Oxygen Transport and Asphyxia

Oxygen Transport Oxygen Transport and Asphyxiaand Asphyxia

AnS 536AnS 536

Spring 2014Spring 2014

GoalsGoals

To transport oxygen from maternal To transport oxygen from maternal blood across the placenta to fetal blood across the placenta to fetal blood, and after birth from the lungs blood, and after birth from the lungs to the blood streamto the blood stream

To move oxygen from blood to To move oxygen from blood to tissues to allow aerobic metabolism tissues to allow aerobic metabolism (efficient production of ATP)(efficient production of ATP)

To move carbon dioxide in the To move carbon dioxide in the reverse directionreverse direction

ErythrocytesErythrocytes After maturation from stem cells in bone After maturation from stem cells in bone

marrow, erythrocytes have a circulating marrow, erythrocytes have a circulating life of ~120dlife of ~120d

Highly specialized cells:Highly specialized cells: Cytoplasm contains ~35% solution of Cytoplasm contains ~35% solution of

hemoglobin, but is devoid of subcellular hemoglobin, but is devoid of subcellular organellesorganelles

Cannot synthesize nucleic acids or proteins, Cannot synthesize nucleic acids or proteins, limited lipid metabolismlimited lipid metabolism

Carbohydrate metabolism devoted to Carbohydrate metabolism devoted to maintaining functional pumps on cell maintaining functional pumps on cell membranemembrane

ErythrocytesErythrocytes

After cell death, hemoglobin degraded After cell death, hemoglobin degraded and iron recycled to bone marrowand iron recycled to bone marrow

As they pass through capillaries, cells As they pass through capillaries, cells deform into ellipsoidal, hemispheric, or deform into ellipsoidal, hemispheric, or teardrop shapesteardrop shapes

Cell fragility increased during newborn Cell fragility increased during newborn periodperiod Increased risk and incidence of hemolytic Increased risk and incidence of hemolytic

diseasesdiseases

Transport of Gases in Transport of Gases in BloodBlood

PPO2O2 not only determines the dissolved not only determines the dissolved oxygen content of blood, but also affects oxygen content of blood, but also affects the amount of oxygen in reversible the amount of oxygen in reversible chemical combination with hemoglobinchemical combination with hemoglobin

Chemical and physiological actions of Chemical and physiological actions of gases depend on the partial pressures gases depend on the partial pressures they exert in the gas phase and in solution they exert in the gas phase and in solution in various body fluidsin various body fluids

HemoglobinHemoglobin

The sigmoidal shape of the oxygen The sigmoidal shape of the oxygen dissociation curve is physiologically importantdissociation curve is physiologically important Permits blood to deliver much more oxygen to Permits blood to deliver much more oxygen to

tissues than a hyperbolic curvetissues than a hyperbolic curve The binding of one molecule of OThe binding of one molecule of O22 increases increases

the affinity of the other sites for oxygenthe affinity of the other sites for oxygen Carbon dioxide binds to the globulin portions Carbon dioxide binds to the globulin portions

of the molecule rather than to the iron of the molecule rather than to the iron moleculesmolecules Accounts for about 10% of COAccounts for about 10% of CO22 transport transport

Video BreakVideo Break

http://www.youtube.com/watch?feature=player_detailpage&v=WXOBJEXxNEo

http://www.dnatube.com/video/274/Hemoglobin-Oxygen-Binding



http://www.dnatube.com/video/274/Hemoglobin-Oxygen-Binding

OO22-Hb Dissociation Curve-Hb Dissociation Curve

Illustrates a relationship between the partial pressure of oxygen (PO2) and percent saturated hemoglobin (Hb)

HemoglobinHemoglobin

When Hb binds to oxygen, it undergoes a When Hb binds to oxygen, it undergoes a conformational change that releases H conformational change that releases H ions from globin chains, decreasing pHions from globin chains, decreasing pH

Increasing pH in RBC will increase the Increasing pH in RBC will increase the affinity of Hb for oxygenaffinity of Hb for oxygen

In capillaries HIn capillaries H++ generated by carbonic generated by carbonic anhydrase activity facilitates oxygen anhydrase activity facilitates oxygen delivery to tissues (high COdelivery to tissues (high CO22 concentrations)concentrations)

Oxygen Loading and Oxygen Loading and UnloadingUnloading

Bohr and Haldane Bohr and Haldane EffectsEffects

Bohr EffectBohr Effect Describes the influence of CODescribes the influence of CO22 and pH on the and pH on the

release of Orelease of O22

↓ ↓ in pH (↑ in acidity) due to COin pH (↑ in acidity) due to CO22 and hydrogen and hydrogen ions can combine reversibly with Hb at the sites ions can combine reversibly with Hb at the sites other than the Oother than the O22 binding sites (allosteric binding) binding sites (allosteric binding)

