David A. Fullerton, MD
Northwestern University Medical Hospital, Chicago, Illinois
Being a very sensitive organ, the lung is particularly vulnerable to the injuries of neutrophils, cytokines, etc., activated during SIRS. These same mechanisms contribute to acute lung injury (ARDS) in thoracic surgical patients undergoing lung resections, thoracic organ transplantation, and cardiopulmonary bypass. In turn, ARDS has a lung parenchymal component and a vascular component. The vascular component of lung injury leads to pulmonary vasoconstriction and pulmonary hypertension. The parenchymal component results in hypoxemia, which impairs systemic oxygen delivery and exacerbates the pulmonary hypertension via hypoxic pulmonary vasoconstriction. The increased pulmonary vascular resistance (PVR) found in this setting may increase right ventricular afterload to such a high level that left ventricular filling is impaired and cardiac output is compromised. Occasionally, the mediators of SIRS may set in motion an irreversible chain of events producing refractory pulmonary vasoconstriction which steadily worsens, producing death.
Fortunately, the thoracic surgeon may intervene clinically. Armed with a working understanding of some of these pathophysiologic mechanisms, the thoracic surgeon may apply this basic science information clinically to optimize care of the thoracic surgical patient. The focus of this review is upon: (1) the intracellular mechanisms of pulmonary vasomotor function and (2) some of the clinical tools available to the thoracic surgeon to therapeutically manipulate these intracellular mechanisms and thereby control the pulmonary circulation.
Mechanisms of Pulmonary Vasomotor Control
Net pulmonary vascular tone results from the mechanistic balance of pulmonary vasorelaxation and vasoconstriction. Hypoxia is among the most important physiologic pulmonary vasoconstricting agents and is an important finding in lung injury. Other physiologically important pulmonary vasoconstrictors include thromboxane, serotonin, histamine, and catecholamines, all of which are increased in SIRS. Such agonists achieve pulmonary vascular contraction by promoting a rise in intracellular calcium.
Pulmonary vasorelaxation may be achieved by two pathways. The principal intracellular mechanisms of pulmonary vasorelaxation are ultimately mediated through either guanosine 3',5'-cyclic monophosphate (cGMP) or adenosine 3',5'-cyclic monophosphate (cAMP). In the normal lung, the low pulmonary vascular smooth muscle tone is at least in part due to basal endothelial release of the endogenous vasodilator, nitric oxide (NO). Endothelium-derived NO lowers pulmonary vascular tone by stimulating guanylate cyclase in subjacent vascular smooth muscle cells to generate cGMP, which produced pulmonary vascular smooth muscle relaxation. Nitrodilators such as sodium nitroprusside work by donating a NO moiety to stimulate guanylate in the smooth muscle cell.
On the other hand, cAMP-mediated pulmonary vascular smooth music relaxation may be accomplished by activation of a limited number of different receptor-linked pathways. These receptors are found on the vascular smooth muscle cell membrane or on the pulmonary vascular endothelial cell. Receptors found on the vascular smooth muscle cell membrane include type 2 beta (B2) adrenergic receptors, type 2 adenosine (A2) receptors, type 2 histamine (H2) receptors and type 2 E prostaglandin (EP2) receptors. Type 2 purinergic (P2) receptors are found on pulmonary vascular endothelial cells. Once activated, these receptors stimulate adenylate cyclase to generate cAMP. Cyclic AMP then activates protein kinase A (PKA). As with cGMP, however, the distal mechanisms by which cAMP-mediated pulmonary vasorelaxation is ultimately achieved are unknown.
At least early in the course of acute lung injury, pulmonary hypertension is secondary to avid pulmonary vasoconstriction. In acute lung injury, the mechanisms of pulmonary vasoconstriction remain intact while the mechanisms of pulmonary vasorelaxation are impaired. Impairment of the mechanisms of relaxation tip the net balance of pulmonary vasomotor control in favor of construction, and may lead to an exaggerated response to vasoconstricting agonists.
Therapeutic Applications
Increased PVR may greatly complicate the perioperative management of thoracic surgical patients. As the primary clinical determinant of right ventricular afterload, increased PVR may result in right ventricular afterload-mismatch, impair transit of blood across the lungs into the left heart, and compromise cardiac output. Pharmacologic agents which produce vasodilation of both the systemic and pulmonary circulations by be hazardous in patients with increased PVR; significant hypotension may be produced if the degree of systemic vasodilation exceeds that of the pulmonary vasodilation. Therefore, a vasodilator which achieves pulmonary vasodilation without producing systemic hypotension is ideal. Two such dilators are inhaled NO and adenosine.
Inhaled NO
Exogenous NO may be administered to patients in the form of inhaled NO. By blending inhaled NO into a ventilator circuit, it is delivered into the alveoli. Inhaled NO is clinically administered in concentrations of 2-80 ppm. It rapidly diffuses across the alveolocapillary membrane into the subjacent vascular smooth muscle cell, activates guanylate cyclase to generate cGMP, which produced pulmonary vasorelaxation. As NO diffuses into the vascular lumen, it is immediately bound to hemoglobin and inactivated by conversion into nitrates and nitrites. Because immediately bound to hemoglobin and inactivated by conversion into nitrates and nitrites. Because its plasma half-life is less then 10 seconds, its vasodilating actions are confined to the pulmonary circulation; systemic vasodilation is avoided. Unfortunately, inhaled NO is a potentially toxic gas and its toxicity is directly related to the concentration of inhaled NO. Its use must be carefully monitored by chemiluminescence to determine the administered concentration and the exhaled concentration of its toxic metabolite, NO2. Concentrations of NO2 should be below 3 ppm.
