Hypoxia

M.D., Ph.D., Associate Professor, Marta R. Gerasymchuk

Hypoxia —
inadequate
oxygenation of
tissue
Hypoxemia —low
arterial oxygen
tension
MD, PhD, Associate Professor, Marta R. Gerasymchuk

FACTORS CONTRIBUTING TO THE
TOTAL AMOUNT OF O2 CARRIED
IN BLOOD
Decrease in O2 content due to a decrease in Hb, PaO2, or
SaO2 causes an increase in EPO
In the alveoli, O2 increases
the partial pressure of O2
(PaO2)
In the plasma of the pulmonary capillaries, O2
increases the partial pressure of O2 (PaO2)
O2 content is a measure of the total amount of O2
carried in blood and includes the Hb concentration as
well as the PaO2 and SaO2
PaO2 & SaO2 are reported in arterial blood gas analyses
O2 diffuses down a gradient
from the atmosphere to the
alveoli, to plasma, and into
the RBCs, where it attaches
to heme groups
In the RBC, O2 attaches to heme groups and increases
the O2 saturation (SaO2)

In hypoxia, there is decreased synthesis of
adenosine triphosphate (ATP).
ATP synthesis occurs in the inner
mitochondrial membrane by the
process of oxidative
phosphorylation
O2 is an electron acceptor
located at the end of the electron
transport chain (ETC) in complex
IV of the oxidative pathway
Lack of O2 and/or a defect in
oxidative phosphorylation
culminates in a decrease in ATP
synthesis

Cyanosis (bluish discoloration of skin and mucous
membranes)
Confusion
Cognitive impairment
Lethargy

syn. Stagnant

Decreased arterial blood flow to
tissue or venous outflow of blood
from tissue
Consequences of ischemia
1. Atrophy (reduction in cell/tissue mass)
2. Infarction of tissue (localized area of tissue
necrosis)
3. Organ dysfunction (inability to perform normal
metabolic functions
Thrombosis of the superior mesenteric vein

Decreased in PaO2 measured in
an arterial blood gas
Normal PaO2 depends on% O2 in
inspired area
Diffusion of O2 from the alveoli
into the pulmonary capillaries
Perfusion
Ventilation
1. Decreased inspired PO2 (PiO2)
Breathing at high
altitude
Breathing reduced
%O2 mist
2. Respiratory acidosis
,
Depression of the
medullary respiratory
center (barbiturates)
Paralysis of the diaph-
ragm (amyotrophic
lateral sclerosis-ALS)
Chronic bronchitis

3. Ventilation defect
Alveoli are perfused, however, there is
impaired O2 delivery to alveoli
Respiratory distress syndrome (RDS) -
a lack of surfactant causes collapse of
the distal airways (called atelectasis)
in both lungs
4. Perfusion defect
Alveoli are ventilated but there is no
perfusion of the alveoli
Pulmonary embolus and
fat embolism
Perfusion defects produce an increase in
pathologic dead space - the exchange of
O2 and CO2 does not occur

5. Diffusion defect
decreased diffusion of O2
through the alveolar-
capillary interface into the
pulmonary capillaries
interstitial
fibrosis
pulmonary
edema
6. Cyanotic congenital
heart disease
(Tetralogy of Fallot)
Shunting of venous
blood into arterial
blood causes a drop
in the PaO2.

M.D., Ph.D, Associate Professor, Marta R. Gerasymchuk

Clubbing is caused by decreased oxygenation, which leads
to fibrous tissue hyperplasia in the area between the nail and
distal portion of each digit, associated with lymphocytic
extravasation, increased vascularity, and edema.
Clubbing
of fingers
caused by
chronic
hypoxemia

 Methemoglobin is converted to the ferrous state (Fe2+) by the reduced NADH-
reductase system located off of the glycolytic pathway in RBCs.
 Electrons from NADH are transferred to cytochrome b5 and then to metHb by
cytochrome b5 reductase to produce ferrous Hb.
 Newborns are particularly at risk for developing methemoglobinemia after
oxidant stresses owing to decreased levels of cytochrome b5 reductase until at
least 4 months of age.
1. Anemia
⬇production
of Hb
iron
deficiency
⬆destruction
of RBCs
hereditary
spherocytosis
⬇production
of RBCs
aplastic
anemia
⬆ sequestration
of RBCs
splenomegaly
Causes
PaO2 and
SaO2 are
normal Total amount of O2 delivered to tissue is decreased (↓O2 content),
which has no effect on normal O2 exchange in the lungs
2. Methemoglobinemia (metHb) Hb with oxidized heme groups (Fe3+)

