Oxygen Transport and Asphyxia AnS 536 Spring 2014

Goals To transport oxygen from maternal blood across the placenta to fetal blood, and after birth from the lungs to the blood stream To transport oxygen from maternal blood across the placenta to fetal blood, and after birth from the lungs to the blood stream To move oxygen from blood to tissues to allow aerobic metabolism (efficient production of ATP) To move oxygen from blood to tissues to allow aerobic metabolism (efficient production of ATP) To move carbon dioxide in the reverse direction To move carbon dioxide in the reverse direction

Erythrocytes After maturation from stem cells in bone marrow, erythrocytes have a circulating life of ~120d After maturation from stem cells in bone marrow, erythrocytes have a circulating life of ~120d Highly specialized cells: Highly specialized cells: Cytoplasm contains ~35% solution of hemoglobin, but is devoid of subcellular organelles Cytoplasm contains ~35% solution of hemoglobin, but is devoid of subcellular organelles Cannot synthesize nucleic acids or proteins, limited lipid metabolism Cannot synthesize nucleic acids or proteins, limited lipid metabolism Carbohydrate metabolism devoted to maintaining functional pumps on cell membrane Carbohydrate metabolism devoted to maintaining functional pumps on cell membrane

Erythrocytes After cell death, hemoglobin degraded and iron recycled to bone marrow After cell death, hemoglobin degraded and iron recycled to bone marrow As they pass through capillaries, cells deform into ellipsoidal, hemispheric, or teardrop shapes As they pass through capillaries, cells deform into ellipsoidal, hemispheric, or teardrop shapes Cell fragility increased during newborn period Cell fragility increased during newborn period Increased risk and incidence of hemolytic diseases Increased risk and incidence of hemolytic diseases

Transport of Gases in Blood P O2 not only determines the dissolved oxygen content of blood, but also affects the amount of oxygen in reversible chemical combination with hemoglobin P O2 not only determines the dissolved oxygen content of blood, but also affects the amount of oxygen in reversible chemical combination with hemoglobin Chemical and physiological actions of gases depend on the partial pressures they exert in the gas phase and in solution in various body fluids Chemical and physiological actions of gases depend on the partial pressures they exert in the gas phase and in solution in various body fluids

Hemoglobin The sigmoidal shape of the oxygen dissociation curve is physiologically important The sigmoidal shape of the oxygen dissociation curve is physiologically important Permits blood to deliver much more oxygen to tissues than a hyperbolic curve Permits blood to deliver much more oxygen to tissues than a hyperbolic curve The binding of one molecule of O 2 increases the affinity of the other sites for oxygen The binding of one molecule of O 2 increases the affinity of the other sites for oxygen Carbon dioxide binds to the globulin portions of the molecule rather than to the iron molecules Carbon dioxide binds to the globulin portions of the molecule rather than to the iron molecules Accounts for about 10% of CO 2 transport Accounts for about 10% of CO 2 transport

Video Break

O 2 -Hb Dissociation Curve Illustrates a relationship between the partial pressure of oxygen (PO 2 ) and percent saturated hemoglobin (Hb)

Hemoglobin When Hb binds to oxygen, it undergoes a conformational change that releases H ions from globin chains, decreasing pH When Hb binds to oxygen, it undergoes a conformational change that releases H ions from globin chains, decreasing pH Increasing pH in RBC will increase the affinity of Hb for oxygen Increasing pH in RBC will increase the affinity of Hb for oxygen In capillaries H + generated by carbonic anhydrase activity facilitates oxygen delivery to tissues (high CO 2 concentrations) In capillaries H + generated by carbonic anhydrase activity facilitates oxygen delivery to tissues (high CO 2 concentrations)

Oxygen Loading and Unloading

Bohr and Haldane Effects Bohr Effect Bohr Effect Describes the influence of CO 2 and pH on the release of O 2 Describes the influence of CO 2 and pH on the release of O 2 ↓ in pH (↑ in acidity) due to CO 2 and hydrogen ions can combine reversibly with Hb at the sites other than the O 2 binding sites (allosteric binding) ↓ in pH (↑ in acidity) due to CO 2 and hydrogen ions can combine reversibly with Hb at the sites other than the O 2 binding sites (allosteric binding) Results in a structural change of Hb, reducing its affinity for O 2 Results in a structural change of Hb, reducing its affinity for O 2 Haldane Effect Haldane Effect Displacement of O 2 from Hb increases affinity for CO 2 and hydrogen ions Displacement of O 2 from Hb increases affinity for CO 2 and hydrogen ions