Results in a structural change of Hb, reducing its Results in a structural change of Hb, reducing its affinity for Oaffinity for O22

Haldane EffectHaldane Effect Displacement of ODisplacement of O22 from Hb increases from Hb increases

affinity for COaffinity for CO22 and hydrogen ions and hydrogen ions


Work together facilitating OWork together facilitating O22 liberation and the liberation and the uptake of COuptake of CO22 and hydrogen ions at the tissue and hydrogen ions at the tissue levellevel

A Bohr or Haldane shift reduces Hb affinity for OA Bohr or Haldane shift reduces Hb affinity for O22

Important in placental OImportant in placental O22 transport transport pH is highest in arteries where OpH is highest in arteries where O22 is picked up is picked up

(umbilical and placental arterioles)(umbilical and placental arterioles) pH is lowest at venules after COpH is lowest at venules after CO22 and hydrogen ions and hydrogen ions

have been picked uphave been picked up Changes in pH and COChanges in pH and CO22 on both maternal and fetal on both maternal and fetal

side of placenta regulate the rate of Oside of placenta regulate the rate of O22 transfer to a transfer to a great extentgreat extent


Fetal pH is lower (more acidic) than Fetal pH is lower (more acidic) than maternal pHmaternal pH

Fetal acidosis is metabolic and not related Fetal acidosis is metabolic and not related to the high PCOto the high PCO22

Primarily due to placentally produced lactate Primarily due to placentally produced lactate and pyruvateand pyruvate

The effect of low pH on OThe effect of low pH on O22 delivery to tissues delivery to tissues is often overlooked, but may be important in is often overlooked, but may be important in maintaining Omaintaining O22 delivery to tissues at an delivery to tissues at an appropriate rateappropriate rate

2,3-Bisphosphoglycerate2,3-Bisphosphoglycerate(2,3-BPG)(2,3-BPG)

Binds with greater affinity to Binds with greater affinity to deoxyhemoglobin deoxyhemoglobin Once it binds to first binding site, it Once it binds to first binding site, it

allosterically affects other sites in allosterically affects other sites in hemoglobin to effectively increase the hemoglobin to effectively increase the rate of release of oxygen at tissue levelrate of release of oxygen at tissue level Right-shift of curveRight-shift of curve

Fetal Hemoglobin (HbF)Fetal Hemoglobin (HbF) HbF has a higher HbF has a higher

affinity for Oaffinity for O22 than HbA than HbA Two alpha-gamma Two alpha-gamma

dimers rather than two dimers rather than two alpha-beta dimersalpha-beta dimers

Creates a LEFT shift in Creates a LEFT shift in the dissociation curve the dissociation curve much like the effect of much like the effect of ↑↑ pH, pH, ↓↓ temperature, temperature, or or ↓ 2,3 BPG ↓ 2,3 BPG

↑ ↑ affinity for Oaffinity for O22 by Hb by Hb in the fetal blood in the fetal blood enhances Oenhances O22 transport transport across the placentaacross the placenta

After birth HbF After birth HbF declines as neonates declines as neonates begin to manufacture begin to manufacture new erythrocytes and new erythrocytes and HbAHbA

HbF binds 2,3-BPG HbF binds 2,3-BPG poorlypoorly

Hemoglobin TransitionsHemoglobin Transitions

Fetal HemoglobinFetal Hemoglobin

Fetal HemoglobinFetal Hemoglobin

Cytochrome PCytochrome P450450

OO22 is MUCH more soluble in lipids (like is MUCH more soluble in lipids (like membranes) than in water (as in plasma or membranes) than in water (as in plasma or cytoplasm)cytoplasm)

Cytochrome PCytochrome P450450 enhances transport processes enhances transport processes due to its high affinity for Odue to its high affinity for O22 and accumulates and accumulates along the endoplasmic reticulum (ER) of along the endoplasmic reticulum (ER) of placental cellsplacental cells

Many different varietiesMany different varieties Most involve drug metabolismMost involve drug metabolism All incorporate oxygen into metabolic processesAll incorporate oxygen into metabolic processes Tissues can up- or down-regulate the levels of this Tissues can up- or down-regulate the levels of this

molecule to enhance Omolecule to enhance O22 transport into cell transport into cell

Cytochrome PCytochrome P450450

ER forms channels from the cell membrane ER forms channels from the cell membrane to the mitochondria allowing Oto the mitochondria allowing O22 to move to move more freely throughout or across the cellmore freely throughout or across the cell

Alignment of PAlignment of P450450 along the ER channels along the ER channels creates a high affinity, Ocreates a high affinity, O22 soluble freeway soluble freeway for Ofor O22 to travel to travel