Causes of Methemoglobinemia
Oxidant stresses Congenital deficiency of cytochrome b5 reductase
nitrite- and/or sulfur-
containing drugs
nitrates (fertilizing agents)
sepsis
Pathogenesis
⬇SaO2 decreases O2
content  an ⬆ in EPO
Fe3+ cannot bind O2;
hence PaO2 is normal,
but SaO2 is decreased
MetHb shifts the
O2-binding curve
(OBC) to the left
Ferric heme groups impair
unloading of O2 by oxygenated
ferrous heme in the RBCs
(impairs cooperativity)
Patients with chocolate-colored blood
(⬆ concentration of deoxyhemoglobin)
Skin color does not return to normal after
administration of O2.
Clinically evident cyanosis occurs at
metHb levels >1.5 g/dL

Cyanosis at low levels (levels <20%)
Headache
Dyspnea
Confusion
Anxiety
Lethargy
Lactic acidosis
(levels >40%)
Lack of O2 causes a shift to anaerobic
glycolysis leading to lactic acidosis
Tachycardia (levels >20%)

Rosemary Jacobs began using
nose drops containing colloidal
silver when she was 11 years old.
Within a few years, her skin had
turned blue. Despite
discontinuing the use of colloidal
silver, Jacobs face remained blue
for decades, as particles of silver
were embedded in her skin and
organs.
Paul Karason began using colloidal silver 15 years ago. He
believes his blue skin was caused by rubbing the
concoction on his skin to treat dermatitis, and not by
drinking it. Karason, who is sometimes referred to as "Papa
Smurf" continues to drink colloidal silver as a cure-all.
Argyria is caused by the ingestion of silver, usually for medicinal purposes.
The effects of silver ingestion are permanent, and if the consumption of silver
continues long enough, can be fatal.

A family illustrating the inheritance of a
deficiency in methemoglobin reductase
 There are, however, rare individuals born with a CONGENITAL
DEFICIENCY OF METHEMOGLOBIN REDUCTASE.
 There is a relatively high incidence of this trait among Alaskan Eskimos
and among some families in Appalachia.
 These individuals may go through life with as much as half of their total
hemoglobin in the form of methemoglobin. As it turns out, however, they
are more blue than sick.
 They can compensate for the defect by making more red blood cells than
normal individuals (polycythemia).
 Even though these extra red cells
are defective, the functional fraction
of hemoglobin is increased.
 These phenotypes are exquisitely
sensitive to methemoglobin-generating
chemicals.
Blue Fugates of Kentucky

Treatment is
intravenous
methylene blue
Accelerates the enzymatic
reduction of MetHb by
NADPHmethemoglobin
reductase located in the
pentose phosphate shunt
This shunt is not
normally operational
in reducing metHb
 A physician in Appalachia amazed some of his blue patients by
giving them a blue dye that turned them pink, at least temporarily.
 Lifetime intravenous injections of methylene blue, however, are
not a satisfactory solution for a problem that is primarily cosmetic.
 Large oral doses of vitamin C are somewhat less effective, but
much safer.

Automobile exhaust
Smoke inhalation
Wood stoves
Indoor gasoline powered
generators
Clogged vents for home
heating units (methane gas)
Causes include:
Produced by incomplete combustion of
carbon-containing compounds

PATHOGENESIS OF CO POISONING HYPOXIA
CO has a high affinity for heme
groups and competes with O2 for
binding sites on Hb
This decreases SaO2 (if blood
is measured with a co-oximeter)
without affecting the PaO2
CO inhibits
cytochrome
oxidase in the ETC
Cytochrome oxidase normally converts O2 into H2O
Inhibition of the enzyme prevents O2
consumption, shuts down the ETC, and disrupts
the diffusion gradient that is required for O2 to
diffuse from the blood into the tissue
Similar to metHb, CO attached to
heme groups impairs unloading of
O2 from oxygenated ferrous heme in
RBCs into tissue
(impairs cooperativity)
CO shifts the O2-binding curve
(OBC) to the left
⬇SaO2 decreases O2 content Increase in EPO

Administer 100% O2 therapy with
nonrebreather mask or endotracheal tube
Cherry-red
discoloration of the
skin and blood
Headache (first
symptom at levels of
10%–20%)
Dyspnea, dizziness
(levels of 20%–30%)
Seizures,
coma (levels
of 50%–60%)
Atraumatic rhabdomyolysis (myoglobin binds
CO & prevents normal muscle function),
delayed neurologic deficits
(memory deficits, apathy)
Laboratory findings ⬆CO levels in blood if measured with a co-oximeter
Lactic acidosis (shift to anaerobic glycolysis)
⬇SaO2 (if measured with a co-oximeter) & a normal PaO2
Treatment
Hyperbaric oxygen therapy

