C H A P T E R 2 2 
Hypoxia
KEY POINTS
■ Intracellular acidosis from anaerobic
metabolism occurs soon after the onset
of cellular hypoxia and is worse when
there is a plentiful supply of blood and
glucose to the cell.
■ Lack of high-energy substrates such
as ATP and direct effects of hypoxia
both inhibit the activity of ion channels,
decreasing the transmembrane
potential of the cell, leading to increased
intracellular calcium levels.
■ In nervous tissue the uncontrolled
release of excitatory amino acids
exacerbates the hypoxic damage.
■ Hypoxia causes the activation of a
transcription protein HIF-1, which
induces the production of numerous
proteins with diverse biological
functions.
All but the simplest forms of life have evolved to
exploit the immense advantages of oxidative
metabolism. The price they have paid is to
become dependent on oxygen for their survival.
The essential feature of hypoxia is the cessation
of oxidative phosphorylation (page 190) when
the mitochondrial Po2 falls below a critical level.
Anaerobic pathways, in particular the glycolytic
pathway (see Fig. 10.12), then come into play.
These trigger a complex series of cellular changes
leading first to reduced cellular function and
ultimately to cell death.
BIOCHEMICAL CHANGES
IN HYPOXIA
Depletion of High-Energy
Compounds
Anaerobic metabolism produces only one-
nineteenth of the yield of the high-energy
phosphate molecule adenosine triphosphate
(ATP) per mole of glucose, compared with
aerobic metabolism (page 191). In organs with a
high metabolic rate such as the brain, it is impos-
sible to increase glucose transport sufficiently to
maintain the normal level of ATP production.
Therefore, during hypoxia, the ATP/adenosine
diphosphate (ADP) ratio falls and there is a rapid
decline in the level of all high-energy compounds
(Fig. 22.1). Similar changes occur in response to
arterial hypotension. These changes will rapidly
block cerebral function, but organs with a lower
energy requirement will continue to function for
a longer time and are thus more resistant to
hypoxia (see later).
Under hypoxic conditions, there are two ways
in which reductions in ATP levels may be mini-
mized, both of which are effective for only a
short time. First, the high-energy phosphate
bond in phosphocreatine may be used to create
ATP,2 and initially this slows the rate of reduc-
tion of ATP (Fig. 22.1). Second, two molecules
of ADP may combine to form one of ATP and
one of AMP (adenosine monophosphate; the
adenylate kinase reaction). This reaction is
driven forward by the removal of AMP, which is
converted to adenosine (a potent vasodilator)
and thence to inosine, hypoxanthine, xanthine
and uric acid, with irreversible loss of adenine
nucleotides. The implications for production of
reactive oxygen species by this pathway are dis-
cussed on page 345.
End Products of Metabolism
The end products of aerobic metabolism are
carbon dioxide and water, both of which are
easily diffusible and lost from the body. The
main anaerobic pathway produces hydrogen and
lactate ions which, from most of the body, escape
into the circulation, where they may be meas-
ured or quantified in terms of the base deficit or
lactate/pyruvate ratio. However, the blood-brain
barrier is relatively impermeable to charged ions,
therefore hydrogen and lactate ions are retained
within the neurones of the hypoxic brain.
Lactacidosis can only occur when circulation is
327
328 PART 2  Applied Physiology

gas partial pressure (kPa)

15

Blood lactate Arterial blood gas

(mmol.l–1) partial pressure
100

Arterial blood
PCO2
10

(mmHg)
50
5 PO2

0 0
10

5 0
concentrations (mmol.kg–1)

4 Phosphocreatine
Brain tissue

ATP
2

1 ADP

0 10

tissue ratios
NADH x10–3 ATP

Brain
NAD ADP 5

0 0
0 1 2 3 4
Minutes of apnoea
FIG. 22.1  ■  Biochemical changes during 4 minutes of respiratory arrest in rats previously breathing 30% oxygen.
Recovery of all values, except blood lactate, was complete within 5 minutes of restarting pulmonary ventilation.
(Data from reference 1.)