Bohr and Haldane Effects Work together facilitating O 2 liberation and the uptake of CO 2 and hydrogen ions at the tissue level Work together facilitating O 2 liberation and the uptake of CO 2 and hydrogen ions at the tissue level A Bohr or Haldane shift reduces Hb affinity for O 2 A Bohr or Haldane shift reduces Hb affinity for O 2 Important in placental O 2 transport Important in placental O 2 transport pH is highest in arteries where O 2 is picked up (umbilical and placental arterioles) pH is highest in arteries where O 2 is picked up (umbilical and placental arterioles) pH is lowest at venules after CO 2 and hydrogen ions have been picked up pH is lowest at venules after CO 2 and hydrogen ions have been picked up Changes in pH and CO 2 on both maternal and fetal side of placenta regulate the rate of O 2 transfer to a great extent Changes in pH and CO 2 on both maternal and fetal side of placenta regulate the rate of O 2 transfer to a great extent

Bohr and Haldane Effects Fetal pH is lower (more acidic) than maternal pH Fetal pH is lower (more acidic) than maternal pH Fetal acidosis is metabolic and not related to the high PCO 2 Fetal acidosis is metabolic and not related to the high PCO 2 Primarily due to placentally produced lactate and pyruvate Primarily due to placentally produced lactate and pyruvate The effect of low pH on O 2 delivery to tissues is often overlooked, but may be important in maintaining O 2 delivery to tissues at an appropriate rate The effect of low pH on O 2 delivery to tissues is often overlooked, but may be important in maintaining O 2 delivery to tissues at an appropriate rate

2,3-Bisphosphoglycerate (2,3-BPG) Binds with greater affinity to deoxyhemoglobin Binds with greater affinity to deoxyhemoglobin Once it binds to first binding site, it allosterically affects other sites in hemoglobin to effectively increase the rate of release of oxygen at tissue level Once it binds to first binding site, it allosterically affects other sites in hemoglobin to effectively increase the rate of release of oxygen at tissue level Right-shift of curve Right-shift of curve

Fetal Hemoglobin (HbF) HbF has a higher affinity for O 2 than HbA HbF has a higher affinity for O 2 than HbA Two alpha-gamma dimers rather than two alpha- beta dimers Two alpha-gamma dimers rather than two alpha- beta dimers Creates a LEFT shift in the dissociation curve much like the effect of ↑ pH, ↓ temperature, or ↓ 2,3 BPG Creates a LEFT shift in the dissociation curve much like the effect of ↑ pH, ↓ temperature, or ↓ 2,3 BPG ↑ affinity for O 2 by Hb in the fetal blood enhances O 2 transport across the placenta After birth HbF declines as neonates begin to manufacture new erythrocytes and HbA HbF binds 2,3-BPG poorly

Hemoglobin Transitions

Fetal Hemoglobin

Cytochrome P 450 O 2 is MUCH more soluble in lipids (like membranes) than in water (as in plasma or cytoplasm) O 2 is MUCH more soluble in lipids (like membranes) than in water (as in plasma or cytoplasm) Cytochrome P 450 enhances transport processes due to its high affinity for O 2 and accumulates along the endoplasmic reticulum (ER) of placental cells Cytochrome P 450 enhances transport processes due to its high affinity for O 2 and accumulates along the endoplasmic reticulum (ER) of placental cells Many different varieties Many different varieties Most involve drug metabolism Most involve drug metabolism All incorporate oxygen into metabolic processes All incorporate oxygen into metabolic processes Tissues can up- or down-regulate the levels of this molecule to enhance O 2 transport into cell Tissues can up- or down-regulate the levels of this molecule to enhance O 2 transport into cell

Cytochrome P 450 ER forms channels from the cell membrane to the mitochondria allowing O 2 to move more freely throughout or across the cell ER forms channels from the cell membrane to the mitochondria allowing O 2 to move more freely throughout or across the cell Alignment of P 450 along the ER channels creates a high affinity, O 2 soluble freeway for O 2 to travel Alignment of P 450 along the ER channels creates a high affinity, O 2 soluble freeway for O 2 to travel P 450 enhances transplacental O 2 transport P 450 enhances transplacental O 2 transport Studies have shown blocking P 450 will decrease transplacental O 2 flux by over 75% Studies have shown blocking P 450 will decrease transplacental O 2 flux by over 75%

