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

558 CNS. Hypercarbia depresses the excitability of the cerebral cortex
and increases the cutaneous pain threshold through a central action.
This central depression has therapeutic importance. For example, in
patients who are hypoventilating from narcotics or anesthetics,
increasing Pco 2
may result in further CNS depression, which in turn
may worsen the respiratory depression. This positive-feedback cycle
can have lethal consequences. The inhalation of high concentrations
of carbon dioxide (~50%) produces marked cortical and subcortical
depression of a type similar to that produced by anesthetic agents.
SECTION II
NEUROPHARMACOLOGY
Methods of Administration. CO 2
is marketed in gray metal cylinders
as the pure gas or as CO 2
mixed with oxygen. It usually is
administered at a concentration of 5-10% in combination with O 2
by means of a face mask. Another method for the temporary
administration of CO 2
is by rebreathing, such as from an anesthesia
breathing circuit when the soda lime canister is bypassed or
from something as simple as a paper bag. A potential safety issue
exists in that tanks containing carbon dioxide plus oxygen are the
same color as those containing 100% CO 2
. When tanks containing
CO 2
and O 2
have been used inadvertently where a fire hazard exists
(e.g., in the presence of electrocautery during laparoscopic surgery),
explosions and fires have resulted.
Therapeutic Uses. CO 2
is used for insufflation during endoscopic
procedures (e.g., laparoscopic surgery) because it is highly soluble
and does not support combustion. Inadvertent gas emboli thus are
dissolved and eliminated more easily by the respiratory system. CO 2
can be used to flood the surgical field during cardiac surgery.
Because of its density, carbon dioxide displaces the air surrounding
the open heart so that any gas bubbles trapped in the heart are carbon
dioxide rather than insoluble nitrogen (Nadolny and Svensson,
2000). Similarly, CO 2
is used to de-bubble cardiopulmonary bypass
and extracorporeal membrane oxygenation (ECMO) circuits. It is
used to adjust pH during cardiopulmonary bypass procedures when
a patient is cooled.
Hypocarbia, with its attendant respiratory alkalosis, still has
some uses in anesthesia. It constricts cerebral vessels, decreasing
brain size slightly, and thus may facilitate the performance of neurosurgical
operations. While short-term hypocarbia is effective for
this purpose, sustained hypocarbia has been associated with worse
outcomes in patients with head injury (Muizelaar et al., 1991).
Consequently, hypocarbia should be instituted with a clearly defined
indication and normocarbia should be re-established as soon the indication
for hypocabia no longer applies.
NITRIC OXIDE
Nitric oxide (NO) is a free-radical gas long known as an
air pollutant and a potential toxin. NO is now known as
a critical endogenous cell-signaling molecule with an
increasing number of potential therapeutic applications.
Endogenous NO is produced from L-arginine by a family of
enzymes called NO synthases (neural, inducible and endothelial).
NO is both an intra-cellular and a cell-cell messenger implicated in
a wide range of physiological and pathophysiological events in
numerous cell types, including the cardiovascular, immune, and
nervous systems. NO activates the soluble guanylyl cyclase, increasing
cellular cyclic GMP (Chapter 3). In the vasculature, basal release of
NO produced by endothelial cells is a primary determinant of resting
vascular tone; NO causes vasodilation when synthesized in
response to shear stress or a variety of vasodilating agents
(Chapter 27). It also inhibits platelet aggregation and adhesion.
Impaired NO production has been implicated in diseases such as atherosclerosis,
hypertension, cerebral and coronary vasospasm, and
ischemia–reperfusion injury. In the immune system, NO serves as
an effector of macrophage-induced cytotoxicity, and overproduction
of NO is a mediator of inflammation. In neurons, NO acts as a
mediator of long-term potentiation, cytotoxicity resulting from N-
methyl-D-aspartate (NMDA), and non-adrenergic non-cholinergic
neurotransmission; NO has been implicated in mediating central
nociceptive pathways (Chapters 8 and 18).
NO is rapidly inactivated in the circulation by oxyhemoglobin
and by the reaction of NO with the heme iron, leading to the formation
of nitrosyl-hemoglobin. Small quantities of methemoglobin
are also produced and these are converted to the ferrous form of
heme iron by cytochrome b5 reductase. The majority of inhaled NO
is excreted in the urine in the form of nitrate. Rapid withdrawal of
NO can result in a rebound increase in pulmonary pressure; gradual
withdrawal should minimize rebound phenomena (Griffiths and
Evans, 2005).
Therapeutic Uses. NO when inhaled selectively dilates
the pulmonary vasculature with minimal systemic cardiovascular
effects due to its rapid inactivation by oxyhemoglobin
in the pulmonary circulation (Cooper,
1999). Ventilation–perfusion matching is preserved or
improved by NO because inhaled NO is distributed
only to ventilated areas of the lung and dilates only
those vessels directly adjacent to the ventilated alveoli.
Thus, inhaled NO decreases elevated pulmonary artery
pressure and pulmonary vascular resistance and often
improves oxygenation. The dose of NO that is required
for an improvement in oxygenation is lower than that
required for a reduction in pulmonary pressure
(Griffiths and Evans, 2005).
Inhaled NO (iNO) has potential as a therapy for numerous
diseases associated with increased pulmonary vascular resistance.
In patients with adult respiratory distress syndrome (ARDS), iNO
is more often used to improve oxygenation rather than reducing pulmonary
pressure. NO does improve oxygenation but this effect is
transient. Moreover, the use of iNO therapy is not associated with
either a reduction in the duration of mechanical ventilation or in
morbidity or mortality (Taylor et al., 2004). iNO-mediated reductions
in pulmonary pressure have prompted its use in patients with
pulmonary hypertension in other clinical settings. Transient reduction
in pulmonary pressure have been reported in patients undergoing
cardiac surgery (Winterhalter et al., 2008) and pulmonary
transplantation (Ardehali et al., 2001). Although transient physiologic
improvements do occur, long-term outcome is essentially
unchanged (Meade et al., 2003). Several small studies and case
reports have suggested potential benefits of inhaled NO in a variety
of conditions, including pulmonary hypertension and right heart