maintained to provide the large quantities of
glucose required for conversion to lactic acid.
In severe cerebral hypoxia, a major part of the
dysfunction and damage is due to intracellular
acidosis rather than simply depletion of high-
energy compounds (see later). Gross hypoper-
fusion is more damaging than total ischaemia,
because the latter limits glucose supply and
therefore the formation of lactic acid. Similarly,
patients who have an episode of cerebral ischae-
mia whilst hyperglycaemic (e.g. a stroke) have
been found to have more severe brain injury than
those with normal or low blood glucose levels at
the time of the hypoxic event.3
Initiation of Glycolysis
The enzyme 6-phosphofructokinase (PFK) is
the rate-limiting step of the glycolytic pathway
(see Fig. 10.12). Activity of PFK is enhanced by
the presence of ADP, AMP and phosphate,
which will rapidly accumulate during hypoxia,
thus accelerating glycolysis. PFK is, however,
inhibited by acidosis, which will quickly limit the
formation of ATP from glucose. The intracel-
lular production of phosphate from ATP break-
down also promotes the activity of glycogen
phosphorylase, which cleaves glycogen mole-
cules to produce fructose-1,6-diphosphate. This
enters the glycolytic pathway below the rate-
limiting PFK reaction, avoiding the expenditure
of two molecules of ATP in its derivation from
glucose. Therefore four molecules of ATP are
produced from one of fructose-1,6-diphosphate
in comparison with two from one molecule
of glucose. There is no subsequent stage in
the glycolytic pathway that is significantly rate
limited by acidosis. Provided glycogen is avail-
able within the cell; this second pathway there-
fore provides a valuable reserve for the production
of ATP.
MECHANISMS OF HYPOXIC
CELL DAMAGE
Many mechanisms contribute to cell damage or
death from hypoxia. The precise role of each is
 22  Hypoxia 329

unclear, but there is general agreement that dif- and extracellular ionic gradients are abolished,
ferent tissues respond to hypoxia in quite varied leading to cell death.
ways. Also, the nature of the hypoxic insult has
a large effect with differing speed of onset,
Potassium and Sodium Flux
degree of hypoxia, blood flow, blood glucose
concentration and tissue metabolic activity all Hypoxia has a direct effect on potassium channels
influencing the resulting tissue dysfunction. (page 100), increasing transmembrane potassium
conductance and causing the immediate hyper-
Immediate Cellular Responses polarization. Potassium begins to leak out from
the cell, increasing the extracellular potassium
to Hypoxia4 concentration, thus tending to depolarize the cell
Because of the dramatic clinical consequences of membrane. Potassium leakage, along with sodium
nervous system damage, neuronal cells are the influx, are accelerated when falling ATP levels
most widely studied and therefore form the basis cause failure of the Na/K ATPase pump. Follow-
for the mechanisms described in this section.2 ing rapid depolarization, sodium and potassium
Changes in the transmembrane potential of a channels probably simply remain open, allowing
hypoxic neurone are shown in Figure 22.2, along free passage of ions across the cell membrane
with the major physiological changes that occur. leading to cellular destruction.
At the onset of anoxia, central nervous system
cells immediately become either slightly hyper- Calcium
polarized (as shown in Fig. 22.2) or depolarized,
depending on the cell type. This is followed by Intracellular calcium concentration increases
a gradual reduction in membrane potential shortly after the onset of hypoxia. Voltage-gated
until a ‘threshold’ value is reached, when a calcium channels open in response to the falling
spontaneous rapid depolarization occurs. At transmembrane potential, and the increasing
this stage there are gross abnormalities in ion intracellular sodium concentration causes the
channel function and the normal intracellular membrane-bound Na/Ca exchanger to reverse
its activity. An altered transmembrane potential
is detected within the cell by ryanodine receptors
on intracellular organelles leading to release of
Potassium leakage from within cell begins
calcium from the endoplasmic reticulum and
Increasing intracellular calcium
Glutamate release begins
mitochondria. This increase in intracellular
Na+/K+ pump failure
calcium is generally harmful, causing the activa-
Synaptic transmission failure
tion of ATPase enzymes just when ATP may be
Rapid depolarization
critically low, the activation of proteases to
damage sarcolemma and the cytoskeleton and
pHi Cell membrane potential (mV)