Fetal Gas Exchange CO 2 diffuses across placenta primarily in molecular form - not as bicarbonate ion CO 2 diffuses across placenta primarily in molecular form - not as bicarbonate ion Fetal P CO2 is higher than maternal Fetal P CO2 is higher than maternal Fetal oxygen consumption is equivalent to adult values Fetal oxygen consumption is equivalent to adult values Placenta is designed to protect the fetus from inadequate or excessive oxygen availability Placenta is designed to protect the fetus from inadequate or excessive oxygen availability

Fetal Gas Exchange Cont… Fetal mechanisms for protection against oxygen radicals are poorly developed prior to birth Fetal mechanisms for protection against oxygen radicals are poorly developed prior to birth Increased oxygen in fetal blood may have more adverse effects than beneficial effects Increased oxygen in fetal blood may have more adverse effects than beneficial effects Induction of superoxide dismutase is due to increased exposure to oxygen postnatally Induction of superoxide dismutase is due to increased exposure to oxygen postnatally

After Birth - O 2 Binding to Hb Factors affecting O 2 binding to Hb in the lung Factors affecting O 2 binding to Hb in the lung Primary factors Primary factors Perfusion of the area of the lung by blood Perfusion of the area of the lung by blood Ventilation rate of the newborn Ventilation rate of the newborn Efficiency of exchange across the tissue Efficiency of exchange across the tissue Other factors Other factors Presence of fluid in the lung (if not cleared after first breath) Presence of fluid in the lung (if not cleared after first breath) Presence of surfactant helps ventilation Presence of surfactant helps ventilation

After Birth - O 2 Binding to Hb Factors affecting O 2 unloading at the tissues Factors affecting O 2 unloading at the tissues Primary Primary Bohr and Haldane effects Bohr and Haldane effects Other factors Other factors Failure to thermoregulate or low body temperatures Failure to thermoregulate or low body temperatures Shifts the Hb dissociation curve adversely to the LEFT Shifts the Hb dissociation curve adversely to the LEFT Higher affinity for O 2, which is less likely to release oxygen to the tissue Higher affinity for O 2, which is less likely to release oxygen to the tissue

Oxygen Transport from the Hemoglobin to the Mitochondria Oxygen transport from the red blood cell (RBC) to the tissues occurs in the capillaries Oxygen transport from the red blood cell (RBC) to the tissues occurs in the capillaries RBC is deformed to an extent that the membrane is in direct contact with the cell membranes of the capillaries where O 2 unloading occurs RBC is deformed to an extent that the membrane is in direct contact with the cell membranes of the capillaries where O 2 unloading occurs O 2 can move across a concentration and pressure gradient (high in the RBC) to the tissues (low gradient) O 2 can move across a concentration and pressure gradient (high in the RBC) to the tissues (low gradient) O 2 then follows membranous channels created by the ER to move through the cells of the tissue being perfused O 2 then follows membranous channels created by the ER to move through the cells of the tissue being perfused

Oxygen Diffusion into Cells Primary determinant of oxygen flow rate into a cell is the P O2 in the capillaries Primary determinant of oxygen flow rate into a cell is the P O2 in the capillaries Second determinant is rate that the cell consumes oxygen Second determinant is rate that the cell consumes oxygen Function of mitochondrial density Function of mitochondrial density

Oxygen Diffusion Cont… Uneven spatial distribution of mitochondria within & between cells may allow both enhanced & parallel oxygen distribution & diffusion Uneven spatial distribution of mitochondria within & between cells may allow both enhanced & parallel oxygen distribution & diffusion Presence of myoglobin and/or cytochrome P 450 permit diffusion facilitation in some tissues (brain, liver, placenta) Presence of myoglobin and/or cytochrome P 450 permit diffusion facilitation in some tissues (brain, liver, placenta) Cytochrome P 450 aligns along endoplasmic reticulum as a high-affinity “bucket brigade” for oxygen - the ER forms a membranous channel (oxygen has higher solubility in fat than watery cytoplasm) from the cell membrane to the mitochondria Cytochrome P 450 aligns along endoplasmic reticulum as a high-affinity “bucket brigade” for oxygen - the ER forms a membranous channel (oxygen has higher solubility in fat than watery cytoplasm) from the cell membrane to the mitochondria As P O2 decreases, extent of facilitation increases (increased ER channels, mitochondria move closer to outer sell membrane, and cytochrome P 450 concentrations increase) As P O2 decreases, extent of facilitation increases (increased ER channels, mitochondria move closer to outer sell membrane, and cytochrome P 450 concentrations increase)

