HYPOXIAHYPOXIADR.TINKU JOSEPHDR.TINKU JOSEPH

DM RESIDENTDM RESIDENTDEPARTMENT OF PULMONARY MEDICINEDEPARTMENT OF PULMONARY MEDICINE

AIMS, KOCHIAIMS, KOCHI..

Email-:tinkujoseph2010@gmail.comEmail-:tinkujoseph2010@gmail.com

TABLE OF CONTENTSTABLE OF CONTENTS

Hypoxia & Hypoxemia.Hypoxia & Hypoxemia. CausesCauses MechanismMechanism TypesTypes Effects of hypoxia.Effects of hypoxia.

HypoxiaHypoxia

A lack of oxygen at the tissue level of the body A lack of oxygen at the tissue level of the body due to a decreased partial pressure of oxygen.due to a decreased partial pressure of oxygen.

Tissue suffers from hypoxia whenever there is Tissue suffers from hypoxia whenever there is decreased delivery of O2 or when tissue fails to decreased delivery of O2 or when tissue fails to utilize available O2.utilize available O2. Normally 1000 ml/minute (550 ml/min/mNormally 1000 ml/minute (550 ml/min/m22) of ) of

oxygen is transported from the lungs to the oxygen is transported from the lungs to the periphery by the circulation periphery by the circulation

Only 25% of this is utilized in a resting person. Only 25% of this is utilized in a resting person.

Causes of HypoxiaCauses of Hypoxia

Anemic HypoxiaAnemic Hypoxia Carbon Monoxide IntoxicationCarbon Monoxide Intoxication Respiratory HypoxiaRespiratory Hypoxia Hypoxia Secondary to High AltitudeHypoxia Secondary to High Altitude Hypoxia Secondary to Right-to-Left Hypoxia Secondary to Right-to-Left

Extrapulmonary ShuntingExtrapulmonary Shunting Circulatory HypoxiaCirculatory Hypoxia Specific Organ HypoxiaSpecific Organ Hypoxia Increased O2 RequirementsIncreased O2 Requirements Improper Oxygen UtilizationImproper Oxygen Utilization

HYPOXAEMIAHYPOXAEMIA

Hypoxaemia is considered to be present when Hypoxaemia is considered to be present when arterial oxyhaemoglobin saturation is less than arterial oxyhaemoglobin saturation is less than 90 %, corresponding to an arterial blood oxygen 90 %, corresponding to an arterial blood oxygen partial pressure (PaO2) of less than 60 mmHgpartial pressure (PaO2) of less than 60 mmHg

CausesCausesa. Alveolar hypoventilationa. Alveolar hypoventilationb. Ventilation-Perfusion (V/Q) mismatchb. Ventilation-Perfusion (V/Q) mismatch

-Impaired diffusion-Impaired diffusionc. Venous admixturec. Venous admixture

Transport of oxygenTransport of oxygen Oxygen delivery to a particular tissue depends onOxygen delivery to a particular tissue depends on1.1. Amount of O2 entering the lungs.Amount of O2 entering the lungs.

2.2. Adequacy of pulmonary gas exchange.Adequacy of pulmonary gas exchange.

3.3. Blood flow to the tissue.Blood flow to the tissue.

4.4. Capacity of blood to carry O2.Capacity of blood to carry O2.

Transport of oxygenTransport of oxygen

The amount of O2 in the blood is determined by:The amount of O2 in the blood is determined by:1.1. Amount of dissolved O2Amount of dissolved O2

2.2. Amount of Hb in blood.Amount of Hb in blood.

3.3. Affinity of Hb for O2.Affinity of Hb for O2.

Transport of oxygenTransport of oxygen Oxygen delivery to tissue takes place in three Oxygen delivery to tissue takes place in three

steps :steps :

1.1. Uptake of 02 by the blood in the lungsUptake of 02 by the blood in the lungs Mainly favoured by O2 pressure gradient.Mainly favoured by O2 pressure gradient. Inspired air 150mmHgInspired air 150mmHg Alveolar air 104mmHgAlveolar air 104mmHg Arterial blood 94mmHgArterial blood 94mmHg Venous blood 40mmHgVenous blood 40mmHg

This pressure gradient favours the diffusion of This pressure gradient favours the diffusion of O2 from the lungs into the blood.O2 from the lungs into the blood.