PP450450 enhances transplacental O enhances transplacental O22 transport transport

Studies have shown blocking PStudies have shown blocking P450450 will will decrease transplacental Odecrease transplacental O22 flux by over 75% flux by over 75%

Fetal Gas ExchangeFetal Gas Exchange

COCO22 diffuses across placenta diffuses across placenta primarily in molecular form - not as primarily in molecular form - not as bicarbonate ionbicarbonate ion

Fetal PFetal PCO2CO2 is higher than maternal is higher than maternal Fetal oxygen consumption is Fetal oxygen consumption is

equivalent to adult valuesequivalent to adult values Placenta is designed to protect the Placenta is designed to protect the

fetus from inadequate or excessive fetus from inadequate or excessive oxygen availabilityoxygen availability

Fetal Gas Exchange Fetal Gas Exchange Cont…Cont…

Fetal mechanisms for protection Fetal mechanisms for protection against oxygen radicals are poorly against oxygen radicals are poorly developed prior to birthdeveloped prior to birth

Increased oxygen in fetal blood may Increased oxygen in fetal blood may have more adverse effects than have more adverse effects than beneficial effectsbeneficial effects Induction of superoxide dismutase is Induction of superoxide dismutase is

due to increased exposure to oxygen due to increased exposure to oxygen postnatallypostnatally

After Birth - OAfter Birth - O22 Binding Binding to Hbto Hb

Factors affecting OFactors affecting O22 binding to Hb in binding to Hb in the lungthe lung Primary factorsPrimary factors

Perfusion of the area of the lung by bloodPerfusion of the area of the lung by blood Ventilation rate of the newbornVentilation rate of the newborn Efficiency of exchange across the tissueEfficiency of exchange across the tissue

Other factorsOther factors Presence of fluid in the lung Presence of fluid in the lung

(if not cleared after first breath)(if not cleared after first breath) Presence of surfactant helps ventilationPresence of surfactant helps ventilation

After Birth - OAfter Birth - O22 Binding Binding to Hbto Hb

Factors affecting OFactors affecting O22 unloading at the unloading at the tissuestissues PrimaryPrimary

Bohr and Haldane effectsBohr and Haldane effects Other factorsOther factors

Failure to thermoregulate or low body Failure to thermoregulate or low body temperaturestemperatures

Shifts the Hb dissociation curve adversely to the LEFTShifts the Hb dissociation curve adversely to the LEFT Higher affinity for OHigher affinity for O22, which is less likely to , which is less likely to

release release oxygen to the tissueoxygen to the tissue

Oxygen Transport from the Oxygen Transport from the Hemoglobin to the Hemoglobin to the

MitochondriaMitochondria Oxygen transport from the red blood cell Oxygen transport from the red blood cell

(RBC) to the tissues occurs in the capillaries(RBC) to the tissues occurs in the capillaries RBC is deformed to an extent that the membrane RBC is deformed to an extent that the membrane

is in direct contact with the cell membranes of is in direct contact with the cell membranes of the capillaries where Othe capillaries where O22 unloading occurs unloading occurs

OO22 can move across a concentration and pressure can move across a concentration and pressure gradient (high in the RBC) to the tissues (low gradient (high in the RBC) to the tissues (low gradient)gradient)

OO22 then follows membranous channels created by then follows membranous channels created by the ER to move through the cells of the tissue the ER to move through the cells of the tissue being perfusedbeing perfused

Oxygen Diffusion into Oxygen Diffusion into CellsCells

Primary determinant of oxygen flow Primary determinant of oxygen flow rate into a cell is the Prate into a cell is the PO2O2 in the in the capillariescapillaries

Second determinant is rate that the Second determinant is rate that the cell consumes oxygencell consumes oxygen Function of mitochondrial densityFunction of mitochondrial density

Oxygen Diffusion Cont…Oxygen Diffusion Cont… Uneven spatial distribution of mitochondria Uneven spatial distribution of mitochondria

within & between cells may allow both enhanced within & between cells may allow both enhanced & parallel oxygen distribution & diffusion& parallel oxygen distribution & diffusion

Presence of myoglobin and/or cytochrome PPresence of myoglobin and/or cytochrome P450450 permit diffusion facilitation in some tissues permit diffusion facilitation in some tissues (brain, liver, placenta)(brain, liver, placenta) Cytochrome PCytochrome P450450 aligns along endoplasmic reticulum aligns along endoplasmic reticulum

as a high-affinity “bucket brigade” for oxygen - the as a high-affinity “bucket brigade” for oxygen - the ER forms a membranous channel (oxygen has higher ER forms a membranous channel (oxygen has higher solubility in fat than watery cytoplasm) from the cell solubility in fat than watery cytoplasm) from the cell membrane to the mitochondriamembrane to the mitochondria