Newest Generation of Blood Substitutes or Hb Substitutes Perfluorocarbon-based solutions Perfluorocarbon-based solutions Offer very high affinity for oxygen Offer very high affinity for oxygen Carried in a solution rather than bound to Hb Carried in a solution rather than bound to Hb O 2 diffuses from an area of high concentration to low concentration whenever blood vessels are in close apposition to tissue O 2 diffuses from an area of high concentration to low concentration whenever blood vessels are in close apposition to tissue Useful when: Useful when: Blood volume has been compromised (as well as red blood cell count and Hb concentration) Blood volume has been compromised (as well as red blood cell count and Hb concentration) Lung function is compromised (respiratory distress syndrome in infants) Lung function is compromised (respiratory distress syndrome in infants)

Fetal, Newborn and Adult Hemoglobin Concentrations Fetal PO 2 Fetal PO mm Hg mm Hg Hypoxic fetus per se Hypoxic fetus per se Not true hypoxia as this value represents a normal range for this stage of life Not true hypoxia as this value represents a normal range for this stage of life ↑ fetal O 2 to adult values would be detrimental ↑ fetal O 2 to adult values would be detrimental Fetal O 2 consumption Fetal O 2 consumption 3-4 mL/kg 3-4 mL/kg Equivalent to adult values Equivalent to adult values ↑ affinity of HbF allows for greater saturation at any given partial pressure ↑ affinity of HbF allows for greater saturation at any given partial pressure Fetal high cardiac output Most important compensatory mechanism O 2 tensions ↓ tension may have teleological purpose Closure of the ductus arteriosus initiates at O 2 tensions greater than 55 mm Hg O 2 saturation in the fetus drops towards term

Fetal, Newborn and Adult Hemoglobin Concentrations O 2 consumption is extremely high in newborns O 2 consumption is extremely high in newborns Piglets Piglets Starts at 9 mL/kg at 37º C Starts at 9 mL/kg at 37º C Raises to mL/kg at 37º C Raises to mL/kg at 37º C 3-fold increase over fetal levels (and adult levels) 3-fold increase over fetal levels (and adult levels) Roughly corresponds to greater surface area/kg of the newborn relative to the adult Roughly corresponds to greater surface area/kg of the newborn relative to the adult This ↑ in O 2 consumption is necessary to maintain body temperature This ↑ in O 2 consumption is necessary to maintain body temperature

Fetal, Newborn and Adult Hemoglobin Concentrations Normal adult [Hb] Normal adult [Hb] g/dL g/dL Newborn [Hb] Newborn [Hb] g/dL g/dL Fetal [Hb] vary Fetal [Hb] vary [Hb] ↓ for the first few months after birth [Hb] ↓ for the first few months after birth Blood volume ↑ Blood volume ↑ Hematopoeisis is slow Hematopoeisis is slow ↓ O 2 carrying capacity at any given O 2 tension ↓ O 2 carrying capacity at any given O 2 tension Cattle Newborn Hb levels are much lower than in mature animals Roughly ½ that of adult levels Fragility of RBCs is increased during newborn period ↑ incidence of hemolytic diseases O 2 radicals stimulate: Lipid peroxidation Intracellular proteolysis Hemolysis in erythrocytes

Fetal, Newborn and Adult Hemoglobin Concentrations Cesarian deliveries (calves) Cesarian deliveries (calves) Significantly ↓ O 2 tension and pH (7.0 vs 7.2) Significantly ↓ O 2 tension and pH (7.0 vs 7.2) Significantly ↑ CO 2 tensions as compared to vaginal deliveries Significantly ↑ CO 2 tensions as compared to vaginal deliveries Dystocia (calves) ↓ bicarbonate (17 mmol/L vs. 26 mmol/L) Severe lactic acidosis Slightly ↑ CO2 tensions Eutocic calves (1st 24 hrs) pH increases to ~7.4 CO 2 remains steady O 2 tension ↑ slowly to 70 mm Hg Bicarbonate ↑ slowly to 28 mmol/L