Diffusion of O2 from the lungs into the blood is Diffusion of O2 from the lungs into the blood is also influenced by :also influenced by :

a) Thickness of alvelocapillary membrane – eg: a) Thickness of alvelocapillary membrane – eg: pulmonary fibrosis.pulmonary fibrosis.

b) Area of membrane - eg: lung collapse or b) Area of membrane - eg: lung collapse or uneven ventilation perfusion ratio the area takes uneven ventilation perfusion ratio the area takes part in gas exchange is less.part in gas exchange is less.

c) Diffusion co-efficient of O2.c) Diffusion co-efficient of O2.

Diffusion co-efficient depends on the solubility Diffusion co-efficient depends on the solubility and molecular weight of a gas.and molecular weight of a gas.

Compared to Co2 the solubility of O2 in H2o is Compared to Co2 the solubility of O2 in H2o is 20 times less. So diffusion rate of O2 is less than 20 times less. So diffusion rate of O2 is less than Co2.Co2.

Diffusion co-efficient of Diffusion co-efficient of O2 – 1.0O2 – 1.0 Co2 – 20.3Co2 – 20.3 Co – 0.81Co – 0.81

Oxygen enters the bloodOxygen enters the blood

Dissolves in plasmaDissolves in plasma

Dissolved oxygen diffuses into RBCDissolved oxygen diffuses into RBC

Combines with haemoglobinCombines with haemoglobin

When one molecule of O2 combines with Hb,the When one molecule of O2 combines with Hb,the affinity to O2 increases. And so further affinity to O2 increases. And so further combination with O2 is facilitated.combination with O2 is facilitated.

Because of this O-D curve is sigmoid in shape.Because of this O-D curve is sigmoid in shape. When Hb takes up O2 the two chains alpha 1& When Hb takes up O2 the two chains alpha 1&

beta 2 move away and when O2 is given up they beta 2 move away and when O2 is given up they move closer.move closer.

This is responsible for increase or decrease of This is responsible for increase or decrease of affinity of Hb to O2affinity of Hb to O2

Blood remains for 0.8 sec in the lung capillaries.Blood remains for 0.8 sec in the lung capillaries. Requires 0.3 sec for complete oxygenation of Requires 0.3 sec for complete oxygenation of

Hb.Hb. Saturated to 97% due to AV admixture & Saturated to 97% due to AV admixture &

uneven ventilation perfusion ratio(physiological)uneven ventilation perfusion ratio(physiological)

2) Transport of O2 in blood2) Transport of O2 in blood Two forms Two forms : dissolved form & combined form as : dissolved form & combined form as

HbO2.HbO2.

DISSOLVED FORM

COMBINED FORM

TOTAL

ARTERIAL 0.30 ml/100ml 19.7ml/100ml 20ml

VENOUS 0.12 14.88 15.0

Difference 5.0ml

2) Transport of O2 in blood2) Transport of O2 in blood

Each gram of Hb carry about 1.34ml of O2.Each gram of Hb carry about 1.34ml of O2. Arterial blood contains 20ml of O2.Arterial blood contains 20ml of O2. Gives about 5ml to tissue.Gives about 5ml to tissue. 100ml of blood delivers about 5ml of O2 to the 100ml of blood delivers about 5ml of O2 to the

tissue.tissue. 5 L of blood flows to organs each minute5 L of blood flows to organs each minute Total O2 delivered to tissue in one minute is Total O2 delivered to tissue in one minute is

250ml.250ml.

Co-efficient of O2 utilization Co-efficient of O2 utilization = (A-V)O2 * 100 = 5 * 100= (A-V)O2 * 100 = 5 * 100 Arterial content 20 Arterial content 20 = 25% = 25%

Only 25% O2 is utilized by tissue.Only 25% O2 is utilized by tissue. Rest O2 acts as reserve which may be mobilized during Rest O2 acts as reserve which may be mobilized during

stressful conditions(eg: exercise)stressful conditions(eg: exercise)

3)Delivery of oxygen to tissue3)Delivery of oxygen to tissue Pressure gradient between the arterial blood and Pressure gradient between the arterial blood and

the tissue is mainly responsible for the release of the tissue is mainly responsible for the release of O2 to the tissue.O2 to the tissue.