Cell death likely

the uncontrolled release of neurotransmitters
0
(see later). At this stage, the cell has probably not
been irretrievably damaged by spontaneous
–30 depolarization, but derangement of calcium
channel function effectively prevents normal
–60 synaptic transmission and therefore cellular
function. Extracellular adenosine, formed from
–90 the degradation of AMP, is also believed to play
7.2 a role in blocking calcium channels during
anoxia.2
6.8
Time Excitatory Amino Acid Release5
Anoxia
The excitatory amino acids glutamate and aspar-
FIG. 22.2  ■  Changes in transmembrane potential and tate are released from many neurones at concen-
intracellular pH (pHi) in a neuronal cell following the
sudden onset of anoxia. Significant physiological trations of 2 to 5 times the normal early in the
events in the course of the hypoxic insult are shown. course of a hypoxic insult, followed by further
Once membrane potential reaches zero, cell death is dramatic increases following rapid depolariza-
almost inevitable (see text for details). The time tion. Glutamate reuptake mechanisms also fail,
between anoxia and rapid depolarization is highly
variable, between about 4 minutes with complete
and extracellular concentrations quickly reach
ischaemia to almost 1 h with hypoxia and preserved neurotoxic levels,5,6 acting via the N-methyl-d-
blood flow. (After reference 2.) aspartate (NMDA) receptor. Cells with depleted
330 PART 2  Applied Physiology
energy stores are particularly susceptible, but the
mechanism by which glutamate and aspartate
bring about cell damage is unknown.
Delayed Cellular Responses
to Hypoxia
Following brain injury in humans, cerebral
oedema often continues to develop for some
hours after the initial insult. There are several
possible explanations for this delayed neuronal
damage with activation of many different cellular
systems implicated. However, it is a quite differ-
ent clinical problem that has recently focussed
attention on cellular adaptations to hypoxia. The
core of many solid malignant tumours has a poor
blood supply, caused by the failure of angiogen-
esis to keep up with the rapid tumour growth.
Tumour hypoxia is associated with highly malig-
nant, aggressive tumours, which often respond
poorly to treatment. For this reason, much
recent research has focussed on understanding
the cellular effects of hypoxia, with a view to
developing new therapeutic approaches.
Table 22.1 shows the numerous genes that
may be induced by hypoxia. Most of the systems
activated by hypoxia assist the cell in overcoming
the hypoxic conditions, for example, erythropoi-
etin to increase haemoglobin concentration, or
glycolytic enzymes to increase anaerobic ATP
formation. Some activated genes may accelerate
cell proliferation and therefore increase tumour
malignancy, whereas other genes are activated
that encourage apoptosis and impair tumour
growth.7
Hypoxia-Inducible Factor 18-11
Many of these cellular adaptations to hypoxia are
mediated by a transcription regulating protein
called hypoxia-inducible factor 1 (HIF-1). Under
TABLE 22.1  Genes Induced by Hypoxia and Their Effects
Function Gene
Oxygen transport Erythropoietin
Transferrin
Increased blood flow VEGF
NO synthase
ATP production Glucose transporter-1
Hexokinase
Aldolase
Pyruvate kinase
Lactate dehydrogenase
pH correction Carbonic anhydrase
Inflammation Interleukin-6 and 8
VEGF, vascular endothelial growth factor; NO, nitric oxide.
normal conditions cytoplasmic HIF-1 is ubiqui-
tous, but a prolyl-hydroxylase protein (PHD-1)
rapidly hydroxylates HIF-1 rendering it inactive.
Oxygen is required as a cosubstrate for this
reaction such that when cellular hypoxia occurs
hydroxylation by PHD-1 fails and HIF-1 remains
stable for long enough to initiate transcription
of hundreds of hypoxia-induced genes, the best
known of which are shown in Table 22.1. The
HIF-1 system is involved in oxygen sensing in
the pulmonary vasculature (page 100) and is now
seen as a major potential target for therapeutic
agents to treat peripheral vascular disease,
cerebral ischaemia, pulmonary hypertension and
cancer.10
Ischaemic Preconditioning12,13
Prior exposure of a tissue to a series of short
periods of hypoxia, interspersed with normal
oxygen levels, has been found to influence
the tissue’s subsequent response to a prolonged
ischaemic insult, a phenomenon known as
ischaemic preconditioning. Though ischaemic
preconditioning has been demonstrated in many
tissues the phenomenon has mostly been studied
in heart muscle, and three forms are described.
Early Protection
Reduction in the damage occurring from an
ischaemic period begins immediately after the
preconditioning has occurred, and lasts for
2 to 3 h. Activation of sarcolemmal and mito-
chondrial ATP-dependent K channels (KATP) is
believed to be the main mechanism by which
protection from ischaemia occurs. After precon-
ditioning, the enhanced activity of KATP channels
helps to maintain the transmembrane potential
nearer to normal values, slowing the rate of pro-
gression of the immediate cellular responses to
Biological Action
Stimulation of red cell production
Iron transport
Angiogenesis
Vasodilatation
Transfer of glucose into cell
}
Glycolysis (see Fig. 10.12)
Buffering of metabolic acidosis
Activation of inflammatory cells