Normal-shifted OBC
PO2 in the tissue
(ranges from 20–
50 mm Hg)
SaO2 of 50% (only released
50% of its O2 to tissue)
Left-shifted OBC
SaO2 of 80% (only
released 20% of its
O2 to tissue)
Right-shifted OBC
SaO2 of 20% (released
80% of its O2 to tissue)
2,3-Bisphosphoglycerate
(2,3-BPG) improves O2
delivery to tissue by
stabilizing the
hemoglobin (Hb) in the
taut form, which
decreases O2 affinity,
hence facilitating the
movement of O2 from Hb
into tissue by diffusion
M.D., Ph.D, Associate Professor, Marta R. Gerasymchuk

Genetical adaptation to life in high altitude:
 The Yak and the native Tibetan have weak or absent HPV
Moudgil, et al. J Appl Physiol 98:390-403, 2005 Picture: http://www.mantra-tibet.com

M . D . , P H . D . , A S S O C I A T E P R O F E S S O R , M A R T A R . G E R A S Y M C H U K
Mitochondrial
causes of ATP
depletion
⬇ ATP
synthesis &
completely
shuts down
the ETC
Enzyme
inhibition of
oxidative
phosphorylation
CO and cyanide (CN)
specifically inhibit
cytochrome oxidase in
complex IV of the ETC
Most
frequently
caused by
combustion
of synthetic
products in
house fires Prolonged
exposure to
NITROPRUSSIDE
(Nitropress, I.V.)
Ingestion of
amygdalin in
almonds
Suicidal
consumption
of CN
compounds

 Cyanide is hazardous by:
 Inhalation  Rapid onset: seconds to minutes
 Ingestion  Delayed onset: 15 to 30 minutes
 Skin contact  Delayed onset: 15 to 30 minutes
Death occurs in 6 to 8 minutes after inhalation of a high.
O2 content of venous blood is essentially the
same as the O2 content of arterial blood
Most adversely affects the:
heart and central nervous system
Clinical findings include:
Metabolic acidosis: nonspecific symptoms
CNS: dizziness,
seizures, nausea,
vomiting, tetany,
drowsiness, trismus,
hallucations, coma
Respiratory: Bitter
almond smell of the
breath; dyspnea, initial
hyperventilation followed
by hypoventilation and
pulmonary edema
CV: arrhythmia,
hypotension.
Tachycardia &
hypertension
Cardiovascular collapse
Concentration 2 to 5 mg/kg of it is LETHAL!

⬆ anion gap metabolic acidosis  due to ⬆
serum lactate levels from anaerobic glycolysis
⬇ of cytochrome oxidase in the ETC  a shift to
anaerobic glycolysis for production of ATP
⬆ venous O2 content when compared to the
arterial O2 content (no extraction of O2 in tissue)

 Activated charcoal
 Supplemental oxygen
 Hydroxocobalamin
Based on the high affinity of
CN for ferric ions in metHb &
for cobalt in hydroxycobalamin
is
excreted
thiocyanate
infusion of
Nathiosulfate
cyanmetHb
Infusion of
sodium
nitrite
Former treatment
cyanocobalamin
Infusion of
hydroxycobalamin
Latter treatment
Vitamin B12
Treatment options are:
 Sodium nitrite
 Sodium thiosulfate
 Amyl nitrite
Direct binding agent, chelate the
cyanide ( dose : 4 - 5 g IV )

Tissues susceptible to hypoxia
1. Watershed areas between terminal branches of major arterial
blood supplies are susceptible to hypoxic injury
In watershed areas, the blood supply from the two vessels does not overlap
The area between the distribution
of the anterior and middle
cerebral arteries
The area between the distribution of the
superior and inferior mesenteric
arteries (i.e., splenic flexure)
Decreased blood supply to vessels
(e.g., thrombosis overlying an
atherosclerotic plaque) produces a
watershed infarction (called ischemic
colitis) at the junction of these two
overlapping blood supplies (splenic
flexure in the left upper quadrant)
Global hypoxia (e.g., shock) may result
in a watershed infarction at the junction
of these two overlapping blood supplies

⬆ myocardial
demand for O2
(exercises) also

subendocardial
I ischemia
2. Subendocardial tissue
Coronary vessels penetrate the epicardial surface  therefore the
subendocardial tissue receives the least amount of O2.
Subendocardial ischemia
Factors decreasing coronary artery blood flow
Coronary artery atherosclerosis
Chest pain

Angina
pectoris
ST-segment
depression
Hypertrophy
associated
with aortic
stenosis or
essential
hypertension

