As stated above, except in special cases such as inhalation of

steam, injury to airways below the larynx and pulmonary

parenchyma nearly always results from chemical irritation.
A number of reviews are available to describe the pathophysiology
of pulmonary failure associated with smoke
inhalation.2,21 Chemicals inhaled with smoke as well as
carbon particles coated with irritants are deposited in the
airways. Aqueous secretions of the mucosa dissolve these
irritants and the respiratory mucosa is bathed in relatively
concentrated caustic solutions. The initial response to this
insult is injury to the respiratory epithelium, resulting in
hyperemia, edema, increased mucous secretions, impaired
ciliary clearance, and bronchoconstriction. Work in experimental
animals has also demonstrated an early separation
of ciliated respiratory epithelial cells from the basement
membrane. This results in denuded areas of the airways and
explains the copious formation of protein-rich exudate.
Fibrin casts tenaciously adherent to the airway surfaces are
formed from this exudate.
Much of the morbidity associated with smoke inhalation
is the result of the inflammatory response to the early direct
effect of chemical irritants. The inflammatory response to
smoke inhalation is similar to the injury produced by aspiration
of acidic gastric contents. The direct injury to tissues caused by the initial insult causes local
accumulation of
inflammatory cells and initiation of a cascade of inflammatory
mediators that exacerbate and sustain tissue damage
(see below).
Airways become blocked by edema, bronchoconstriction,
fibrin casts, necrotic debris, and inflammatory infiltrate (Fig.
19.2). Degraded surfactant causes alveolar instability and
collapse. These changes result in impaired hypoxic pulmonary
vasoconstriction and areas of atelectasis, and postobstructive
sequestration of material that provide a medium for
bacterial growth and risk of pneumonia. Impaired function
of alveolar macrophages slows the removal of these materials
and facilitates the development of infection. Pulmonary
compliance is reduced, which can greatly increase the work
of breathing.
As a result of these changes pulmonary gas exchange is
impaired. Atelectasis due to airway obstruction increases
dead space and shunt to an extent, but the impaired gas
exchange due to smoke inhalation appears to be primarily a
ventilationperfusion imbalance.22 It has been suggested
that this mechanism of pulmonary dysfunction is fundamentally
different from other types of ARDS.17,23 Other
etiologies of ARDS, such as sepsis, involve disruption of the
pulmonary capillary membrane and alveolar flooding,
resulting primarily in true shunt. This distinction can influence
the ventilator strategies employed. Patients with respiratory
failure due to smoke inhalation injury have small
airway obstruction, and care should focus on pulmonary
toilet together with recruiting and stabilizing alveoli, which
tend to collapse, whereas in ARDS due to other etiologies
the strategy is to concentrate on avoiding ventilator-induced
lung injury. In some burn centers this is a rationale for the
use of high-frequency percussive ventilation.17
Just as the bronchi are the focus of the diagnosis of inhalation
injury, it is also the focus of its pathology.24 The hyperemia
and edema that are seen in the airway and which are so
important for the diagnosis of inhalation injury are the result
of an almost 20-fold increase in bronchial blood flow.25,26

Following the airway injury, there are changes in the lung

parenchyma. There is a release of the chemokine interleukin
(IL)-8 and an influx of neutrophils into the airway and
alveoli. Reactive oxygen (ROS) and nitrogen species (RNS)
are formed.27 One of the latter, peroxynitrite, damages DNA.
DNA damage results in activation of poly-(ADP ribose)
polymerase.28 Poly-(ADP ribose) protects the damaged DNA
but also activates the nuclear factor NF-B.29 This causes the
formation of the inducible form of nitric oxide synthase and
additional release of IL-8, attracting and activating additional
neutrophils and forming more reactive nitrogen and oxygen
species.30 The oxidation, nitration, and nitrosation of lung
tissues results in membrane damage, edema formation and
impaired oxygen diffusion.31,32 Alveoli that are not ventilated
are not perfused with blood because alveolar hypoxia causes
pulmonary vasoconstriction. NO released by nitric oxide
synthase causes a loss of hypoxic pulmonary vasoconstriction,
leading to perfusion of unventilated alveoli and thus a
fall in arterial oxygen saturation.33
Ablation of the bronchial blood flow will prevent most of
the pathophysiology involved in inhalation injury to the
pulmonary parenchyma.24,34,35 These changes in bronchial
blood flow are not associated with heat. They can be produced
in experimental animals by smoke that has been
cooled to body temperature.36 As mentioned above, the
blood flow to the airway is so effective in cooling or heating
inhaled air that it is almost impossible for hot gases to reach
the bronchi.36,37 These changes in blood flow also appear to
be independent of the chemical composition of smoke, as
they are mediated by a neuroinflammation. We have recently
reported that following insufflation of smoke into deeply
anesthetized sheep, the airway blood flow increased 10-fold,
but after administration of an inhibitor of the neuropeptide
calcitonin gene-related peptide (CGRP) the smoke-induced
hyperemia was markedly reduced.38 Neuropeptides (peptides
released from nerves within the lung tissue) induce vasodilatation
by causing activation of nitric oxide synthase, leading
to the formation of NO. It has also been reported that an
inhibitor of the neuro isoform of nitric oxide synthase would
block the hyperemia and much of the pathophysiology mentioned
above, including the loss of hypoxic pulmonary vasoconstriction.
39,40 These findings have led us to the following
hypothesis: the chemicals in smoke activate sensory nerves to
release neuropeptides that activate NOS1 to release NO and
superoxide to form peroxynitrite, which damages DNA, activating
PARP, that stimulates NF-B which in turn will upregulate
the inducible form of nitric oxide synthetase, leading to
massive formation of ROS and RNS, tissue damage and
hypoxia and dyspnea. Some of the activated polymorphonuclear
cells that escape from the pulmonary and bronchial
circulation into the systemic circulation are carried to systemic
organs, promoting multiorgan system damage.