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

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1 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

2 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

3 A. Principles of Cardiovascular Physiology

4 Determinants of Cardiac Function and Oxygen Delivery to Tissues Strange GR. APLS: The Pediatric Emergency Medicine Course. 3 rd ed. Elk Grove Village, Ill: American Academy of Pediatrics; 1998:34

5 Factors Regulating Cardiac Output, Blood Pressure and Systemic Vascular Resistance Blood Pressure Cardiac Output = Vascular Resistance Blood Pressure = Cardiac Output x Vascular Resistance 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. Modified from Klabunde RE,

6 Distribution of Pressure & Volume in the Circulation

7 Oxygen Delivery and Consumption 1. Oxygen Delivery to Alveoli [Alveolar Minute Ventilation] x [FiO 2 ] (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 [FiO 2 ] 2. Oxygen Delivery to Tissues (O 2 Carrying Capacity) x (Cardiac Output) (dl/kg/min) 3. Oxygen Consumption (VO 2 ) VO 2 = CO x (CaO 2 - CvO 2 ) CO = cardiac output (dl/min), CaO 2 = arterial oxygen content, CvO 2 = oxygen content of mixed venous blood

8 OXYGEN DEMAND OXYGEN CONSUMPTION 1. Mechanisms of compensation for decreased O 2 delivery (O 2 demand delivery coupling): a. increased blood flow (vasodilation and capillary recruitment) b. Increased O 2 extraction 2. Beyond critical O 2 delivery cells switch from aerobic metabolism (38mol ATP/mol of glucose) to anaerobic metabolism (2mol ATP and 2mol Lactate/mol of glucose)

9 Sympathetic and Parasympathetic Regulation of Myocardial Function α 1 DA Modified from Klabunde RE,

10 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. Modified from Klabunde RE,

11 Cardiovascular Actions of Adrenergic Receptors Adrenergic, Dopaminergic and Vasopressin Receptors α 1 /α 2 β 2 α 1 β 1 /β 2 DA 1 /DA 2 V 1a Vascular Vascular Cardiac Cardiac Vascular/Cardiac Vascular Vasoconstriction Vasodilation * + Inotropy /++ + Chronotropy ++++ Cond. Velocity ++++ * = renal, mesenteric, coronary circulation > pulmonary circulation > extracranial vessels of the neck

12 β-receptor-mediated Effects in the Myocyte and Vascular Smooth Muscle Cell Myocyte Vascular Smooth Muscle Cell Modified from Klabunde RE,

13 α-receptor-mediated Effects in Vascular Smooth Muscle Cells Vascular smooth muscle has two primary types of α-adrenoceptors: α 1 and α 2. The α 1 -adrenoceptors are located on the vascular smooth muscle. In contrast, α 2 - adrenoceptors are located on the sympathetic nerve terminals as well as on vascular smooth muscle. Smooth muscle (postjunctional) α 1 and α 2 -adrenoceptors are linked to a Gq-protein, which activates smooth muscle contraction through the IP 3 signal transduction pathway. Prejunctional α 2 - adrenoceptors located on the sympathetic nerve terminals serve as a negative feedback mechanism for norepinephrine release. Modified from Klabunde RE,

14 Pathways egulating Vascular Smooth Muscle (VSM) Tone 1. Phosphatidylinositol (PIP 2 ) pathway in VSM is similar to that in the heart. NE acting via α 1 -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 (IP 3 ) and diacylglycerol (DAG) formation. IP 3 stimulates calcium release from SR and DAG activates PK-C, also contribute to VSMC contraction. 2. G s -protein coupled pathway stimulates AC to form camp. In VSM, unlike the heart, an increase in camp stimulated by a β 2 -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 (β 2 - 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 cgmpdependent protein kinase and K + channels and inhibition of calcium entry into the VSMC and IP 3 formation. Modified from Klabunde RE,

15 B. Fetal Circulation

16 The Fetal Circulation Kiserud and Acharya, Prenat Diagn 24:149; 24

17 Fetal Circulation and Hemoglobin Oxygen Saturation in the Late Gestation Fetus Modified from Heymann MA; Maternal-Fetal Medicine; 3 rd ed., WB Saunders, 1994; p 277