As PAs PO2O2 decreases, extent of facilitation increases decreases, extent of facilitation increases (increased ER channels, mitochondria move closer to (increased ER channels, mitochondria move closer to outer sell membrane, and cytochrome Pouter sell membrane, and cytochrome P450450 concentrations increase)concentrations increase)

Newest Generation of Blood Newest Generation of Blood Substitutes or Hb Substitutes or Hb

SubstitutesSubstitutes Perfluorocarbon-based solutionsPerfluorocarbon-based solutions

Offer very high affinity for oxygenOffer very high affinity for oxygen Carried in a solution rather than bound to HbCarried in a solution rather than bound to Hb OO22 diffuses from an area of high diffuses from an area of high

concentration to low concentration whenever concentration to low concentration whenever blood vessels are in close apposition to tissueblood vessels are in close apposition to tissue

Useful when:Useful when: Blood volume has been compromised (as well as Blood volume has been compromised (as well as

red blood cell count and Hb concentration)red blood cell count and Hb concentration) Lung function is compromised Lung function is compromised

(respiratory distress syndrome in infants)(respiratory distress syndrome in infants)

Fetal, Newborn and Adult Fetal, Newborn and Adult Hemoglobin ConcentrationsHemoglobin Concentrations

Fetal POFetal PO22 22-29 mm Hg22-29 mm Hg Hypoxic fetus per seHypoxic fetus per se

Not true hypoxia as this Not true hypoxia as this value represents a normal value represents a normal range for this stage of liferange for this stage of life

↑ ↑ fetal Ofetal O22 to adult values to adult values would be detrimentalwould be detrimental

Fetal OFetal O22 consumption consumption 3-4 mL/kg3-4 mL/kg Equivalent to adult Equivalent to adult

valuesvalues ↑ ↑ affinity of HbF allows affinity of HbF allows

for greater saturation at for greater saturation at any given partial any given partial pressurepressure

Fetal high cardiac Fetal high cardiac outputoutput Most important Most important

compensatory compensatory mechanismmechanism

OO22 tensions tensions ↓ ↓ tension may have tension may have

teleological purposeteleological purpose Closure of the Closure of the

ductus arteriosus ductus arteriosus initiates at Oinitiates at O22 tensions tensions greater than greater than 55 mm Hg 55 mm Hg

OO22 saturation in the fetus saturation in the fetus drops towards termdrops towards term

Fetal, Newborn and Adult Fetal, Newborn and Adult Hemoglobin ConcentrationsHemoglobin Concentrations OO22 consumption is extremely high in consumption is extremely high in

newbornsnewborns PigletsPiglets

Starts at 9 mL/kg at 37º CStarts at 9 mL/kg at 37º C Raises to 25-30 mL/kg at 37º CRaises to 25-30 mL/kg at 37º C 3-fold increase over fetal levels (and adult 3-fold increase over fetal levels (and adult

levels)levels) Roughly corresponds to greater surface area/kg Roughly corresponds to greater surface area/kg

of the newborn relative to the adultof the newborn relative to the adult This ↑ in OThis ↑ in O22 consumption is necessary to consumption is necessary to

maintain body temperaturemaintain body temperature


Normal adult [Hb]Normal adult [Hb] 14-15 g/dL14-15 g/dL

Newborn [Hb]Newborn [Hb] 16-17 g/dL16-17 g/dL Fetal [Hb] varyFetal [Hb] vary

[Hb] ↓ for the first [Hb] ↓ for the first few months after few months after birthbirth Blood volume ↑Blood volume ↑ Hematopoeisis is slowHematopoeisis is slow ↓ ↓ OO22 carrying carrying

capacity at any given capacity at any given OO22 tension tension

CattleCattle Newborn Hb levels are Newborn Hb levels are

much lower than in much lower than in mature animalsmature animals

Roughly ½ that of adult Roughly ½ that of adult levelslevels

Fragility of RBCs is Fragility of RBCs is increased during newborn increased during newborn periodperiod

↑ ↑ incidence of hemolytic incidence of hemolytic diseasesdiseases

OO22 radicals stimulate: radicals stimulate: Lipid peroxidationLipid peroxidation Intracellular proteolysisIntracellular proteolysis Hemolysis in erythrocytesHemolysis in erythrocytes


Cesarian deliveries Cesarian deliveries (calves)(calves) Significantly ↓ OSignificantly ↓ O22

tension and pH (7.0 tension and pH (7.0 vs 7.2)vs 7.2)

Significantly ↑ COSignificantly ↑ CO22 tensions as compared tensions as compared to vaginal deliveriesto vaginal deliveries