Arterial blood 97mmHgArterial blood 97mmHg Interstitial fluid 40mmHgInterstitial fluid 40mmHg Intracellular 25mmHgIntracellular 25mmHg Other factors : 1) pao2 2) paco2 3) tempOther factors : 1) pao2 2) paco2 3) temp 4) H+ ion 5) 2-3 DPG4) H+ ion 5) 2-3 DPG

Hbo2 dissociation curve:Hbo2 dissociation curve: A curve showing relationship A curve showing relationship

between po2 & % of Hb between po2 & % of Hb saturation.saturation.

At po2 of 26mmHg Hb is 50% At po2 of 26mmHg Hb is 50% saturated.This is called p-50.saturated.This is called p-50.

At 40mmHg,Hb is 75% At 40mmHg,Hb is 75% saturated.saturated.

At 60mmHg,Hb is 90% At 60mmHg,Hb is 90% saturated.saturated.

So even if the Po2 of inspired air So even if the Po2 of inspired air falls to 60mmg,Hb saturation is falls to 60mmg,Hb saturation is not affected muchnot affected much

When curve shift to the right,O2 is released.When curve shift to the right,O2 is released. This is influenced by 1) This is influenced by 1) pao2 in tissue – gives more pao2 in tissue – gives more

pressure gradient so O2 released.pressure gradient so O2 released. 2) paco2 – shifts curve to right.2) paco2 – shifts curve to right. 3) temp – facilitates diffusion process.3) temp – facilitates diffusion process. 4) H+ ion- - shifts curve to right.The effect of pco2 & 4) H+ ion- - shifts curve to right.The effect of pco2 &

H+ ion on O-D curve is called Bohr effect.H+ ion on O-D curve is called Bohr effect. 5) 2-3 DPG – HbA has more affinity to 2-3 DPG than 5) 2-3 DPG – HbA has more affinity to 2-3 DPG than

O2.HbF has less affinity to 2-3 DPG compared to HbA.O2.HbF has less affinity to 2-3 DPG compared to HbA.

2-3 DPG usually binds to beta chains.2-3 DPG usually binds to beta chains. 2-3 DPG is formed as a side reaction during 2-3 DPG is formed as a side reaction during

glycolyisis.glycolyisis. Its production more in Its production more in

hypoxia,alkalosis,anaemia, reduced in stored hypoxia,alkalosis,anaemia, reduced in stored blood, hyperthyroidism & fever.blood, hyperthyroidism & fever.

Hbo2 + 2-3 DPG Hb 2-3 DPG + O2Hbo2 + 2-3 DPG Hb 2-3 DPG + O2

Transport of carbon DioxideTransport of carbon Dioxide

Co2 is transported from tissues to lungs.Co2 is transported from tissues to lungs. Delivery of co2 to lungs depend on :Delivery of co2 to lungs depend on :

1.1. The blood O2 contentThe blood O2 content

2.2. Number of RBC present in the blood.Number of RBC present in the blood.

3.3. Amount of reduced Hb.Amount of reduced Hb.

Transport of Co2 takes place in 3 steps.Transport of Co2 takes place in 3 steps. 1) uptake of Co2 by the blood1) uptake of Co2 by the blood: co2 enters the blood : co2 enters the blood

mainly because of pressure gradient.mainly because of pressure gradient. IntracellularIntracellular – 46mmHg – 46mmHg

Interstitial fluid Interstitial fluid – 45mmHg– 45mmHg

Arterial blood Arterial blood – 40mmHg– 40mmHg This is also facilitated by the release of O2 to the tissue.This is also facilitated by the release of O2 to the tissue. When Co2 enters the blood it either enters into plasma When Co2 enters the blood it either enters into plasma

or directly into RBC.or directly into RBC.

In the plasma:In the plasma: A) It is hydrated to H2co3 which splits up to H+ and A) It is hydrated to H2co3 which splits up to H+ and

HCO3. H+ is neutralized.HCO3. H+ is neutralized. Co2 + H2o H2CO3 H+ + HCO3Co2 + H2o H2CO3 H+ + HCO3 B) some amount of Co2 combines with plasma proteins B) some amount of Co2 combines with plasma proteins

and forms carbamino compounds.and forms carbamino compounds. C) Some amount dissolves in plasma.C) Some amount dissolves in plasma. In the RBC: In the RBC: A) It gets hydrated and takes part in chloride shift.A) It gets hydrated and takes part in chloride shift. Carbonic acid thus formed splits up into H+ and HCO3.Carbonic acid thus formed splits up into H+ and HCO3. H+ is accepted by HbH+ is accepted by Hb

HCO3 concentration increases & diffuses out into HCO3 concentration increases & diffuses out into plasma and to maintain electro neutrality CL ion enters plasma and to maintain electro neutrality CL ion enters RBC.RBC.