hypoxia described earlier. During prolonged
hypoxia, fluid and electrolyte imbalances also
occur across the mitochondrial membrane
impairing the ability of the cell to make the best
use of any oxygen remaining in the cell. Acti-
vated mitochondrial KATP channels will again
reduce the rate at which these changes occur.
Extracellular triggers that bring about precondi-
tioning include adenosine, purines, bradykinin
or catecholamines, all acting via G-proteins and
protein kinase C to cause activation of the KATP
channels.
Late Protection
This describes the protection from ischaemia
seen about 12 h after the preconditioning and is
less effective than early protection. It is again
mediated by activation of KATP channels, this
time brought about by gene transcription of pro-
teins such as inducible nitric oxide synthase,
superoxide dismutase (page 347) or cyclooxyge-
nase (page 210).
Remote Ischaemic Preconditioning14,15
This phenomenon offers the most potential for
future clinical use. The technique involves mul-
tiple (usually—three to four) short periods of
ischaemia induced in an arm or leg by inflating
a blood pressure cuff above systolic blood pres-
sure for 5 minutes. Damage caused by ischaemia
in a remote organ, usually the heart during
revascularization surgery, has then been demon-
strated to be less in the ‘preconditioned’ patients.
The mechanisms remain largely a mystery,
including identifying the messenger system
between the tissues and even whether this is
humoral, neuronal or immune cell in nature.14
Agents Used for Preconditioning
Several drugs, but particularly inhalational
anaesthetics, can precondition cardiac muscle in
a manner similar to brief ischaemic episodes.12,16
The mechanism is also similar, with most of the
effective drugs somehow enhancing KATP channel
activity. Similar responses occur to the noble
gases helium and xenon, possibly mediated by
modulation of nitric oxide,17 antagonism of the
NMDA receptor18 or activation of KATP chan-
nels.19 Xenon is currently undergoing clinical
trials for neuroprotection against encephalopa-
thy from cerebral ischaemia in neonates.20
Therefore unfortunately, despite impressive
laboratory results, ischaemic preconditioning
has thus far failed to translate into a useful option
in routine clinical practice, but it does show
22  Hypoxia 331
enormous potential for situations where ischae-
mia can be predicted in advance.
PO2 LEVELS AT WHICH
HYPOXIA OCCURS
Cellular PO2
‘Critical Po2’ refers to the oxygen partial pres-
sure below which oxidative cellular metabolism
fails. For isolated mitochondria, this is known to
be less than 0.13 kPa (1 mm Hg), and possibly
as low as 0.01 kPa (0.1 mm Hg) in muscle cells
despite their large oxygen consumption. Venous
Po2 approximates to end-capillary Po2 and,
though highly variable, is usually in excess of 3
kPa (∼20 mm Hg) even in maximally working
skeletal muscle. Thus when the minimal Po2 in
the nearby capillary is approximately 200 times
greater than that required by the mitochondria,
it is difficult to envisage how cellular hypoxia can
occur in all but the most extreme situations.
There are reasons why this is not the case
in vivo.
Measurement of intracellular Po2 is difficult.