Dystocia (calves)Dystocia (calves) ↓ ↓ bicarbonate bicarbonate

(17 mmol/L vs. 26 mmol/L)(17 mmol/L vs. 26 mmol/L) Severe lactic acidosisSevere lactic acidosis Slightly ↑ CO2 tensionsSlightly ↑ CO2 tensions

Eutocic calves (1st 24 Eutocic calves (1st 24 hrs)hrs) pH increases to ~7.4pH increases to ~7.4 COCO22 remains steady remains steady

OO22 tension ↑ slowly to tension ↑ slowly to 70 mm Hg70 mm Hg

Bicarbonate ↑ slowly to Bicarbonate ↑ slowly to 28 mmol/L28 mmol/L

Fetal Protective Fetal Protective MechanismsMechanisms

Placenta is a protective barrier from inadequate Placenta is a protective barrier from inadequate and excessive oxygen availabilityand excessive oxygen availability

Either maternal hypoxia or hyperoxia will only Either maternal hypoxia or hyperoxia will only have minimal effects on fetal oxygen have minimal effects on fetal oxygen concentrationsconcentrations

Fetal mechanisms for protection against oxygen Fetal mechanisms for protection against oxygen radicals are poorly developed prior to birthradicals are poorly developed prior to birth Increased OIncreased O22 in the fetal blood may have more in the fetal blood may have more

adverse effects than beneficialadverse effects than beneficial Change of OChange of O22 at birth induces activity of several at birth induces activity of several

kidney and liver enzyme systemskidney and liver enzyme systems Stability of OStability of O22 levels in the fetal system are critical to levels in the fetal system are critical to

maintaining metabolic stability of the fetusmaintaining metabolic stability of the fetus

Oxygen DeficiencyOxygen Deficiency

Oxygen lack can be induced at any Oxygen lack can be induced at any point in oxygen delivery system:point in oxygen delivery system: Reduced oxygen in ambient gas mixture Reduced oxygen in ambient gas mixture

that is inhaledthat is inhaled Impaired pulmonary exchangeImpaired pulmonary exchange Reduced oxygen content in bloodReduced oxygen content in blood Impaired exchange at cellular levelImpaired exchange at cellular level

Oxygen Deficiency Cont…Oxygen Deficiency Cont…

Chronic decreases in oxygen Chronic decreases in oxygen availability results in longer-term availability results in longer-term adaptive responses in delivery adaptive responses in delivery systemsystem [Hb] increases (kidney medulla [Hb] increases (kidney medulla

produces erythropoietin)produces erythropoietin) Affinity of Hb for oxygen may increaseAffinity of Hb for oxygen may increase Increase in rate and depth of ventilationIncrease in rate and depth of ventilation Increased cardiac outputIncreased cardiac output

Fetal Response to Fetal Response to HypoxiaHypoxia

Depends on acuteness Depends on acuteness or chronicity of or chronicity of conditioncondition

Can potentially have Can potentially have long term detrimental long term detrimental effectseffects Neurological and/or Neurological and/or

metabolic responsesmetabolic responses Hypoxic hypoxiaHypoxic hypoxia

Hyperventilation and Hyperventilation and ↓ metabolic response↓ metabolic response

Tissue or organ damageTissue or organ damage

Hypercapnic Hypercapnic hypoxiahypoxia ↓ ↓ in neural in neural

autoregulationautoregulation Lack of response of Lack of response of

neonateneonate SIDS seen especially SIDS seen especially

in newborns of in newborns of smokerssmokers

CO binds tightly to CO binds tightly to Hb, OHb, O22 not adequately not adequately exchangedexchanged

Fetal Response to Fetal Response to HypoxiaHypoxia

Ischemic hypoxiaIschemic hypoxia Severe neurodevelopmental disabilitiesSevere neurodevelopmental disabilities Can lead to deathCan lead to death Lactic acidosis due to anaerobic glycolysisLactic acidosis due to anaerobic glycolysis Cardiovascular function depressedCardiovascular function depressed

Intermittent hypoxiaIntermittent hypoxia Affect autonomic responsesAffect autonomic responses Impaired performance in cognitive tasksImpaired performance in cognitive tasks

Neonatal Resistance to Neonatal Resistance to HypoxiaHypoxia

First reference to neonates ability to withstand First reference to neonates ability to withstand anoxia by Boyle (1670)anoxia by Boyle (1670) Kittens survived without oxygen longer then mature Kittens survived without oxygen longer then mature

animals of same body weightanimals of same body weight Earliest studies (Herman Kabat - late 1930’s)Earliest studies (Herman Kabat - late 1930’s)

Demonstrated that young animals could tolerate Demonstrated that young animals could tolerate extended periods of complete stoppage of brain extended periods of complete stoppage of brain circulation to a greater extent than adultscirculation to a greater extent than adults