HCO3 Cl exchange is brought about by band three HCO3 Cl exchange is brought about by band three protein present in RBC membrane.protein present in RBC membrane.

Chloride bicarbonate shift RBC gains more number of Chloride bicarbonate shift RBC gains more number of ions. H2O moves into RBC to maintain tonicity.ions. H2O moves into RBC to maintain tonicity.

RBC volume increases. That is why hematocrit of RBC volume increases. That is why hematocrit of venous blood is more.venous blood is more.

Also called Humberger phenomenon.Also called Humberger phenomenon.

B) some amount of Co2 directly combines with Hb & B) some amount of Co2 directly combines with Hb & forms carbamino Hbforms carbamino Hb

C) small amount of Co2 combines with proteins C) small amount of Co2 combines with proteins present in RBC directly and forms carbamino proteins.present in RBC directly and forms carbamino proteins.

D) small amount of Co2 dissolves in cytoplasm of D) small amount of Co2 dissolves in cytoplasm of RBC.RBC.

2)Transport in the blood2)Transport in the blood

Each 100ml of blood picks up about 4ml of Each 100ml of blood picks up about 4ml of Co2.Co2.

Co2 is transported in arterial & venous blood in Co2 is transported in arterial & venous blood in various forms.various forms.

a) Dissolved form.a) Dissolved form. b ) Carbamino compounds.b ) Carbamino compounds. c ) Bicarbonate.c ) Bicarbonate.

3)Delivery of Co2 to the lungs3)Delivery of Co2 to the lungs

Pressure gradientPressure gradient Venous blood – 45mmHgVenous blood – 45mmHg

Alveoli – 40mmHgAlveoli – 40mmHg

Types of HypoxiaTypes of Hypoxia

1.1. Hypoxic hypoxia.Hypoxic hypoxia.

2.2. Anaemic hypoxia.Anaemic hypoxia.

3.3. Stagnant hypoxia.Stagnant hypoxia.

4.4. Histotoxic hypoxia.Histotoxic hypoxia.

Hypoxic hypoxemiaHypoxic hypoxemia

Decrease in arterial Po2.Decrease in arterial Po2. Increase in Pco2 and H+ ions.Increase in Pco2 and H+ ions. Blood oxygen is reduced.So, delivery of O2 to tissue is Blood oxygen is reduced.So, delivery of O2 to tissue is

affected.affected. Conditions:Conditions: A) A) Low Po2 in inspired air Low Po2 in inspired air : eg: mines,high : eg: mines,high

altitudes,closed chambers.altitudes,closed chambers. B) B) HypoventilationHypoventilation : eg: airway obstruction,paralysis of : eg: airway obstruction,paralysis of

respiratory muscles,depression of respiratory respiratory muscles,depression of respiratory centre,kyphoscoliosis.centre,kyphoscoliosis.

C) Diffusion defect: eg: pulmonary oedema, pulmonary C) Diffusion defect: eg: pulmonary oedema, pulmonary fibrosis,lung collapse.fibrosis,lung collapse.

D) Abnormal ventilation perfusion ratio: In large A-V D) Abnormal ventilation perfusion ratio: In large A-V shunts,atelectasis,lung collapse and cyanotic congenital shunts,atelectasis,lung collapse and cyanotic congenital heart disease.heart disease.

Anaemic hypoxemiaAnaemic hypoxemia Arterial Po2 is normal but the amount of hemoglobin Arterial Po2 is normal but the amount of hemoglobin

available to carry O2 is reduced.available to carry O2 is reduced. Conditions:Conditions: A) low Hb level A) low Hb level – Po2 of inspired air is normal, lungs – Po2 of inspired air is normal, lungs

normal so diffusion of O2 into blood is normal. Hence normal so diffusion of O2 into blood is normal. Hence po2 of blood is normal.But O2 content is reduced.po2 of blood is normal.But O2 content is reduced.

