EFFECTS OF INHALED ANESTHETICS ON PULMONARY VASCULAR
RESISTANCE
Determinants of Pulmonary Vascular Resistance
Determining the actions of drugs on pulmonary arterial pressures
and pulmonary vascular resistance (PVR) is a complicated task because many vasoactive
agents have direct effects on the pulmonary circulation and indirect actions mediated
by alterations in cardiac output, preload, afterload, and autonomic nervous system
activity. Increased vascular-distending pressure may increase the cross-sectional
diameter of the pulmonary vascular bed and cause a compensatory reduction in PVR.
Similarly, changes in lung volume may alter the dimensions of the pulmonary vasculature
and affect resistance. Increases in lung volume above functional residual capacity
(FRC) caused by elevated airway pressure and reductions in lung volume below FRC
are associated with passive increases in PVR. High lung volumes compress pulmonary
vessels, whereas vessels are shorter, narrower, and more tortuous because of loss
of supportive tethering of surrounding lung parenchyma at low lung volumes. Resistance
of the pulmonary arterial circulation appears to be lowest at a lung volume equivalent
to the FRC. Changes in pulmonary arterial pressure and PVR also have significant
effects on gas or fluid exchange in the lung. An increase in PVR causes a corresponding
increase in pulmonary arterial pressure if cardiac output remains constant. This
increase in pulmonary arterial pressure promotes transudation of fluid into the interstitium
of the lung. PVR is also increased by positive end-expiratory pressure, alveolar
hypoxia and hypercarbia, and critical closing pressure (i.e., a parallel shift in
pressure-flow curves). Inhaled anesthetics tend to reduce lung volume and may therefore
have indirect effects on PVR through this mechanism as well.
Direct changes in pulmonary vascular tone alter PVR by altering
the slope of pressure-flow relation. Such direct changes may be induced by a rapid
rise in ICa2+
, alterations in sympathetic nervous system tone, local changes
in arterial oxygen and carbon dioxide tension, or alterations in the circulating
concentrations of catecholamines. Contractile responses to agonists such as phenylephrine
are mediated by Ca2+
entry, ICa2+
release,[115]
and a tyrosine kinase-mediated signal transduction pathway, independent of VDCs.
[116]
These responses are inhibited by K+
channel inhibition.[117]
Hypercapnia at constant
pH (i.e., isohydria) does not alter isolated pulmonary arterial tone, but normocapnic
acidosis relaxes isolated pulmonary arteries by an endothelium-independent mechanism.
[118]
Nevertheless, pulmonary arterial endothelial
dysfunction has also been reported to potentiate hypercapnic vasoconstriction.[119]
Vasoactive substances released locally or in blood perfusing the
lung also affect vascular tone. NO synthases are widely distributed in the lung
and extensively involved in vascular homeostasis.[120]
NO synthesis is intimately linked to the pulmonary oxygen environment. For example,
a decrease in oxygen tension prolongs the duration of NO action, but conversely provides
less substrate for its production.[121]
[122]
[123]
NO synthase appears to play little or no
role
in the regulation of PVR in the healthy, normoxic lung,[120]
[124]
but this substance is a critical mediator
of
PVR during hypoxia.[125]
[126]
In addition to producing vasodilation in ventilated, normoxic pulmonary regions
during one-lung hypoxia, NO may also release an endogenous inhibitor of NO synthase
that vasoconstricts nonventilated, hypoxic regions.[127]
The action of endogenous NO on PVR and the utility of exogenous NO as a treatment
for pulmonary hypertension have been extensively investigated over the past few years.
[128]
NO may be beneficial in the treatment of
high-altitude
pulmonary edema[129]
and neonatal pulmonary hypertension
resulting from a variety of congenital heart diseases, hypoplastic lung, and meconium
aspiration.[130]
However, NO inhalation during
acute bronchospasm may paradoxically worsen hypoxemia.[131]
Whether this adverse action is mediated by direct bronchodilatory actions on less-constricted
peripheral airways or by worsening intrapulmonary shunt through arterial vasodilation
is unclear. Pulmonary endothelial dysfunction after cardiopulmonary bypass impairs
endothelium-dependent vasodilation to agents such as acetylcholine and bradykinin.
[132]
This cardiopulmonary bypass-induced endothelial
dysfunction may affect the efficacy of NO administration in this setting to some
degree. Nevertheless, use of NO in pediatric and adult cardiac surgical patients
has become a common means of reducing PVR in this setting.
Similar to NO, carbon monoxide (CO) is another molecular gas that
stimulates guanylyl cyclase and increases cGMP levels in pulmonary arterial vascular
smooth muscle cells to regulate vascular tone.[133]
Inhaled CO also attenuates hypoxemia-induced increases in PVR through this mechanism.
[134]
Regional changes in PVR affect the regional distribution of blood
flow within the lung and produce changes in ventilation-perfusion matching and simultaneous
alterations in gas exchange. An increase in PVR in an area of atelectasis causes
localized tissue hypoxia but optimizes overall gas exchange (e.g., decreases alveolar-arterial
oxygen tension gradient [PAO2
-PaO2
])
by shifting blood flow away from the atelectatic segment to a well-ventilated region
of the lung. This phenomenon is called hypoxic pulmonary vasoconstriction
(HPV) and is unique to the pulmonary circulation because other vascular beds (i.e.,
coronary and cerebral) dilate in response to hypoxia. HPV exerts an important protective
effect to maintain oxygenation, and drugs that interfere with HPV may adversely affect
gas exchange. For example, administration of a direct pulmonary vasodilator such
as sodium nitroprusside attenuates HPV, increases pulmonary shunting, and reduces
arterial oxygenation in dogs with oleic acid-induced pulmonary edema.[135]
Similarly, isoflurane also increases ventilation-perfusion mismatch and oxygen delivery
in mechanically ventilated dogs with experimental lung injury.[136]
However, the pulmonary vasodilator effect of inhaled anesthetics is minimal in normal
lungs.[137]
[138]
[139]
Small decreases in PVR produced by inhaled
agents are frequently offset by a concomitant reduction in cardiac output in vivo.
The net effect of these actions results in little if any change in pulmonary artery
pressure and a small decrease in total pulmonary blood flow. In contrast, nitrous
oxide does not substantially affect cardiac output and pulmonary blood flow and causes
small increases in PVR.
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