The return of normal function was much faster in the The return of normal function was much faster in the neonate, even if the period of anoxia was longer neonate, even if the period of anoxia was longer

Survival time varies with maturity at birthSurvival time varies with maturity at birth Newborn rats will survive 50 minutes in pure nitrogen Newborn rats will survive 50 minutes in pure nitrogen

compared to newborn guinea pigs that survive only 7 compared to newborn guinea pigs that survive only 7 minutesminutes

Guinea pigs are comparatively mature animals at birthGuinea pigs are comparatively mature animals at birth


Changes in heart functionChanges in heart function Infant rats survived in nitrogen lived 50 Infant rats survived in nitrogen lived 50

minutes while the adults stopped minutes while the adults stopped breathing at 2-4 minutesbreathing at 2-4 minutes The heart continued to beat after cessation The heart continued to beat after cessation

of breathingof breathing Electrocardial alterations were notedElectrocardial alterations were noted


Changes in regional blood flowChanges in regional blood flow Altered in sheep during anoxiaAltered in sheep during anoxia

OO22 is conserved in crucial tissues at expense of hind limbs is conserved in crucial tissues at expense of hind limbs

Fetal animalsFetal animals Preferential flow to the heart, brain, and adrenal glandsPreferential flow to the heart, brain, and adrenal glands Limited placental and pulmonary flowLimited placental and pulmonary flow Loss of respiratory reflexes prior to loss of heart functionLoss of respiratory reflexes prior to loss of heart function Brain flow maintains function in the midbrain, brainstem, Brain flow maintains function in the midbrain, brainstem,

and cerebellum at the expense of the cerebral cortexand cerebellum at the expense of the cerebral cortex Blood flow may decrease to other non-essential regions of Blood flow may decrease to other non-essential regions of

the body to the point of permanent impairment after the body to the point of permanent impairment after reperfusionreperfusion

i.e. neonatal necrotizing enterocolitisi.e. neonatal necrotizing enterocolitis


Changes in energy statusChanges in energy status Ability of neonate to obtain energy in the Ability of neonate to obtain energy in the

absence of Oabsence of O22 is critical for survival is critical for survival 1931 – Reiss observed that whole body 1931 – Reiss observed that whole body

lactate content of asphyxiated neonates was lactate content of asphyxiated neonates was 460% higher than baseline460% higher than baseline

23% increase in asphyxiated adults23% increase in asphyxiated adults Large carbohydrate reserve was still Large carbohydrate reserve was still

available in neonateavailable in neonate Hypoglycemia reduces survival time by 50% Hypoglycemia reduces survival time by 50%

in neonatesin neonates

Neonatal Survival at Neonatal Survival at BirthBirth

Survival time also varies with Survival time also varies with maturity at birthmaturity at birth

In term fetus, constriction of In term fetus, constriction of umbilical veins produce immediate umbilical veins produce immediate bradycardia and decrease in arterial bradycardia and decrease in arterial blood pressureblood pressure Constricting arterial flow or severing Constricting arterial flow or severing

the cord will induce bradycardia with the cord will induce bradycardia with an increase in arterial pressure and an increase in arterial pressure and increases carotid blood flowincreases carotid blood flow

Changes in Heart Changes in Heart FunctionFunction

Prior to delivery ~50% of fetal Prior to delivery ~50% of fetal cardiac output directed towards the cardiac output directed towards the placentaplacenta

In bovine fetuses shortly prior to In bovine fetuses shortly prior to parturition subjected to anoxia by parturition subjected to anoxia by clamping umbilical cord, survival clamping umbilical cord, survival time was only 4 minutestime was only 4 minutes Heart activity continued for prolonged Heart activity continued for prolonged

period after cessation of respiratory period after cessation of respiratory attemptsattempts

Free Radicals & Reactive Free Radicals & Reactive Oxygen MetabolitesOxygen Metabolites

Oxygen can be toxicOxygen can be toxic Pure oxygen in ambient air is fatal to all Pure oxygen in ambient air is fatal to all

mammalsmammals Chronic exposure to high oxygen can Chronic exposure to high oxygen can

destroy ability of carotid bodies to destroy ability of carotid bodies to detect low oxygen concentrationsdetect low oxygen concentrations

Most oxygen toxicity attributed to Most oxygen toxicity attributed to increased free radical productionincreased free radical production

Free RadicalsFree Radicals Reactive oxygen metabolites (ROM) Reactive oxygen metabolites (ROM)

generated as byproduct of cellular generated as byproduct of cellular respiration and during respiratory burst respiration and during respiratory burst responses of neutrophils and macrophages.responses of neutrophils and macrophages.

ROM reportedly contributes to aging, ROM reportedly contributes to aging, promotion of cancer, & initiation of promotion of cancer, & initiation of inflammation.inflammation.