Fetal Protective Mechanisms Placenta is a protective barrier from inadequate and excessive oxygen availability Placenta is a protective barrier from inadequate and excessive oxygen availability Either maternal hypoxia or hyperoxia will only have minimal effects on fetal oxygen concentrations Either maternal hypoxia or hyperoxia will only have minimal effects on fetal oxygen concentrations Fetal mechanisms for protection against oxygen radicals are poorly developed prior to birth Fetal mechanisms for protection against oxygen radicals are poorly developed prior to birth Increased O 2 in the fetal blood may have more adverse effects than beneficial Increased O 2 in the fetal blood may have more adverse effects than beneficial Change of O 2 at birth induces activity of several kidney and liver enzyme systems Change of O 2 at birth induces activity of several kidney and liver enzyme systems Stability of O 2 levels in the fetal system are critical to maintaining metabolic stability of the fetus Stability of O 2 levels in the fetal system are critical to maintaining metabolic stability of the fetus

Oxygen Deficiency Oxygen lack can be induced at any point in oxygen delivery system: Oxygen lack can be induced at any point in oxygen delivery system: Reduced oxygen in ambient gas mixture that is inhaled Reduced oxygen in ambient gas mixture that is inhaled Impaired pulmonary exchange Impaired pulmonary exchange Reduced oxygen content in blood Reduced oxygen content in blood Impaired exchange at cellular level Impaired exchange at cellular level

Oxygen Deficiency Cont… Chronic decreases in oxygen availability results in longer-term adaptive responses in delivery system Chronic decreases in oxygen availability results in longer-term adaptive responses in delivery system [Hb] increases (kidney medulla produces erythropoietin) [Hb] increases (kidney medulla produces erythropoietin) Affinity of Hb for oxygen may increase Affinity of Hb for oxygen may increase Increase in rate and depth of ventilation Increase in rate and depth of ventilation Increased cardiac output Increased cardiac output

Fetal Response to Hypoxia Depends on acuteness or chronicity of condition Depends on acuteness or chronicity of condition Can potentially have long term detrimental effects Can potentially have long term detrimental effects Neurological and/or metabolic responses Neurological and/or metabolic responses Hypoxic hypoxia Hypoxic hypoxia Hyperventilation and ↓ metabolic response Hyperventilation and ↓ metabolic response Tissue or organ damage Tissue or organ damage Hypercapnic hypoxia ↓ in neural autoregulation Lack of response of neonate SIDS seen especially in newborns of smokers CO binds tightly to Hb, O 2 not adequately exchanged

Fetal Response to Hypoxia Ischemic hypoxia Ischemic hypoxia Severe neurodevelopmental disabilities Severe neurodevelopmental disabilities Can lead to death Can lead to death Lactic acidosis due to anaerobic glycolysis Lactic acidosis due to anaerobic glycolysis Cardiovascular function depressed Cardiovascular function depressed Intermittent hypoxia Intermittent hypoxia Affect autonomic responses Affect autonomic responses Impaired performance in cognitive tasks Impaired performance in cognitive tasks

Neonatal Resistance to Hypoxia First reference to neonates ability to withstand anoxia by Boyle (1670) First reference to neonates ability to withstand anoxia by Boyle (1670) Kittens survived without oxygen longer then mature animals of same body weight Kittens survived without oxygen longer then mature animals of same body weight Earliest studies (Herman Kabat - late 1930’s) Earliest studies (Herman Kabat - late 1930’s) Demonstrated that young animals could tolerate extended periods of complete stoppage of brain circulation to a greater extent than adults Demonstrated that young animals could tolerate extended periods of complete stoppage of brain circulation to a greater extent than adults The return of normal function was much faster in the neonate, even if the period of anoxia was longer The return of normal function was much faster in the neonate, even if the period of anoxia was longer Survival time varies with maturity at birth Survival time varies with maturity at birth Newborn rats will survive 50 minutes in pure nitrogen compared to newborn guinea pigs that survive only 7 minutes Newborn rats will survive 50 minutes in pure nitrogen compared to newborn guinea pigs that survive only 7 minutes Guinea pigs are comparatively mature animals at birth Guinea pigs are comparatively mature animals at birth