When there is mild anaemia usually O2 supply to tissue When there is mild anaemia usually O2 supply to tissue is not affected due to concomitant rise in 2-3 DPG.is not affected due to concomitant rise in 2-3 DPG.

However during exercise sufficient O2 cannot be However during exercise sufficient O2 cannot be delivered to the tissue.delivered to the tissue.

B) Carbon monoxide poisoning B) Carbon monoxide poisoning – there is high affinity – there is high affinity of Hb to O2.of Hb to O2.

Due to effect of COHb,so O2 delivery to tissue is Due to effect of COHb,so O2 delivery to tissue is reduced.reduced.

C) Altered Hb (methaemoglobin)C) Altered Hb (methaemoglobin) – iron is in ferric – iron is in ferric form and oxygen does not dissociate.form and oxygen does not dissociate.

Stagnant hypoxemiaStagnant hypoxemia(ischemic hypoxemia)(ischemic hypoxemia)

Blood flow to tissue is so low that adequate 02 is Blood flow to tissue is so low that adequate 02 is not delivered to it despite a normal Po2 and not delivered to it despite a normal Po2 and hemoglobin concentration.hemoglobin concentration.

Conditions:Conditions: A) ShockA) Shock B) Heart failureB) Heart failure C) Intravascular obstruction.C) Intravascular obstruction.

Histotoxic hypoxemiaHistotoxic hypoxemia

Amount of 02 delivered to tissue is adequate but, Amount of 02 delivered to tissue is adequate but, because of the action of toxic agent the tissue cells because of the action of toxic agent the tissue cells cannot make use of the 02 supplied to them.cannot make use of the 02 supplied to them.

Conditions:Conditions: A) Cyanide poisoning A) Cyanide poisoning – cytochrome oxidase function is – cytochrome oxidase function is

paralysed. So tissue cannot utilise O2. oxygen content paralysed. So tissue cannot utilise O2. oxygen content of the arterial blood and blood flow rate are normalof the arterial blood and blood flow rate are normal ..

B) Diptheria B) Diptheria – toxins inhibit the synthesis of one of the – toxins inhibit the synthesis of one of the cytochromes and prevent oxygen utilization.cytochromes and prevent oxygen utilization.

Treatment :Treatment : 1) Methylene blue or nitrates.1) Methylene blue or nitrates. These act by forming methaemoglobin which reacts These act by forming methaemoglobin which reacts

with cyanide to form cyanometheamoglobin a non with cyanide to form cyanometheamoglobin a non toxic compound.toxic compound.

2) Hyberbaric oxygen therapy is less useful.2) Hyberbaric oxygen therapy is less useful. 3) Diphtheria is treated with appropriate drugs3) Diphtheria is treated with appropriate drugs..

Symptoms of Hypoxemia and HypoxiaSymptoms of Hypoxemia and Hypoxia

Respiratory Respiratory Tachypnoea,breathlesness,dyspnoea,cyanosisTachypnoea,breathlesness,dyspnoea,cyanosis

Cardiovascular :Cardiovascular : increased cardiac output, palpitaions, increased cardiac output, palpitaions, tachycardia,arrhythmias,hypotension,angina,vasodilatiotachycardia,arrhythmias,hypotension,angina,vasodilation,diaphoresis and shock.n,diaphoresis and shock.

CNS :CNS :Headache,impaired judgement,inappropriate Headache,impaired judgement,inappropriate behavouir,confusion,euphoria,delirium,restlesness, behavouir,confusion,euphoria,delirium,restlesness, papilledema,seizures.papilledema,seizures.

Neuromuscular :Neuromuscular :weakness, tremor, asterixis, weakness, tremor, asterixis, hyperreflexia, incoordination.hyperreflexia, incoordination.

