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

factors, however, are insufficient to limit the destructive
actions of oxygen when patients are exposed to
high concentrations over an extended time period.
Tissues show differential sensitivity to oxygen toxicity,
which is likely the result of differences in both their
production of reactive compounds and their protective
mechanisms.
Respiratory Tract. The pulmonary system is usually the first to
exhibit toxicity, a function of its continuous exposure to the highest
oxygen tensions in the body. Subtle changes in pulmonary function
can occur within 8-12 hours of exposure to 100% O 2
. Increases in
capillary permeability, which will increase the alveolar/arterial oxygen
gradient and ultimately lead to further hypoxemia, and decreased
pulmonary function can be seen after only 18 hours of exposure
(Clark, 1988). Serious injury and death, however, require much
longer exposures. Pulmonary damage is directly related to the
inspired oxygen tension, and concentrations of < 0.5 atm appear to
be safe over long time periods. The capillary endothelium is the most
sensitive tissue of the lung. Endothelial injury results in loss of surface
area from interstitial edema and leaks into the alveoli.
Decreases of inspired oxygen concentrations remain the cornerstone
of therapy for oxygen toxicity. Tolerance also may play a role
in protection from oxygen toxicity; animals exposed briefly to high
O 2
tensions are subsequently more resistant to toxicity. Sensitivity in
humans also can be altered by preexposure to both high and low O 2
concentrations (Clark, 1988). These studies strongly suggest that
changes in alveolar surfactant and cellular levels of antioxidant
enzymes play a role in protection from oxygen toxicity.
Nervous System. Retinopathy of prematurity (ROP) is an eye disease
in premature infants involving abnormal vascularization of the
developing retina that can result from oxygen toxicity or relative
hypoxia (Lutty et al., 2006). Retinal changes can progress to blindness
and are likely caused by fibrovascular proliferation. Central
nervous system problems are rare, and toxicity occurs only under
hyperbaric conditions where exposure exceeds 200 kPa (2 atm).
Symptoms include seizures and visual changes, which resolve when
oxygen tension is returned to normal. Increased inspired oxygen concentrations
are often administered to patients who have sustained
acute ischemic central nervous system injury. In premature neonates
and those who have sustained in utero asphyxia, hyperoxia and
hypocapnia are associated with worse neurologic outcomes (Klinger
et al., 2005). Similarly, in preclinical studies, resuscitation from cardiac
arrest with high inspired oxygen concentrations leads to worse
outcomes (Balan et al., 2006). These data indicate that oxygen therapy
should be titrated to maintain an acceptable Po 2
and that hyperoxemia
should be avoided (Sola, 2008).
CARBON DIOXIDE
Transfer and Elimination of CO 2
Carbon dioxide is produced by metabolism at approximately
the same rate as O 2
is consumed. At rest, this
value is ~3 mL/kg per minute, but it may increase dramatically
with exercise. CO 2
diffuses readily from the
cells into the blood, where it is carried partly as bicarbonate
ion (HCO 3–
), partly in chemical combination
with hemoglobin and plasma proteins, and partly in
solution at a partial pressure of ~6 kPa (46 mm Hg) in
mixed venous blood. CO 2
is transported to the lung,
where it is normally exhaled at the rate it is produced,
leaving a partial pressure of ~5.2 kPa (40 mm Hg) in
the alveoli and in arterial blood. An increase in PCO 2
results in a respiratory acidosis and may be due to
decreased ventilation or the inhalation of CO 2
, whereas
an increase in ventilation results in decreased PCO 2
and
a respiratory alkalosis. Since CO 2
is freely diffusible,
the changes in blood PCO 2
and pH soon are reflected by
intracellular changes in PCO 2
and pH.
Effects of Carbon Dioxide
Alterations in PCO 2
and pH have widespread effects in
the body, particularly on respiration, circulation, and
the CNS. Complete discussions of these and other
effects are found in textbooks of respiratory physiology
(Nunn, 2005a).
Respiration. CO 2
is a rapid, potent stimulus to ventilation in direct
proportion to the inspired CO 2
. Inhalation of 10% carbon dioxide
can produce minute volumes of 75 L/min in normal individuals. CO 2
stimulates breathing by acidifying central chemoreceptors and the
peripheral carotid bodies (Guyenet, 2008). Elevated Pco 2
causes
bronchodilation, whereas hypocarbia causes constriction of airway
smooth muscle; these responses may play a role in matching pulmonary
ventilation and perfusion (Duane et al., 1979).
Circulation. The circulatory effects of CO 2
result from the combination
of its direct local effects and its centrally mediated effects on
the autonomic nervous system. The direct effect of CO 2
on the heart,
diminished contractility, results from pH changes and a decreased
myofilament Ca 2+ responsiveness (van den Bos et al., 1979). The
direct effect on systemic blood vessels results in vasodilation. CO 2
causes widespread activation of the sympathetic nervous system and
an increase in the plasma concentrations of epinephrine, norepinephrine,
angiotensin, and other vasoactive peptides. The results of sympathetic
nervous system activation generally are opposite to the local
effects of carbon dioxide. The sympathetic effects consist of
increases in cardiac contractility, heart rate, and vasoconstriction
(Chapter 12).
The balance of opposing local and sympathetic effects, therefore,
determines the total circulatory response to CO 2
. The net effect
of CO 2
inhalation is an increase in cardiac output, heart rate, and
blood pressure. In blood vessels, however, the direct vasodilating
actions of CO 2
appear more important, and total peripheral resistance
decreases when the PCO 2
is increased. CO 2
also is a potent coronary
vasodilator. Cardiac arrhythmias associated with increased PCO 2
are due to the release of catecholamines.
Hypocarbia results in opposite effects: decreased blood pressure
and vasoconstriction in skin, intestine, brain, kidney, and heart.
These actions are exploited clinically in the use of hyperventilation
to diminish intracranial hypertension.
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CHAPTER 19
GENERAL ANESTHETICS AND THERAPEUTIC GASES