The most widely used technique is applicable
only to muscle cells and involves measurement
of myoglobin saturation, from which Po2 may be
determined. These studies have indicated that
intracellular Po2 is in the range 0.5 to 2 kPa
(3–15 mm Hg) depending on cell activity. Diffu-
sion of oxygen within cells is believed to be slow
because of the proteinaceous nature of the cyto-
plasm, and therefore large variations in intracel-
lular Po2 are likely to exist. Thus in intact cells,
as opposed to isolated mitochondria, critical Po2
is more likely to be of the order of 0.5 to 1.3 kPa
(3–10 mm Hg), which is much closer to the end-
capillary value.21
Critical Arterial Po2 for
Cerebral Function
The minimal safe level of arterial Po2 is that
which will maintain a safe tissue Po2. This will
depend on many factors besides arterial Po2,
including haemoglobin concentration, tissue
perfusion and tissue oxygen consumption. These
factors are in accord with Barcroft’s classification
of ‘anoxia’ into anoxic, anaemic and stagnant
(page 192).
This argument may be extended to consider
in which circumstances the venous Po2 (and by
implication tissue Po2) may fall below its critical
level corresponding, in normal blood, to 32%
saturation and oxygen content of 6.4 ml.dl−1. If
the brain has a mean oxygen consumption of
332 PART 2  Applied Physiology
46 ml.min−1 and a blood flow of 620 ml.min−1,
the arterial/venous oxygen content difference
will be 7.4 ml.dl−1. Therefore, with normal cere-
bral perfusion, haemoglobin concentration, pH, etc.,
this would correspond to a critical arterial oxygen
content of 13.8 ml.dl−1, saturation 68% and Po2
4.8 kPa (36 mm Hg). This calculation and others
under various different conditions are set out in
Table 22.2. However, the other factors previ-
ously listed will probably not be normal. They
may be unfavourable as a result of multiple
pathologies in the patient (e.g. anaemia or a
decreased cerebral blood flow). Alternatively,
there may be favourable factors, such as poly-
cythaemia in chronic hypoxaemia, or reduced
cerebral oxygen requirements during hypother-
mia or anaesthesia. The possible combinations
of circumstances are so great that it is not feasi-
ble to consider every possible situation. Instead,
certain important examples have been selected
which illustrate the fundamentals of the problem,
and these are shown in Table 22.2.
Uncompensated ischaemia is dangerous, and,
with a 45% reduction in cerebral blood flow, any
reduction of arterial Po2 exposes the brain to the
risk of hypoxia. Uncompensated anaemia is
almost equally dangerous, although an increase
in cerebral blood flow restores a satisfactory
safety margin. In the example in Table 22.2, a
40% reduction of blood oxygen-carrying capac-
ity and a 40% increase of cerebral blood flow
permits the arterial Po2 to fall to 5.3 kPa (40 mm
Hg) without the cerebral venous Po2 falling
below 2.7 kPa (20 mm Hg). The last line in
Table 22.2 shows the very dangerous combina-
tion of anaemia (haemoglobin concentration
111 g.l−1) and cerebral blood flow three-quarters
of normal. Neither abnormality is very serious
considered separately, but in combination the
arterial Po2 cannot be reduced below its normal
value without the risk of cerebral hypoxia.
