istvan seri md phd · factors regulating cardiac output, blood pressure and systemic vascular...

Istvan Seri MD PhD Center for Fetal and Neonatal Medicine

USC Division of Neonatal Medicine Children Hospital Los Angeles and

LAC+USC Medical Center Keck School of Medicine

University of Southern California Los Angeles, CA

•  I have no relevant financial relationships with the manufacturers of any commercial products and/or provider of commercial services discussed in this activity

•  I intend to discuss an unapproved/investigative use of a commercial product/device in my presentation

•  I’m a scientific consultant for Dey LP and have received compensation, honoraria and unrestricted educational grants

•  I collaborate with Somanetics Corp to perform experiments on systemic hemodynamics and regional tissue oxygenation using the newborn piglet model and have received independent grant support to establish an international research fellowship project

A. Principles of Cardiovascular Physiology

Determinants of Cardiac Function and Oxygen Delivery to Tissues

Strange GR. APLS: The Pediatric Emergency Medicine Course. 3rd ed. Elk Grove Village, Ill: American Academy of Pediatrics; 1998:34

Factors Regulating Cardiac Output, Blood Pressure and Systemic Vascular Resistance

Modified from Klabunde RE, www.cvphysiology.com

Although mathematically SVR is the dependent variable in the above equation, physiologically SVR and CO are the independent (regulated) variables and MAP is the

dependent variable.

Blood Pressure Vascular Resistance

Cardiac Output = Blood Pressure = Cardiac Output x Vascular Resistance

Distribution of Pressure & Volume in the Circulation

Oxygen Delivery and Consumption

1.  Oxygen Delivery to Alveoli [Alveolar Minute Ventilation] x [FiO2] (mL/kg/min)

Alveolar Minute Ventilation = (Tidal Volume - Dead Space) x (Respiratory Rate)

Oxygen Delivery to Alveoli = [(Tidal Volume - Dead Space) x (Respiratory Rate)] x [FiO2]

2. Oxygen Delivery to Tissues (O2 Carrying Capacity) x (Cardiac Output) (dL/kg/min)

3. Oxygen Consumption (VO2)

VO2 = CO x (CaO2 - CvO2)

CO = cardiac output (dL/min),

CaO2 = arterial oxygen content,

CvO2 = oxygen content of mixed venous blood

OXYGEN DEMAND – OXYGEN CONSUMPTION

1.  Mechanisms of compensation for decreased O2 delivery

(O2 demand – delivery coupling):

a.  increased blood flow (vasodilation and capillary recruitment)

b.  Increased O2 extraction

2.  Beyond “critical O2 delivery” cells switch from aerobic

metabolism (38mol ATP/mol of glucose) to anaerobic

metabolism (2mol ATP and 2mol Lactate/mol of glucose)

Sympathetic and Parasympathetic Regulation of Myocardial Function


α1

DA

Frank-Starling Mechanism: Preload, Myocardial Contractility and Afterload

Increased venous return increases ventricular filling (EDV) and preload, which is the initial stretching of the cardiac myocytes prior to contraction. Myocyte stretching increases the sarcomere length causing an increase in force generation. This mechanism enables the heart to eject the additional venous return, thereby increasing stroke volume. This is the length-tension and force-velocity relationships for cardiac muscle. Increasing preload increases the active tension developed by the muscle fiber and increases the velocity of fiber shortening at a given afterload and inotropic state. Mechanism: increasing the sarcomere length increases troponin C calcium sensitivity, which increases the rate of cross-bridge attachment and detachment, and the amount of tension developed by the muscle fiber. The effect of increased sarcomere length on the contractile proteins is termed length-dependent activation.


Adrenergic, Dopaminergic and Vasopressin Receptors   α1/α2 β2 α1 β1/β2 DA1/DA2 V1a   Vascular Vascular Cardiac Cardiac Vascular/Cardiac Vascular

Cardiovascular Actions of Adrenergic Receptors

0

++++

0

0

0

0

0

++

0

0

0

0

++++

++++

++++

0

++++*

+/++

0

0

++++

0

0

0

0

Vasoconstriction

Vasodilation

+ Inotropy

+ Chronotropy

Cond. Velocity

++++

0

0

0

0

* = renal, mesenteric, coronary circulation > pulmonary circulation > extracranial vessels of the neck

Myocyte Vascular Smooth Muscle Cell

β-Receptor-Mediated Effects in the Myocyte and Vascular Smooth Muscle Cell


Vascular smooth muscle has two primary types of α-adrenoceptors: α1 and α2. The α1-adrenoceptors are located on the vascular smooth muscle. In contrast, α2-adrenoceptors are located on the sympathetic nerve terminals as well as on vascular smooth muscle. Smooth muscle (postjunctional) α1 and α2-adrenoceptors are linked to a Gq-protein, which activates smooth muscle contraction through the IP3 signal transduction pathway. Prejunctional α2-adrenoceptors located on the sympathetic nerve terminals serve as a negative feedback mechanism for norepinephrine release.

α-Receptor-Mediated Effects in Vascular Smooth Muscle Cells


2. Gs-protein coupled pathway stimulates AC to form cAMP. In VSM, unlike the heart, an increase in cAMP stimulated by a β2-adrenoceptor agonist such as EPI causes relaxation. The mechanism for this is cAMP inhibition of MLCK by decreasing its phosphorylation an thus the interactions between actin and myosin. Medications increasing cAMP (β2-agonists, PDase inhibitors) cause vasodilation. 3. Nitric oxide (NO)-cGMP system. NO activates guanylyl cyclase (GC) causing increased cGMP formation cGMP and vasodilation. cGMP relaxes VSM by activation of cGMP-dependent protein kinase and K+ channels and inhibition of calcium entry into the VSMC and IP3 formation.

