DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

substantial hypoventilation, with the PA CO2
rising to over 9.8 kPa (72
mm Hg), to cause the PA O2
to fall below 7.8 kPa (60 mm Hg). This
cause of hypoxemia is readily prevented by administration of even
small amounts of supplemental O 2
.
Shunt and V˙/Q˙ mismatch are related causes of hypoxemia but
with an important distinction in their responses to supplemental oxygen.
Optimal gas exchange occurs when blood flow (Q˙) and ventilation
(V˙) are matched quantitatively. However, regional variations
in V˙/Q˙ matching typically exist within the lung, particularly in the
presence of lung disease. As ventilation increases relative to blood
flow, the alveolar PO 2
(PA O2
) increases; because of the flat shape of
the oxyhemoglobin dissociation curve at high PO 2
(Figure 19–8),
this increased PA O2
does not contribute much to the oxygen content
of the blood. Conversely, as the V˙/Q˙ ratio falls and perfusion
increases relative to ventilation, the PA O2
of the blood leaving these
regions falls relative to regions with better matched ventilation and
perfusion. Since the oxyhemoglobin dissociation curve is steep at
these lower PO 2
values, the oxygen saturation and content of the pulmonary
venous blood falls significantly. At the extreme of low V˙/Q˙
ratios, there is no ventilation to a perfused region, and a pure shunt
results; thus the blood leaving the region has the same low PO 2
and
high PA CO2
as mixed venous blood.
The deleterious effect of V˙/Q˙ mismatch on arterial oxygenation
is a direct result of the asymmetry of the oxyhemoglobin dissociation
curve. Adding supplemental oxygen generally will make up
for the fall in PA O2
in low V˙/Q˙ units and thereby improve arterial
oxygenation. However, since there is no ventilation to units with pure
shunt, supplemental oxygen will not be effective in reversing hypoxemia
from this cause. Because of the steep oxyhemoglobin dissociation
curve at low PO 2
, even moderate amounts of pure shunt will
cause significant hypoxemia despite oxygen therapy (Figure 19–9).
For the same reason, factors that decrease mixed venous PO 2
, such
as decreased cardiac output or increased O 2
consumption, enhance
the hypoxemic effects of mismatch and shunt.
Nonpulmonary Causes of Hypoxia. In addition to failure of
the respiratory system to oxygenate the blood adequately,
a number of other factors can contribute to
hypoxia at the tissue level. These may be divided into
categories of O 2
delivery and O 2
utilization. Oxygen
delivery decreases globally when cardiac output falls
or locally when regional blood flow is compromised,
such as from a vascular occlusion (e.g., stenosis, thrombosis,
or microvascular occlusion) or increased downstream
pressure (e.g., compartment syndrome, venous
stasis, or venous hypertension). Decreased O 2
-carrying
capacity of the blood likewise will reduce oxygen delivery,
such as occurs with anemia, CO poisoning, or
hemoglobinopathy. Finally, hypoxia may occur when
transport of O 2
from the capillaries to the tissues is
decreased (edema) or utilization of the O 2
by the cells
is impaired (CN − toxicity).
Effects of Hypoxia. There has been a considerable
increase in our understanding of the cellular and biochemical
changes that occur after acute and chronic
Arterial P O2
60
kPa
50
40
30
20
10
0
mmHg
400
300
200
100
0
0.2 0.3
F O2
Shunt fraction
0 5% 10%
0.4 0.5 0.6 0.7 0.8 0.9 1.0
15%
20%
25%
30%
50%
Figure 19–9. Effect of shunt on arterial oxygenation. The isoshunt
diagram shows the effect of changing inspired oxygen concentration
on arterial oxygenation in the presence of different
amounts of pure shunt. As shunt fraction increases, even an
inspired oxygen fraction (FI O2
) of 1.0 is ineffective at increasing
the arterial PO 2
. This estimation assumes hemoglobin (Hb) 10-14
g/dL, arterial Pco 2
3.3-5.3 kPa (25-40 mm Hg), and an
arterial–venous (a–v) O 2
content difference of 5 mL/100 mL.
(Redrawn from Benatar SR, Hewlett AM, Nunn JF. The use of
iso-shunt lines for control of oxygen therapy. Br J Anaesth, 1973,
45:711–718, with permission. Copyright © The Board of
Management and Trustees of the British Journal of Anaesthesia.
Reproduced with permission of Oxford University Press/British
Journal of Anaesthesia.)
hypoxia. Regardless of the cause, hypoxia produces a
marked alteration in gene expression, mediated in part
by hypoxia inducible factor-1α (Brahimi-Horn and
Pouyssegur, 2009). Ultimately, hypoxia results in the
cessation of aerobic metabolism, exhaustion of highenergy
intracellular stores, cellular dysfunction, and
death. The time course of cellular demise depends on
the tissue’s relative metabolic requirements, O 2
and
energy stores, and anaerobic capacity. Survival times
(the time from the onset of circulatory arrest to significant
organ dysfunction) range from 1-2 minutes in
the cerebral cortex to around 5 minutes in the heart and
10 minutes in the kidneys and liver, with the potential
for some degree of recovery if reperfused. Revival
times (the duration of hypoxia beyond which recovery
is no longer possible) are ~4 to 5 times longer. Less
severe degrees of hypoxia have progressive physiological
553
CHAPTER 19
GENERAL ANESTHETICS AND THERAPEUTIC GASES