Table 22.2 is not to be taken too literally,
because there are many minor factors that have
not been considered. However, it is a general
rule that maximal cerebral vasodilatation may be
expected to occur in any condition (other than
cerebral ischaemia) that threatens cerebral oxy-
genation. Also, there are circumstances in which
the critical organ is not the brain but the heart,
liver or kidney.
The most important message of this discus-
sion is that there is no simple answer to
the question: What is the safe lower limit of
arterial Po2? Acclimatized mountaineers have
remained conscious at high altitude with arterial
Po2 values as low as 3.28 kPa (25 mm Hg;
Chapter 15). Patients presenting with severe res-
piratory disease tend to remain conscious down
to similar levels of arterial Po2. However, both
acclimatized mountaineers and patients with
chronic respiratory disease have com­pensatory
polycythaemia and maximal cerebral vasodilata-
tion. Uncompensated subjects who are acutely
exposed to hypoxia are unlikely to remain con-
scious at such low values for arterial Po2,
but considerable individual variation must be
expected.
EFFECTS OF HYPOXIA
The clinical effects of acute hypoxia are described
on page 247. Hypoxia presents a serious threat
to the body, and compensatory mechanisms
usually take priority over other changes. Thus,
for example, in hypoxia with concomitant hypoc-
apnia, hyperventilation and an increase in cere-
bral blood flow occur in spite of the decreased
Pco2. Certain compensatory mechanisms will
come into play whatever the reason for the
hypoxia, although their effectiveness will depend
to a large extent on the cause. For example,
hyperventilation will be largely ineffective in
stagnant or anaemic hypoxia because hyperven-
tilation while breathing air can do little to
increase the oxygen content of arterial blood,
and usually nothing to increase perfusion.
Hyperventilation results from a decreased
arterial Po2 but the response is nonlinear
(see Fig. 4.8). There is little effect until arterial
Po2 is reduced to about 7 kPa (52 mm Hg):
maximal response is at 4 kPa (30 mm Hg). The
interrelationship between hypoxia and other
factors in the control of breathing is discussed in
Chapter 4.
Pulmonary distribution of blood flow is improved
by hypoxia as a result of hypoxic pulmonary
vasoconstriction (page 98).
The sympathetic system is concerned in many of
the responses to hypoxia, particularly the increase
in organ perfusion. The immediate response is
reflex and is initiated by chemoreceptor stimula-
tion: it occurs before there is any measurable
increase in circulating catecholamines, although
this does occur in due course. Reduction of cer-
ebral and probably myocardial vascular resist-
ance is not dependent on the autonomic system
but depends on local responses in the vicinity of
the vessels themselves. With the exception of
pulmonary vessels, hypoxia causes vasodilatation
of blood vessels almost everywhere in the body.
This results mainly from a direct effect of adeno-
sine and other metabolites generated by hypoxia.
Cardiac output is increased by hypoxia,
together with the regional blood flow to almost
every major organ, particularly the brain.