Pathways Regulating Vascular Smooth Muscle (VSM) Tone 1. Phosphatidylinositol (PIP2) pathway in VSM is similar to that in the heart. NE acting via α1-adrenoceptors, angiotensin II (AII) acting via AII receptors, and endothelin-I (ET-1) acting through ETA receptors activate phospholipase C (PL-C) causing inositol triphosphate (IP3) and diacylglycerol (DAG) formation. IP3 stimulates calcium release from SR and DAG activates PK-C, also contribute to VSMC contraction.


B. Fetal Circulation

Kiserud and Acharya, Prenat Diagn 24:1049; 2004

The Fetal Circulation

60

53

53

55

45

40

83

35

55

60

70

43

53

Fetal Circulation and Hemoglobin Oxygen Saturation in the Late Gestation Fetus

Modified from Heymann MA; Maternal-Fetal Medicine; 3rd ed., WB Saunders, 1994; p 277

Role of the Pulmonary Circulation in the Distribution of Human Fetal Cardiac Output During the Second Half of

Pregnancy

Rasanen J et al, Circulation 1996; 94:1068-7

Proportions of RVCO, LVCO, QDA, QP, and QFO of the fetal combined CO at three different gestational ages: 20, 30, and 38 weeks

C. Transitional Circulation

1. Blood pressure, heart rate, SaO2

2. Systemic blood flow (CO = BP / SVR)

3. Distribution of blood flow to organs

4. Vital organ assignment and O2 demand-delivery coupling

5. Association with clinically relevant outcomes

6. Design of appropriate interventional trials

CIRCULATORY COMPROMISE IN THE TRANSITIONAL PERIOD

20

25

30

35

40

45

50

55

Mea

n Bl

ood

Pres

sure

(mm

Hg)

0 12 24 36 48 60 72 Age (h)

27-32 weeks

33-36 weeks

37-43 weeks

23-26 weeks

Nuntnarumit et al, Clin Perinatol; 1999

* = 90% of neonates have a mean BP value at or above the lower limit of the 80% confidence interval of BP

GESTATIONAL- AND POSTNATAL-AGE DEPENDENCE OF BLOOD PRESSURE Lower Limit of the 80% Confidence Interval of BP in Neonates ( First 3 Postnatal Days)*

DEFINITION OF HYPOTENSION BY POPULATION-BASED NORMATIVE BLOOD PRESSURE DATA

1. Blood pressure, heart rate and indirect assessment of tissue perfusion

2. Systemic blood flow (CO = BP / SVR)

3. Distribution of blood flow to organs

4. Vital organ assignment and O2 demand-delivery coupling

5. Association with clinically relevant outcomes

6. Design of appropriate interventional trials

UNDERSTANDING CIRCULATORY COMPROMISE IN THE TRANSITIONAL PERIOD

LV Output

Systemic Blood Flow

+ PDA

RV Output

Systemic Blood Flow

SVC Flow

RA LA

LV RV

PA Ao

Ductus

Assessment of Systemic Blood Flow during Transition [1-12 (24) hours]

Transitional Circulation

Tiny PDA, Left to Right Shunt

AAo = Ascending aorta; LPA = Left pulmonary artery; RPA = Right pulmonary artery; PDA = Patent ductus arteriosus

Large PDA, Left to Right Shunt

AAo

LPA

RPA

PDA

LV Output

Systemic Blood Flow + PDA

RV Output

Systemic Blood Flow

+ PFO

RA LA

Ductus

LV RV

PA Ao

SVC Flow

Assessment of Systemic Blood Flow during Transition [12 (24) - 48 hours]

D. Pathophysiology of Shock

ETIOLOGY OF NEONATAL SHOCK

PHASES OF NEONATAL SHOCK

1. Compensated phase ↑ Heart rate; ↓ Urine output; No change in blood pressure;

Blood flow distributed to vital organs (brain, heart, adrenal glands) at the expense of non-vital organ perfusion

2. Uncompensated phase ↑ Heart rate; ↓ Urine output; ↓ Blood pressure

Blood flow decreases in all organs, tissue hypoperfusion and acidemia develop

3. Irreversible phase Irreversible cellular damage

Oxygen Delivery

Oxy

gen

Cons

umpt

ion

Pathophysiology of Neonatal Shock Imbalance between oxygen delivery and oxygen consumption

Normal Range of Oxygen

Consumption

Comprehensive Bedside Hemodynamic Monitoring and Data Acquisition in the Transitional Period

GA = 26 wks PA = <24 hours rSO2-1 = Brain Tissue O2

rSO2-2 = Renal Tissue O2 Sys = Systolic BP Dia = Diastolic BP Mean = Mean BP SpO2 = O2 saturation Data Sampling Rate = Data Output Rate =

Cardiovascular Physiology and Pathophysiology-Based Management of Neonatal Shock

Blood Pressure = Cardiac output x Systemic Vascular Resistance

Neuroendocrine and paracrin regulatory

mechanisms Heart Rate x Stroke Volume

•  Catecholamines •  β-Receptor Agonists •  Temperature •  Pacing

Afterload Preload Contractility

•  Volume •  Diuretics •  Inotropes

•  Calcium •  Vasopressors •  Vasodilators •  Temperature

Lower limit of normal cardiac output (systemic blood flow) in preterm neonates = 150 mL/kg/min

QUESTIONS?

istvan seri md phd · factors regulating cardiac output, blood pressure and systemic vascular...

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