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

failure associated with orthotopic heart transplantation, weaning
from cardiopulmonary bypass in adult and congenital heart disease
patients, ventricular assist device placement, primary pulmonary
hypertension, pulmonary embolism, acute chest syndrome in sicklecell
patients, congenital diaphragmatic hernia, high-altitude pulmonary
edema, and lung transplantation (Haddad et al., 2000).
Larger prospective, randomized studies for these disease conditions
either have not yet been performed or have failed to confirm any
changes in outcome.
Inhaled NO is FDA-approved for only one indication, persistent
pulmonary hypertension of the newborn (Mourani et al.,
2004). A recent systematic review of the available data in neonates
has shown that in very sick neonates with poor oxygenation, iNO
does improve oxygenation but it does not improve mortality,
reduce the incidence of bronchopulmonary dysplasia that is common
in this population, or reduce the incidence of brain injury
(Hintz et al., 2007, Su and Chen, 2008). Whether there are subsets
of patients who may have a favorable response to iNO remains to
be determined.
Diagnostic Uses. Inhaled NO also is used in several diagnostic
applications. Inhaled NO can be used during cardiac catheterization
to safely and selectively evaluate the pulmonary vasodilating capacity
of patients with heart failure and infants with congenital heart
disease. Inhaled NO also is used to determine the diffusion capacity
(DL) across the alveolar–capillary unit. NO is more effective than
carbon dioxide in this regard because of its greater affinity for hemoglobin
and its higher water solubility at body temperature (Haddad
et al., 2000).
NO is produced from the nasal passages and from the lungs
of normal human subjects and can be detected in exhaled gas. The
measurement of fractional exhaled NO (FeNO) is a noninvasive
marker for airway inflammation with utility in the assessment of respiratory
tract diseases including asthma, respiratory tract infection
and chronic lung diseases (Taylor et al., 2006).
Toxicity. Administered at low concentrations (0.1-50 ppm), inhaled
NO appears to be safe and without significant side effects.
Pulmonary toxicity can occur with levels higher than 50-100 ppm.
In the context of NO as an atmospheric pollutant, the Occupational
Safety and Health Administration places the 7-hour exposure limit
at 50 ppm. Part of the toxicity of NO may be related to its further oxidation
to nitrogen dioxide (NO 2
) in the presence of high concentrations
of O 2
. Even low concentrations of NO 2
(2 ppm) have been
shown to be highly toxic in animal models, with observed changes
in lung histopathology, including loss of cilia, hypertrophy, and focal
hyperplasia in the epithelium of terminal bronchioles. It is important,
therefore, to keep NO 2
formation during NO therapy at a low
level. This can be achieved by the administration of NO at a site in
the respiratory circuit as close to the patient as possible and timing
the delivery of NO to inspiration. Laboratory studies have suggested
potential additional toxic effects of chronic low doses of inhaled NO,
including surfactant inactivation and the formation of peroxynitrite
by interaction with superoxide. Nitric oxide and peroxynitrite have
been implicated in cellular mechanisms of oxygen toxicity in the
lung and central nervous system (Allen et al., 2009). The ability of
NO to inhibit or alter the function of a number of iron- and hemecontaining
proteins, including cyclooxygenase, lipoxygenases, and
oxidative cytochromes, as well as its interactions with ADP-ribosylation,
suggests a need for further investigation of the toxic potential of NO
under therapeutic conditions (Haddad et al., 2000).
The development of methemoglobinemia is a significant complication
of inhaled NO at higher concentrations, and rare deaths have
been reported with overdoses of NO. The blood content of methemoglobin,
however, generally will not increase to toxic levels with appropriate
use of inhaled NO. Methemoglobin concentrations should be
monitored intermittently during NO inhalation (Haddad et al., 2000).
Inhaled NO can inhibit platelet function and has been shown
to increase bleeding time in some clinical studies, although bleeding
complications have not been reported.
In patients with impaired function of the left ventricle, NO
has a potential to further impair left ventricular performance by dilating
the pulmonary circulation and increasing the blood flow to the
left ventricle, thereby increasing left atrial pressure and promoting
pulmonary edema formation. Careful monitoring of cardiac output,
left atrial pressure, or pulmonary capillary wedge pressure is important
in this situation.
Despite these concerns, there are limited reports of inhaled
NO-related toxicity in humans. The most important requirements for
safe NO inhalation therapy include:
• continuous measurement of NO and NO 2
concentrations using
either chemiluminescence or electrochemical analyzers
• frequent calibration of monitoring equipment
• intermittent analysis of blood methemoglobin levels
• the use of certified tanks of NO
• administration of the lowest NO concentration required for therapeutic
effect
Methods of Administration. Courses of treatment of patients with
inhaled NO are highly varied, extending from 0.1 to 40 ppm in dose
and for periods of a few hours to several weeks in duration. The minimum
effective inhaled NO concentration should be determined for
each patient to minimize the chance for toxicity. Given that sensitivity
to NO can vary in the patient during the course of administration,
the determination of dose response relationship on a frequent
basis should assist in the titration of the optimum dose of NO.
Commercial NO systems are available that will accurately deliver
inspired NO concentrations between 0.1 and 80 ppm and simultaneously
measure NO and NO 2
concentrations. A constant inspired concentration
of NO is obtained by administering NO in nitrogen to the
inspiratory limb of the ventilator circuit in either a pulse or continuous
mode. While inhaled NO may be administered to spontaneously
breathing patients by a closely fitting mask, it usually is
delivered during mechanical ventilation. Nasal prong administration
is being employed in therapeutic trials of home administration for
treatment of primary pulmonary hypertension (Griffiths et al., 2005).
HELIUM
Helium (He) is an inert gas whose low density, low solubility,
and high thermal conductivity provide the basis
for its medical and diagnostic uses. Helium is produced
by separation from liquefied natural gas and is supplied
in brown cylinders. Helium can be mixed with oxygen
and administered by mask or endotracheal tube. Under
hyperbaric conditions, it can be substituted for the bulk
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CHAPTER 19
GENERAL ANESTHETICS AND THERAPEUTIC GASES