TABLE 22.2  Lowest Arterial Oxygen Levels Compatible with a Cerebral Venous PO2 of 2.7 kPa (20 mm Hg) under Various
Conditions

Cerebral Venous Blood Arterial/ Arterial Blood

Venous O2
Blood O2 Brain O2 Cerebral PO2 Content PO2
Capacity Consumption Blood Flow SAT. O2 CONTENT Difference O2 CONTENT SAT.
(ml.dl−1) (ml.min−1) (ml.min−1) kPa mm Hg (%) (ml.dl−1) (ml.dl−1) (ml.dl−1) (%) kPa mm Hg
Normal values 20 46 620 4.4 33 63 12.6 7.4 20.0 98 13.8 100
Uncompensated arterial 20 46 620 2.7 20 32 6.4 7.4 13.8 68 4.8 36
hypoxaemia
Arterial hypoxaemia with 20 46 1240 2.7 20 32 6.4 3.7 10.1 50 3.6 27
increased cerebral blood
flow
Arterial hypoxaemia with 25 46 620 2.7 20 32 8.0 7.4 15.4 61 4.3 32
polycythaemia
Arterial hypoxaemia with 20 46 620 2.7 20 46 9.2 7.4 16.6 82 4.9 37
alkalosis*
Arterial hypoxaemia with 20 23 620 2.7 20 57 11.4 3.7 15.1 75 3.6 27
hypothermia†
Uncompensated cerebral 20 46 340 2.7 20 32 6.4 13.5 19.9 98 15 112
ischaemia
Uncompensated anaemia 12 46 620 2.7 20 32 3.8 7.4 11.2 93 8.9 67
Anaemia with increased 12 46 870 2.7 20 32 3.8 5.3 9.1 75 5.3 40
cerebral blood flow
Combined anaemia and 15 46 460 2.7 20 32 4.8 10.0 14.8 97 12 92
ischaemia

*pH 7.6.
†
Temperature 30°C; cerebral O2 consumption reduced to half normal.
22  Hypoxia
333
334 PART 2  Applied Physiology
Haemoglobin concentration is transiently in-
creased with acute hypoxia in humans,
particularly during apnoea, caused by splenic
contraction.22 The response is probably medi-
ated by catecholamines, and though of minor
importance for humans is a vital reflex for diving
mammals (page 371). Haemoglobin is increased
in chronic hypoxia due to residence at altitude
or respiratory disease.
The oxyhaemoglobin dissociation curve is dis-
placed to the right by an increase in 2,3-DPG
and by acidosis which may also be present. This
tends to increase tissue Po2 (see Fig. 10.10).
Anaerobic metabolism is increased in severe
hypoxia in an attempt to maintain the level of
ATP (see previous discussion).
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CHAPTER 22  HYPOXIA
• When a cell becomes hypoxic the high-energy
molecule ATP is quickly depleted and cellu-
lar functions fail. Initially phosphocreatine
and ADP can be used to produce an emer-
gency supply of ATP, but when these are
exhausted inefficient anaerobic metabolism
must be used. This produces large amounts
of intracellular lactic acid, particularly if the
tissue is still receiving blood flow and a supply
of glucose.
• In neuronal tissue, potassium channels are
also affected by hypoxia, leading to an initial
hyperpolarization of the cell followed by a
gradual depolarization due to leakage of
potassium from the cell and failure of the
sodium/potassium ATPase pump. The
depolarization also causes a gradual increase
in intracellular calcium. When a threshold
membrane potential is reached the cell fully
depolarizes and the ion channels remain
open. Excitatory neurotransmitters such
as glutamate are often released and cause
further damage by reactivating the cell ion
channels.
• Hypoxia also activates a ubiquitous intracel-
lular protein called hypoxia-inducible factor
22  Hypoxia 334.e1
which in its active form modifies transcrip-
tion of many genes to attenuate the effects of
longer term hypoxia. These include eryth-
ropoietin to increase oxygen carriage, vascu-
lar growth factors to improve blood supply
to the region, various enzymes involved in
glycolysis to improve anaerobic ATP produc-
tion and inflammatory mediators.
• Ischaemic preconditioning describes a tech-
nique of deliberately inducing ischaemia in
tissues before a predicted ischaemic insult to
activate the cellular response to hypoxia and
so attenuate the damage. Early and late
forms of protection have been demonstrated
and are believed to arise from activation of
mitochondrial ATP-dependent potassium
channels. Preconditioning may also work
remotely, for example, inducing ischaemia
in limbs before cardiac surgery reduces the
hypoxic damage to the myocardium during
surgery.
• Clinical effects of hypoxia include hyperven-
tilation, redistribution of pulmonary blood
flow from hypoxic pulmonary vasoconstric-
tion, activation of the sympathetic system and
increases in haemoglobin concentration.