Neonatal Resistance to Hypoxia Changes in heart function Changes in heart function Infant rats survived in nitrogen lived 50 minutes while the adults stopped breathing at 2-4 minutes Infant rats survived in nitrogen lived 50 minutes while the adults stopped breathing at 2-4 minutes The heart continued to beat after cessation of breathing The heart continued to beat after cessation of breathing Electrocardial alterations were noted Electrocardial alterations were noted

Neonatal Resistance to Hypoxia Changes in regional blood flow Changes in regional blood flow Altered in sheep during anoxia Altered in sheep during anoxia O 2 is conserved in crucial tissues at expense of hind limbs O 2 is conserved in crucial tissues at expense of hind limbs Fetal animals Fetal animals Preferential flow to the heart, brain, and adrenal glands Preferential flow to the heart, brain, and adrenal glands Limited placental and pulmonary flow Limited placental and pulmonary flow Loss of respiratory reflexes prior to loss of heart function Loss of respiratory reflexes prior to loss of heart function Brain flow maintains function in the midbrain, brainstem, and cerebellum at the expense of the cerebral cortex Brain flow maintains function in the midbrain, brainstem, and cerebellum at the expense of the cerebral cortex Blood flow may decrease to other non-essential regions of the body to the point of permanent impairment after reperfusion Blood flow may decrease to other non-essential regions of the body to the point of permanent impairment after reperfusion i.e. neonatal necrotizing enterocolitis i.e. neonatal necrotizing enterocolitis

Neonatal Resistance to Hypoxia Changes in energy status Changes in energy status Ability of neonate to obtain energy in the absence of O 2 is critical for survival Ability of neonate to obtain energy in the absence of O 2 is critical for survival 1931 – Reiss observed that whole body lactate content of asphyxiated neonates was 460% higher than baseline 1931 – Reiss observed that whole body lactate content of asphyxiated neonates was 460% higher than baseline 23% increase in asphyxiated adults 23% increase in asphyxiated adults Large carbohydrate reserve was still available in neonate Large carbohydrate reserve was still available in neonate Hypoglycemia reduces survival time by 50% in neonates Hypoglycemia reduces survival time by 50% in neonates

Neonatal Survival at Birth Survival time also varies with maturity at birth Survival time also varies with maturity at birth In term fetus, constriction of umbilical veins produce immediate bradycardia and decrease in arterial blood pressure In term fetus, constriction of umbilical veins produce immediate bradycardia and decrease in arterial blood pressure Constricting arterial flow or severing the cord will induce bradycardia with an increase in arterial pressure and increases carotid blood flow Constricting arterial flow or severing the cord will induce bradycardia with an increase in arterial pressure and increases carotid blood flow

Changes in Heart Function Prior to delivery ~50% of fetal cardiac output directed towards the placenta Prior to delivery ~50% of fetal cardiac output directed towards the placenta In bovine fetuses shortly prior to parturition subjected to anoxia by clamping umbilical cord, survival time was only 4 minutes In bovine fetuses shortly prior to parturition subjected to anoxia by clamping umbilical cord, survival time was only 4 minutes Heart activity continued for prolonged period after cessation of respiratory attempts Heart activity continued for prolonged period after cessation of respiratory attempts

Free Radicals & Reactive Oxygen Metabolites Oxygen can be toxic Oxygen can be toxic Pure oxygen in ambient air is fatal to all mammals Pure oxygen in ambient air is fatal to all mammals Chronic exposure to high oxygen can destroy ability of carotid bodies to detect low oxygen concentrations Chronic exposure to high oxygen can destroy ability of carotid bodies to detect low oxygen concentrations Most oxygen toxicity attributed to increased free radical production Most oxygen toxicity attributed to increased free radical production

Free Radicals Reactive oxygen metabolites (ROM) generated as byproduct of cellular respiration and during respiratory burst responses of neutrophils and macrophages. Reactive oxygen metabolites (ROM) generated as byproduct of cellular respiration and during respiratory burst responses of neutrophils and macrophages. ROM reportedly contributes to aging, promotion of cancer, & initiation of inflammation. ROM reportedly contributes to aging, promotion of cancer, & initiation of inflammation. Oxidative damage is non-specific for targets Oxidative damage is non-specific for targets Affects lipids, proteins, nucleic acids, carbohydrates, vitamins, and minerals Affects lipids, proteins, nucleic acids, carbohydrates, vitamins, and minerals