Inhaled NO has been used successfully to treat the acute lung injury associated with lung transplantation. When used in patients with ARDS, inhaled NO has been used safely to improve arterial oxygenation and lower PVR. It has been administered for up to 53 days. Of interest, however, several studies have demonstrated that approximately one-third of patients with ARDS do not respond to inhaled NO.
The acute lung injury associated with cardiopulmonary bypass is well recognized; even in the absence of hypoxemia it may produce pulmonary vasoconstriction. This pulmonary vasoconstriction is at least in part derived from injury to the pulmonary vascular endothelial cells and a resultant loss of endogenous, endothelium-derived NO. Surgeons have been able to overcome this deficiency of endogenous NO by administration of exogenous NO as inhaled NO. In adult and pediatric cardiac surgical patients, inhaled NO has produced pulmonary vasodilation, associated with an improvement in cardiac output, without systemic vasodilation.
As inpatients with ARDS, it is noteworthy that some cardiac patients (patients with valvular heart disease) are unresponsive to the pulmonary vasodilating actions of inhaled NO. The reason for this variability in NO responsiveness is unclear, but may be due to a decreased production on cGMP or an increased breakdown of cGMP by phosphodiesterase (PDE). A clinical strategy to overcome this unresponsiveness has been outlined. Using a two-pronged approach of stimulating cGMP production with inhaled NO and preventing the breakdown of cGMP by inhibiting the enzyme responsible for its degradation, PDE, pulmonary vasorelaxation may be achieved. Administration of inhaled NO and the clinically accessible PDE in inhibitor, dipyridamole, converted from NO nonresponders to responders.
Adenosine
While NO produces vascular smooth muscle relaxation through cGMP, cGMP-mediated pulmonary vasorelaxation may not always be functional in the setting of pulmonary hypertension or acute lung injury. The surgeon should keep in mind that cAMP-mediated pulmonary vasorelaxation may be achieved. Unfortunately, most available agonist which stimulate cAMP production require intravenous administration and produce unwanted systemic vasodilation as well. An exception may be intravenous administration of adenosine.
As an endogenous vasodilator, the role of adenosine in the coronary and other circulations is well recognized. It is rapidly clear from the circulation by adenosine deaminase, found in vascular endothelial cells and erythrocytes; its plasma half-life is less than ten seconds. Isolated rabbit lung preparation, adenosine is cleared by a single pass through the lung. It has been shown to relax isolated human pulmonary arterial rings via an adenosine A2 receptor-mediated mechanism.
In patients with pulmonary hypertension following cardiopulmonary bypass, a central venous infusion of adenosine (50 ?/kg/min) produced a significant reduction in mean pulmonary arterial pressure, transpulmonary gradient and PVR without decreasing mean systemic arterial pressure. In turn, these vasodilatory effects on the pulmonary circulation resulted in an increase om cardiac index and a reduction in right ventricular stroke work index. In this way the vasodilating actions of adenosine were focused on the pulmonary circulation, allowing adenosine to be used clinically as a "selective" pulmonary vasodilator.
Mechanisms of pulmonary vasorelaxation are impaired in acute lung injury; initial attempts to achieve pulmonary vasodilation may fail. However, the surgeon gains an advantage with knowledge of the various intracellular signal transduction pathways responsible for pulmonary vasodilation. Pulmonary vasoconstriction refractory to cGMP-mediated relaxation (inhaled NO) may be responsive to relaxation by a cGMP-mediated pathway (adenosine). The surgeon may successfully control the pulmonary circulation with one pharmacologic tool when another fails.
1. Fullerton DA, McIntyre RC Jr: Inhaled nitric oxide: therapeutic applications in cardiothoracic surgery. Ann Thorac Surg 1996; 61:1865-1874.
2. Fullerton DA, Jaggers, Jones SD, Brown JM, McIntyre Jr RC. Adenosine for refractory pulmonary hypertension. Ann Thorac Surg 1996;62:874-877.
3. Sheridan BC, McIntyre RC, Agrafojo J, Meldrum DR, Meng X, Fullerton DA: Neutrophil depletion attenuates dysfunction of cGMP-mediated pulmonary vasorelaxation in endotoxin-induced acute lung injury. Am J Physio 1996;271:L820-L828.
4. Fullerton DA, Jaggers J, Wollmering M, Piedalue F, Grover FL, McIntyre RC Jr: Variable response to inhaled nitric oxide following cardiac surgery. Ann Thorac Surg 1997;63:1251-1256.
5. McIntyre RC Jr., Moore FA, Moore EE, Piedalue F, Hoenel JS, Fullerton DA. Inhaled nitric oxide variably improves oxygenation and pulmonary hypertension in patients with acute respiratory distress syndrome. J Trauma 1995;39:418-425.
6. Fullerton DA, Jones SD, Grover FL, McIntyre RC Jr: Adenosine effectively controls pulmonary hypertension following cardiac surgery. Ann Thorac Surg 1996:61:1118-24.