Metabolic: Metabolic: sodium and water retension,lactic acidosissodium and water retension,lactic acidosis

Hypoxic Injury To Cells (1)Hypoxic Injury To Cells (1)

REVERSIBLE changes:REVERSIBLE changes: impaired aerobic respiration (mitochondria) impaired aerobic respiration (mitochondria) decreased ATP (energy) decreased ATP (energy) anerobic glycolysis anerobic glycolysis glycogen depletion glycogen depletion accumulation of lactic acid (intracellular acidosis) accumulation of lactic acid (intracellular acidosis)

with associated nuclear chromatin clumpingwith associated nuclear chromatin clumping

Hypoxic Injury To Cells (2)Hypoxic Injury To Cells (2)

IRREVERSIBLE changesIRREVERSIBLE changes:: vacuolization of mitochondriavacuolization of mitochondria swelling of lysosomes swelling of lysosomes damage to plasma membranesdamage to plasma membranes

loss of phospholipids (decreased synthesis and increased loss of phospholipids (decreased synthesis and increased degradation). degradation).

cytoskeletal alterations (damage to cytoskeletal-membrane cytoskeletal alterations (damage to cytoskeletal-membrane connections, effects of cell swelling, activation of proteases) connections, effects of cell swelling, activation of proteases)

effects of free radicals (toxic oxygen radicals or toxic oxygen effects of free radicals (toxic oxygen radicals or toxic oxygen species, produced by PMN's) species, produced by PMN's)

lipid breakdown products (free fatty acids and other with a lipid breakdown products (free fatty acids and other with a detergent effect on cell membrane)detergent effect on cell membrane)

Hypoxic Injury To Cells (3)Hypoxic Injury To Cells (3)

influx of Ca++ into the cell and mitochondria with inhibition influx of Ca++ into the cell and mitochondria with inhibition of cellular enzymesof cellular enzymes

denaturation of proteins and coagulation of cells (coagulative denaturation of proteins and coagulation of cells (coagulative necrosis)necrosis)

cell components are degraded by inflammatory processes, cell components are degraded by inflammatory processes, with associated further enzyme leakages and release of with associated further enzyme leakages and release of inflammatory mediatorsinflammatory mediators

final breakdown product of dead cells include free fatty acids final breakdown product of dead cells include free fatty acids which attract Ca++ with formation of soapswhich attract Ca++ with formation of soaps

Effects of HypoxiaEffects of Hypoxia

Changes in the central nervous system, Changes in the central nervous system, particularly the higher centersparticularly the higher centers

Impaired judgment, motor incoordinationImpaired judgment, motor incoordination Fatigue, drowsiness, apathy, inattentiveness, Fatigue, drowsiness, apathy, inattentiveness,

delayed reaction time, and reduced work delayed reaction time, and reduced work capacitycapacity

Death usually results from respiratory failure Death usually results from respiratory failure (Brainstem hypoxia)(Brainstem hypoxia)

Hypoxic-ischemic Hypoxic-ischemic encephalopathyencephalopathy

Impaired judgment, inattentiveness, motor Impaired judgment, inattentiveness, motor incoordination, and, at times, euphoriaincoordination, and, at times, euphoria

Circulatory arrest --> consciousness is lost Circulatory arrest --> consciousness is lost within secondswithin seconds

Circulation is restored within 3 to 5 min --> full Circulation is restored within 3 to 5 min --> full recovery may occur (eg. Neonatal asphyxia)recovery may occur (eg. Neonatal asphyxia)

Hypoxia-ischemia lasts beyond 3 to 5 min --> Hypoxia-ischemia lasts beyond 3 to 5 min --> some degree of permanent cerebral damagesome degree of permanent cerebral damage

Hypoxic-ischemic Hypoxic-ischemic encephalopathyencephalopathy

““Delayed injuryDelayed injury”” ( may continue for days to ( may continue for days to weeks): 6-24 hours after the initial injury, a new weeks): 6-24 hours after the initial injury, a new phase of neuronal destruction sets in, phase of neuronal destruction sets in, characterized by apoptosischaracterized by apoptosis

Pulmonary Hypertension (PH)Pulmonary Hypertension (PH)

A common companion of many congenital A common companion of many congenital disease (CHD)disease (CHD)

Eisenmenger syndrome: right-to-left shuntsEisenmenger syndrome: right-to-left shunts Heart-lung transplantationHeart-lung transplantation

ErythrocytosisErythrocytosis

Increased erythropoietin productionIncreased erythropoietin production Phlebotomy for recurrent hyperviscosity Phlebotomy for recurrent hyperviscosity

symptomssymptoms

HyperviscosityHyperviscosity

Phlebotomy, when required for symptoms of Phlebotomy, when required for symptoms of hyperviscosity not due to dehydration or iron hyperviscosity not due to dehydration or iron deficiency, is a simple outpatient removal of 500 deficiency, is a simple outpatient removal of 500 mL of blood over 45 min with isovolumetric mL of blood over 45 min with isovolumetric replacement with isotonic saline (5% dextrose if replacement with isotonic saline (5% dextrose if congestive heart failure exists)congestive heart failure exists)