Nature of ROM Various forms of ROM Various forms of ROM Examples include superoxide anion, hydrogen peroxide, and hydroxyl radicals Examples include superoxide anion, hydrogen peroxide, and hydroxyl radicals All produced by sequential addition of a single electron to oxygen All produced by sequential addition of a single electron to oxygen Other free radicals formed that are physiologically important in neonatal period: Other free radicals formed that are physiologically important in neonatal period: Ex: nitric oxide: acts as endothelium-derived relaxation factor for blood vessels Ex: nitric oxide: acts as endothelium-derived relaxation factor for blood vessels

Nature of ROM Cont… All free radicals have short half-lives All free radicals have short half-lives OH - half-life a nanosecond OH - half-life a nanosecond O 21 half-life 2  s O 21 half-life 2  s NO half-life 4-6 s NO half-life 4-6 s By definition free radicals have unpaired electrons in outer orbital and are capable of independent existence By definition free radicals have unpaired electrons in outer orbital and are capable of independent existence Oxidative potential of ROM due to configuration of outer electrons Oxidative potential of ROM due to configuration of outer electrons

Protective Mechanisms ROM produced during normal metabolism of mammals ROM produced during normal metabolism of mammals Protective mechanisms developed to scavenge radicals and minimize their damaging effects Protective mechanisms developed to scavenge radicals and minimize their damaging effects Protective compounds included specific degradative enzymes, antioxidant vitamins, and others Protective compounds included specific degradative enzymes, antioxidant vitamins, and others Ex of vitamins: C, E, and carotenoids Ex of vitamins: C, E, and carotenoids Ex of enzymes: superoxide dismutase Ex of enzymes: superoxide dismutase

ROMs in the Perinatal Period Disorders associated with oxygenation of infants with respiratory distress syndrome include: chronic lung disease, retinopathy of prematurity, and intraventricular hemorrhage Disorders associated with oxygenation of infants with respiratory distress syndrome include: chronic lung disease, retinopathy of prematurity, and intraventricular hemorrhage Neonates have low circulating concentrations of vitamins E, C, and A at birth Neonates have low circulating concentrations of vitamins E, C, and A at birth Colostrum rich in fat-soluble vitamins and vitamin C, so high intake of colostrum important for premature infants or infants with respiratory distress. Colostrum rich in fat-soluble vitamins and vitamin C, so high intake of colostrum important for premature infants or infants with respiratory distress.

Structural Features in Oxygen Delivery Two factors to consider when looking at structure: Two factors to consider when looking at structure: 1. Features which allow blood flow to be distributed to various organs and tissues in an appropriate amount 1. Features which allow blood flow to be distributed to various organs and tissues in an appropriate amount 2. Design properties which determine gas exchange between blood and the cells 2. Design properties which determine gas exchange between blood and the cells Blood vessels permit oxygen delivery required by each tissue in proportion to the functional demands on the tissue Blood vessels permit oxygen delivery required by each tissue in proportion to the functional demands on the tissue

Structural Features Cont… Only brain maintains relatively constant metabolic activity at all times, all other organs go through periods of rest and activity Only brain maintains relatively constant metabolic activity at all times, all other organs go through periods of rest and activity Any particular organ must be able to allow adequate flow to meet peak metabolic needs and have potential to decrease blood flow when metabolic activity is low Any particular organ must be able to allow adequate flow to meet peak metabolic needs and have potential to decrease blood flow when metabolic activity is low

Poiseuille’s Law Blood flow can be described mathematically: Blood flow can be described mathematically: q=((  /(8 x n)) x (r 4 /l) x p q=((  /(8 x n)) x (r 4 /l) x p Where: Where: q= flow rate q= flow rate n= viscosity n= viscosity l= length l= length r= radius r= radius p= pressure p= pressure

Blood Flow Structures Blood flow through a system of tubes of finite diameter so results in a pressure drop Blood flow through a system of tubes of finite diameter so results in a pressure drop Arteries must be designed as large as possible to minimize these pressure drops at branch points but small enough to minimize blood volume that is moved by heart action Arteries must be designed as large as possible to minimize these pressure drops at branch points but small enough to minimize blood volume that is moved by heart action Body utilizes pressure changes to assist blood flow distribution since it will follow the path of least resistance Body utilizes pressure changes to assist blood flow distribution since it will follow the path of least resistance