3. Renal cortex and medulla
The straight portion
of the proximal tubule in
the cortex is most
susceptible to
hypoxia
Primary site for reclaiming
bicarbonate & reabsorbing sodium
The thick
ascending
limb of the
medulla is
also susceptible
to hypoxia
(location of
Na+/K+/2Cl –
symporter)
Primary site for regenerating free water,
which is necessary for normal dilution &
concentration of urine
4. Neurons in the central
nervous system Purkinje cells in
cerebellum and neurons in
the cerebral cortex
Irreversible damage
occurs ~ 5 minutes after
global hypoxia (shock)
Most adversely affected cell in
tissue hypoxia

5. Hepatocytes located around the central venule
 In the portal triads (PT), hepatic artery tributaries
carrying oxygenated blood and portal vein tributaries
carrying unoxygenated blood empty their blood into the
liver sinusoids (mixed oxygenated and unoxygenated
blood), which drain blood into the central venules (V).
 The central venules become the hepatic vein, which
empties into the inferior vena cava.
 Hepatocytes closest to the portal triads (zone I) receive
the most oxygen and nutrients, whereas those furthest
from the portal triads (zone III around the central
venules) receive the least amount of oxygen and
nutrients.
 Production of free radicals from drugs
(acetaminophen), tissue hypoxia (shock, CO
poisoning), and alcohol-related fatty change of the
liver initially damage zone III hepatocytes, which, owing
to their relative lack of O2, are more susceptible to injury.
 Depending on the severity of the injury, the other liver
zones may also become involved.

Protein synthesis is decreased due to detachment of
ribosomes from the rough endoplasmic reticulum (RER)
1. Reversible changes in the cells
Decreased synthesis of ATP in the mitochondria causes
the cells to shift to anaerobic glycolysis for ATP synthesis
Pyruvate is converted to lactate, which
decreases intracellular pH (lactic acidosis)
Intracellular lactic acid denatures structural and
enzymic proteins, this may result in coagulation
necrosis in the cell
Na+/K+-ATPase pump is impaired from lack of ATP
Diffusion of Na+ and H2O into cells causes cellular swelling, which
is the first visible sign of tissue hypoxia detected by the light
microscope, potentially reversible with restoration of O2

2. Irreversible changes in the cell
Calcium (Ca2+)-ATPase pump is impaired because of insufficient
ATP  normal function is to pump Ca2+ out of the cytosol
Increased cytosolic Ca2+ has five lethal effects
Cytosolic Ca2+ activates enzymes
 Activation of phospholipase ⬆ cell & organelle membrane permeability.
 Activation of proteases damages the cytoskeleton.
 Activation of endonucleases causes fading of nuclear chromatin (karyolysis).
 Activation of ATPase leads to ⬇ATP.
 Cytosolic Ca2+ directly activates caspases causing apoptosis of the cell
Cytosolic Ca2+ enters the mitochondria
 Mitochondrial membrane permeability is increased  Cytochrome c in the
ETC is released into the cytosol where it activates the caspases causing
apoptosis (programmed cell death).
 Mitochondrial conductance channels (pores) are opened leading to loss of H+
ions and membrane potential  therefore oxidative phosphorylation cannot
occur, leading to a decrease in ATP synthesis.

Should be determined through evaluation of the
patient (clinical assessment and blood gas result)
In general the indication are:
 Hypoxemia/hypoxia
 Excessive work of breathing
 Excessive myocardial work
 Improvement of oxygenation in patient with
decreased O2 carrying capacity (anemia)
 Promotion of absorption of air in the body cavity

Hypoventilation and Carbon Dioxide Narcosis
-the increased PO2 decreased and eliminates the
hypoxic drive ( esp. in pt. with chronic CO2 retention )
-Under this circumstances O2 must be given at low
concentration <30%
Absorption Atelectasis
-Nitrogen a relatively insoluble and exists 80% by volume
of the alveolar gas.N2 assists in maintaining alveolar
stability.
-O2 therapy replaced N2.
-Once O2 absorb into the blood the alveolar will collapse
esp. in alveolar distal to the obstruction.

Pulmonary Oxygen Toxicity
-The exposure of the high O2 and for prolonged period
can lead to parenchymal changes
-In general FiO2 > 50% for prolonged period shows
increased O2 toxicity
-Pulmonary changes mimic ARDS (Exudative changes and
proliferative changes.)
-Symptoms: cough, burning discomfort, nausea and
vomiting, headache, malaise and etc.
Retrolental Fibroplasia
-Excessive O2 to pre-mature infants may result in
constriction of immature retinal vessels, endothelial
damage, retinal detachment and possible blindness
-Recommended that PO2 be maintained between 60-90
mmHg range in neonate

Fire
 O2 support combustion
 Do not smoke while receiving O2 therapy

Hypoxia

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Hypoxia

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