Iron repletion must be done graduallyIron repletion must be done gradually

Abnormal Abnormal HemostasisHemostasis

Increased blood volume and engorged capillariesIncreased blood volume and engorged capillaries Abnormalities in platelet functionAbnormalities in platelet function Abnormalities of the extrinsic and intrinsic Abnormalities of the extrinsic and intrinsic

coagulation systemcoagulation system

Pathogenesis of Ischemic-associated Pathogenesis of Ischemic-associated ThrombosisThrombosis

transcription factor early growth response-1 transcription factor early growth response-1 (Egr-1) --> de novo transcription/translation of (Egr-1) --> de novo transcription/translation of tissue facto in mononuclear phagocytes and tissue facto in mononuclear phagocytes and smooth muscle cells --> vascular fibrin smooth muscle cells --> vascular fibrin deposition.deposition.

Concomitant suppression of fibrinolysis by Concomitant suppression of fibrinolysis by hypoxia-mediated upregulation of plasminogen hypoxia-mediated upregulation of plasminogen activator inhibitor-1activator inhibitor-1

Hypoxia-induced PHHypoxia-induced PH

alveolar hypoxia involves most of the lung and is prolonged --> alveolar hypoxia involves most of the lung and is prolonged --> any usefulness of acute hypoxic any usefulness of acute hypoxic pulmonary vasoconstrictionpulmonary vasoconstriction is is offset by a rise in pulmonary arterial pressure. offset by a rise in pulmonary arterial pressure.

structural changes in small peripheral pulmonary arteries: structural changes in small peripheral pulmonary arteries: increased wall thickness of muscular arteries, the appearance of increased wall thickness of muscular arteries, the appearance of new muscle in normally non-muscular arteries. new muscle in normally non-muscular arteries. Eg. COPD, populations living at high attitudeEg. COPD, populations living at high attitude

Genetic susceptabilityGenetic susceptability HIF (Hypoxia inducible factor)-1HIF (Hypoxia inducible factor)-1 Endothelin-1Endothelin-1 Angiotensin IIAngiotensin II

Oxidant tissue injury in hypoxic PHOxidant tissue injury in hypoxic PH

Increase of radical production induced by lung tissue Increase of radical production induced by lung tissue hypoxiahypoxia

Hypoxia Hypoxia alveolar macrophages alveolar macrophages hydrogen hydrogen peroxideperoxide

Nitric oxide; serum concentration of nitrotyrosine Nitric oxide; serum concentration of nitrotyrosine (radical product of nitric oxide and superoxide (radical product of nitric oxide and superoxide interaction)interaction)

Radicals Radicals metabolism of vascular wall matrix proteins metabolism of vascular wall matrix proteins vascular remodeling vascular remodeling Thickened and less Thickened and less compliant peripheral pulmonary vasculaturecompliant peripheral pulmonary vasculature

Chronic-intermittent hypoxia Chronic-intermittent hypoxia induced hypertensioninduced hypertension

chronic-intermittent hypoxia (as obstructive chronic-intermittent hypoxia (as obstructive sleep apnea syndrome --> activation of the sleep apnea syndrome --> activation of the sympathetic nervous system (included cortical sympathetic nervous system (included cortical and brainstem components) --> hypertensionand brainstem components) --> hypertension

Other organs under hypoxic Other organs under hypoxic environment environment

More acute hypoxic damages than chronic More acute hypoxic damages than chronic damagesdamages KidneyKidney LiverLiver IntestineIntestine PancreasPancreas

ReferenceReference

HarrisonHarrison’’s Principles of Internal Medicine, 15th ed.s Principles of Internal Medicine, 15th ed. Review of medical physiology by william F. Ganong, 20Review of medical physiology by william F. Ganong, 20 thth ed. ed. Fundamentals of medical physiology L prakasam Reddy 3Fundamentals of medical physiology L prakasam Reddy 3 rdrd ed. ed. Photographs taken from various websites. Photographs taken from various websites.