18 Role of the Pulmonary Circulation in the Distribution of Human Fetal Cardiac Output During the Second Half of Pregnancy Proportions of RVCO, LVCO, QDA, QP, and QFO of the fetal combined CO at three different gestational ages: 2, 3, and 38 weeks Rasanen J et al, Circulation 1996; 94:168-7

19 C. Transitional Circulation

20 CIRCULATORY COMPROMISE IN THE TRANSITIONAL PERIOD 1. Blood pressure, heart rate, SaO 2 2. Systemic blood flow (CO = BP / SVR) 3. Distribution of blood flow to organs 4. Vital organ assignment and O 2 demand-delivery coupling 5. Association with clinically relevant outcomes 6. Design of appropriate interventional trials

21 CIRCULATORY COMPROMISE IN THE TRANSITIONAL PERIOD 1. Blood pressure, heart rate, SaO 2 2. Systemic blood flow (CO = BP / SVR) 3. Distribution of blood flow to organs 4. Vital organ assignment and O 2 demand-delivery coupling 5. Association with clinically relevant outcomes 6. Design of appropriate interventional trials

22 DEFINITION OF HYPOTENSION BY POPULATION-BASED NORMATIVE BLOOD PRESSURE DATA GESTATIONAL- AND POSTNATAL-AGE DEPENDENCE OF BLOOD PRESSURE Lower Limit of the 8% Confidence Interval of BP in Neonates ( First 3 Postnatal Days)* Mean Blood Pressure (mm Hg) weeks weeks weeks weeks Age (h) * = 9% of neonates have a mean BP value at or above the lower limit of the 8% confidence interval of BP Nuntnarumit et al, Clin Perinatol; 1999

23 UNDERSTANDING CIRCULATORY COMPROMISE IN THE TRANSITIONAL PERIOD 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 O 2 demand-delivery coupling 5. Association with clinically relevant outcomes 6. Design of appropriate interventional trials

24 Assessment of Systemic Blood Flow during Transition [1-12 (24) hours] SVC Flow RA LA RV LV Ductus Systemic Blood Flow RV Output PA Ao LV Output Systemic Blood Flow + PDA

25 Transitional Circulation AAo = Ascending aorta; LPA = Left pulmonary artery; RPA = Right pulmonary artery; PDA = Patent ductus arteriosus PDA LPA AAo RPA Large PDA, Left to Right Shunt Tiny PDA, Left to Right Shunt

26 Assessment of Systemic Blood Flow during Transition [12 (24) - 48 hours] SVC Flow RA LA RV LV Ductus Systemic Blood Flow + PFO RV Output PA Ao LV Output Systemic Blood Flow + PDA

27 D. Pathophysiology of Shock

28 ETIOLOGY OF NEONATAL SHOCK

29 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

30 Pathophysiology of Neonatal Shock Imbalance between oxygen delivery and oxygen consumption Oxygen Consumption Normal Range of Oxygen Consumption Oxygen Delivery

31 Comprehensive Bedside Hemodynamic Monitoring and Data Acquisition in the Transitional Period GA = 26 wks PA = <24 hours rso2-1 = Brain Tissue O 2 rso2-2 = Renal Tissue O 2 Sys = Systolic BP Dia = Diastolic BP Mean = Mean BP SpO 2 = O 2 saturation Data Sampling Rate = Data Output Rate =

32 Cardiovascular Physiology and Pathophysiology-Based Management of Neonatal Shock Blood Pressure = Cardiac output x Systemic Vascular Resistance Heart Rate x Stroke Volume Neuroendocrine and paracrin regulatory mechanisms Catecholamines β-receptor Agonists Temperature Pacing Volume Diuretics Preload Contractility Inotropes Calcium Afterload Vasopressors Vasodilators Temperature Lower limit of normal cardiac output (systemic blood flow) in preterm neonates = 15 ml/kg/min

33 QUESTIONS?