
a
a
R = 0.842
R = 0.792 R = 0.972
R = 0.982 R = 0.882
R = 0.882 R = 0.952
R = 0.942
R = 0.922
R = 0.952 R = 0.892
R = 0.902 R = 0.892
R = 0.902 R = 0.822
R = 0.832
0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8
Source: Dobreva, A., Brady-Nicholls, R., Larripa, K., Puelz, C., Mehlsen, J., & Olufsen, M. S. (2021). A physiological model of the inflammatory-thermal-pain-cardiovascular interactions during an endotoxin challenge. The Journal of Physiology, 599(5), 1459-1485.
18 patient-specific parameters
12 patient specific parameters, and 6 population parameters
๐๐ธ๐๐ก = โ๐'๐ธ
๐๐ธ๐๐ก
=๐ฟ๐๐1
๐กfiE โ ๐กgFveFโ ๐'๐ธ if ๐ก โค ๐กfiE
โ๐'๐ธ if ๐ก > ๐กfiE
where
๐กgFveF = infusion start time
๐กfiE = infusion end time
๐ฟ๐๐1 = total dose ng/kg
Transition from Bolus to Continuous Dose
Continuous Infusion Inflammation Model
= Bolus= Continuous= Optimized
Volunteer 7
Begin with bolus dose inflammation model
Adapt bolus dose inflammation model to become a continuous dose inflammation model
Investigate the transition from 1) recovery to chronic inflammation2) chronic inflammation to sepsis
Investigate immune response to continuous infusion
Connect continuous dose inflammation model to cardiovascular model
Estimate cardiac biomarkers and study sepsis treatments
Current & Future Work
References & Acknowledgments
Funding: The National Science Foundation NSF/DMS(RTG) #1246991
Image References:1. https://wp.math.ncsu.edu/cdg/2. https://www.rigshospitalet.dk/english/Pages/default.aspx3. https://en.wikipedia.org/wiki/North_Carolina_State_University4. https://online.seterra.com/en-an/vgp/38015. http://www.iemoji.com/view/emoji/2742/objects/microbe6. https://patientsafetymovement.org/blog/uci-health-spotlight-on-central-line-
associated-bloodstream-infections/7. https://www.nature.com/articles/s41581-018-0005-
7?WT.feed_name=subjects_acute-kidney-injury8. https://www.news-medical.net/health/What-are-Cytokines.aspx9. https://www.worldsepsisday.org/sepsis10. https://www.health.harvard.edu/blog/increase-in-resting-heart-rate-is-a-signal-
worth-watching-20111221401311. https://time.com/4630345/systolic-blood-pressure-hypertension/12. https://www.boundtree.com/IV-Drug-Delivery/Syringes/Syringes-with-Needle-
Luer-lock-Tip-3cc/p/group00261413. https://www.ocrevus.com/patient/infusion-experience.html14. https://en.wikipedia.org/wiki/National_Science_Foundation
Publications:1. A Dobreva, R Brady-Nicholls, K Larripa, C Puelz, J Mehlsen,
MS Olufsen (2021). A physiological model of the inflammatory-thermal-pain-cardiovascular interactions during an endotoxin challenge. J Physiol,
2. R Brady, DO Frank-Ito, HT Tran, S Janum, SB Pedersen, JT Ottesen, J Mehlsen, MS Olufsen (2018.) Mathematical modeling of endotoxin-induced inflammatory response in young men. Math Modeling Natural Phenomena