Oxidative damage is non-specific for targetsOxidative damage is non-specific for targets Affects lipids, proteins, nucleic acids, Affects lipids, proteins, nucleic acids,

carbohydrates, vitamins, and mineralscarbohydrates, vitamins, and minerals

Nature of ROMNature of ROM

Various forms of ROMVarious forms of ROM Examples include superoxide anion, hydrogen Examples include superoxide anion, hydrogen

peroxide, and hydroxyl radicalsperoxide, and hydroxyl radicals All produced by sequential addition of a All produced by sequential addition of a

single electron to oxygensingle electron to oxygen Other free radicals formed that are Other free radicals formed that are

physiologically important in neonatal physiologically important in neonatal period:period: Ex: nitric oxide: acts as endothelium-derived Ex: nitric oxide: acts as endothelium-derived

relaxation factor for blood vesselsrelaxation factor for blood vessels

Nature of ROM Cont…Nature of ROM Cont…

All free radicals have short half-livesAll free radicals have short half-lives OHOH-- half-life a nanosecond half-life a nanosecond OO2121 half-life 2 half-life 2 ss NO half-life 4-6 sNO half-life 4-6 s

By definition free radicals have unpaired By definition free radicals have unpaired electrons in outer orbital and are capable electrons in outer orbital and are capable of independent existenceof independent existence Oxidative potential of ROM due to Oxidative potential of ROM due to

configuration of outer electronsconfiguration of outer electrons

Protective MechanismsProtective Mechanisms ROM produced during normal metabolism ROM produced during normal metabolism

of mammalsof mammals Protective mechanisms developed to Protective mechanisms developed to

scavenge radicals and minimize their scavenge radicals and minimize their damaging effectsdamaging effects

Protective compounds included specific Protective compounds included specific degradative enzymes, antioxidant degradative enzymes, antioxidant vitamins, and othersvitamins, and others Ex of vitamins: C, E, and carotenoidsEx of vitamins: C, E, and carotenoids Ex of enzymes: superoxide dismutaseEx of enzymes: superoxide dismutase

ROMs in the Perinatal ROMs in the Perinatal PeriodPeriod

Disorders associated with oxygenation of Disorders associated with oxygenation of infants with respiratory distress syndrome infants with respiratory distress syndrome include: chronic lung disease, retinopathy include: chronic lung disease, retinopathy of prematurity, and intraventricular of prematurity, and intraventricular hemorrhagehemorrhage

Neonates have low circulating Neonates have low circulating concentrations of vitamins E, C, and A at concentrations of vitamins E, C, and A at birthbirth Colostrum rich in fat-soluble vitamins and Colostrum rich in fat-soluble vitamins and

vitamin C, so high intake of colostrum vitamin C, so high intake of colostrum important for premature infants or infants important for premature infants or infants with respiratory distress.with respiratory distress.

Structural Features in Structural Features in Oxygen DeliveryOxygen Delivery

Two factors to consider when looking at Two factors to consider when looking at structure:structure: 1. Features which allow blood flow to be 1. Features which allow blood flow to be

distributed to various organs and tissues in an distributed to various organs and tissues in an appropriate amountappropriate amount

2. Design properties which determine gas 2. Design properties which determine gas exchange between blood and the cellsexchange between blood and the cells

Blood vessels permit oxygen delivery Blood vessels permit oxygen delivery required by each tissue in proportion to required by each tissue in proportion to the functional demands on the tissuethe functional demands on the tissue

Structural Features Structural Features Cont…Cont…

Only brain maintains relatively constant Only brain maintains relatively constant metabolic activity at all times, all other metabolic activity at all times, all other organs go through periods of rest and organs go through periods of rest and activityactivity

Any particular organ must be able to Any particular organ must be able to allow adequate flow to meet peak allow adequate flow to meet peak metabolic needs and have potential to metabolic needs and have potential to decrease blood flow when metabolic decrease blood flow when metabolic activity is lowactivity is low

Poiseuille’s LawPoiseuille’s Law

Blood flow can be described Blood flow can be described mathematically:mathematically: q=((q=((/(8 x n)) x (r/(8 x n)) x (r44/l) x p/l) x p Where:Where:

q= flow rateq= flow rate n= viscosityn= viscosity l= lengthl= length r= radiusr= radius p= pressurep= pressure

Blood Flow StructuresBlood Flow Structures

Blood flow through a system of tubes of Blood flow through a system of tubes of finite diameter so results in a pressure finite diameter so results in a pressure dropdrop