Capillaries Capillaries follow a number of basic rules: Capillaries follow a number of basic rules: 1. Capillary walls are continuous to confine blood even in the finest vessels 1. Capillary walls are continuous to confine blood even in the finest vessels 2. Walls are minimal to facilitate gas and nutrient exchange with cells 2. Walls are minimal to facilitate gas and nutrient exchange with cells Two layers: endothelial and basement membrane Two layers: endothelial and basement membrane 3. Shape of network reflects shape of associated cells or groups of cells, and maintain a close apposition to these cells 3. Shape of network reflects shape of associated cells or groups of cells, and maintain a close apposition to these cells 4. Density of network is proportional to metabolic needs of the cells 4. Density of network is proportional to metabolic needs of the cells

Capillaries Capillaries follow a number of basic rules: Capillaries follow a number of basic rules: 1. Capillary walls are continuous to confine blood even in the finest vessels 1. Capillary walls are continuous to confine blood even in the finest vessels 2. Walls are minimal to facilitate gas and nutrient exchange with cells 2. Walls are minimal to facilitate gas and nutrient exchange with cells Two layers: endothelial and basement membrane Two layers: endothelial and basement membrane 3. Shape of network reflects shape of associated cells or groups of cells, and maintain a close apposition to these cells 3. Shape of network reflects shape of associated cells or groups of cells, and maintain a close apposition to these cells 4. Density of network is proportional to metabolic needs of the cells 4. Density of network is proportional to metabolic needs of the cells

Capillary Architecture for Gas Exchange Countercurrent design is most efficient for gas exchange Countercurrent design is most efficient for gas exchange Placental capillaries mostly countercurrent with some multicapillary or crosscurrent Placental capillaries mostly countercurrent with some multicapillary or crosscurrent

Umbilical Circulation Rate of umbilical blood flow is dependent on vascular resistance and the pressure gradients created through the descending aorta, placental circulation, and inferior vena cava Rate of umbilical blood flow is dependent on vascular resistance and the pressure gradients created through the descending aorta, placental circulation, and inferior vena cava In vitro umbilical vessels show almost no direct local effect in response to large changes in blood gas tension In vitro umbilical vessels show almost no direct local effect in response to large changes in blood gas tension

Timing of Umbilical Cord Rupture Blood flow continues through the placenta for ~1.5 min after first breath Blood flow continues through the placenta for ~1.5 min after first breath Constriction of umbilical vessels and stoppage of placental flow is initiated primarily by the change in oxygen tension associated with the shift from placental to pulmonary respiration Constriction of umbilical vessels and stoppage of placental flow is initiated primarily by the change in oxygen tension associated with the shift from placental to pulmonary respiration Bradykinins are peptides produced and released by pulmonary tissue in response to increased oxygen and bind to receptors in umbilical vessels, causing constriction and forcing more blood from placenta into newborn (placental blood transfusion) Bradykinins are peptides produced and released by pulmonary tissue in response to increased oxygen and bind to receptors in umbilical vessels, causing constriction and forcing more blood from placenta into newborn (placental blood transfusion) Transfer of placental blood into fetal system is not complete until umbilical constriction occurs Transfer of placental blood into fetal system is not complete until umbilical constriction occurs

Timing of Umbilical Rupture Cont… Umbilical arteries close prior to umbilical veins Umbilical arteries close prior to umbilical veins Only a small residual volume of blood remains in the placenta if cord is clamped after respiration is initiated Only a small residual volume of blood remains in the placenta if cord is clamped after respiration is initiated Delaying cord clamping in premature infants results in increased packed cell volume and arterial-alveolar oxygen tension differences and decreased reliance on supplemental oxygen compared to early clamping Delaying cord clamping in premature infants results in increased packed cell volume and arterial-alveolar oxygen tension differences and decreased reliance on supplemental oxygen compared to early clamping

Postnatal Oxygen Requirements Oxygen consumption of newborns is extremely high Oxygen consumption of newborns is extremely high ~3-fold increase over fetal levels ~3-fold increase over fetal levels Increase in oxygen consumption necessary primarily to maintain body temperature Increase in oxygen consumption necessary primarily to maintain body temperature