Arteries must be designed as large as Arteries must be designed as large as possible to minimize these pressure drops possible to minimize these pressure drops at branch points but small enough to at branch points but small enough to minimize blood volume that is moved by minimize blood volume that is moved by heart actionheart action Body utilizes pressure changes to assist blood Body utilizes pressure changes to assist blood

flow distribution since it will follow the path of flow distribution since it will follow the path of least resistanceleast resistance

CapillariesCapillaries Capillaries follow a number of basic rules:Capillaries follow a number of basic rules:

1. Capillary walls are continuous to confine 1. Capillary walls are continuous to confine blood even in the finest vesselsblood even in the finest vessels

2. Walls are minimal to facilitate gas and 2. Walls are minimal to facilitate gas and nutrient exchange with cellsnutrient exchange with cells

Two layers: endothelial and basement membraneTwo layers: endothelial and basement membrane 3. Shape of network reflects shape of 3. Shape of network reflects shape of

associated cells or groups of cells, and associated cells or groups of cells, and maintain a close apposition to these cellsmaintain a close apposition to these cells

4. Density of network is proportional to 4. Density of network is proportional to metabolic needs of the cellsmetabolic needs of the cells

CapillariesCapillaries Capillaries follow a number of basic rules:Capillaries follow a number of basic rules:

1. Capillary walls are continuous to confine 1. Capillary walls are continuous to confine blood even in the finest vesselsblood even in the finest vessels

2. Walls are minimal to facilitate gas and 2. Walls are minimal to facilitate gas and nutrient exchange with cellsnutrient exchange with cells

Two layers: endothelial and basement membraneTwo layers: endothelial and basement membrane 3. Shape of network reflects shape of 3. Shape of network reflects shape of

associated cells or groups of cells, and associated cells or groups of cells, and maintain a close apposition to these cellsmaintain a close apposition to these cells

4. Density of network is proportional to 4. Density of network is proportional to metabolic needs of the cellsmetabolic needs of the cells

Capillary Architecture Capillary Architecture for Gas Exchangefor Gas Exchange

Countercurrent design is Countercurrent design is most efficient for gas most efficient for gas exchangeexchange

Placental capillaries Placental capillaries mostly countercurrent mostly countercurrent with some multicapillary with some multicapillary or crosscurrentor crosscurrent

Umbilical CirculationUmbilical Circulation

Rate of umbilical blood flow is Rate of umbilical blood flow is dependent on vascular resistance and dependent on vascular resistance and the pressure gradients created through the pressure gradients created through the descending aorta, placental the descending aorta, placental circulation, and inferior vena cavacirculation, and inferior vena cava

In vitro umbilical vessels show almost In vitro umbilical vessels show almost no direct local effect in response to no direct local effect in response to large changes in blood gas tensionlarge changes in blood gas tension

Timing of Umbilical Cord Timing of Umbilical Cord RuptureRupture

Blood flow continues through the placenta for Blood flow continues through the placenta for ~1.5 min after first breath~1.5 min after first breath

Constriction of umbilical vessels and stoppage Constriction of umbilical vessels and stoppage of placental flow is initiated primarily by the of placental flow is initiated primarily by the change in oxygen tension associated with the change in oxygen tension associated with the shift from placental to pulmonary respirationshift from placental to pulmonary respiration Bradykinins are peptides produced and released by Bradykinins are peptides produced and released by

pulmonary tissue in response to increased oxygen pulmonary tissue in response to increased oxygen and bind to receptors in umbilical vessels, causing and bind to receptors in umbilical vessels, causing constriction and forcing more blood from placenta constriction and forcing more blood from placenta into newborn (placental blood transfusion)into newborn (placental blood transfusion)

Transfer of placental blood into fetal system is not Transfer of placental blood into fetal system is not complete until umbilical constriction occurscomplete until umbilical constriction occurs

Timing of Umbilical Timing of Umbilical Rupture Cont…Rupture Cont…

Umbilical arteries close prior to umbilical Umbilical arteries close prior to umbilical veinsveins

Only a small residual volume of blood Only a small residual volume of blood remains in the placenta if cord is clamped remains in the placenta if cord is clamped after respiration is initiatedafter respiration is initiated

Delaying cord clamping in premature infants Delaying cord clamping in premature infants results in increased packed cell volume and results in increased packed cell volume and arterial-alveolar oxygen tension differences arterial-alveolar oxygen tension differences and decreased reliance on supplemental and decreased reliance on supplemental oxygen compared to early clampingoxygen compared to early clamping

Postnatal Oxygen Postnatal Oxygen RequirementsRequirements

Oxygen consumption of newborns is Oxygen consumption of newborns is extremely highextremely high ~3-fold increase over fetal levels~3-fold increase over fetal levels

Increase in oxygen consumption Increase in oxygen consumption necessary primarily to maintain body necessary primarily to maintain body temperaturetemperature

Documents

Oxygen Transport and Asphyxia