Inhaled NO and Pulmonary Vasodilation
To the Editor:
Hare et al1 concluded that inhaled nitric oxide (NO) caused selective pulmonary vasodilation in patients receiving left ventricular assist device support and that this accounted for the increase in mean left atrial pressure, which they considered a beneficial hemodynamic effect.
The evidence for pulmonary vasodilation was that pulmonary vascular resistance (PVR) decreased. However, pulmonary vasodilation (an observable quantity) and decreased PVR (a calculated quantity) are not synonymous, and either can exist in the absence of the other: PVR (dynes · s · cm−5)=80×(Mean Pulmonary Artery Pressure−Mean Left Atrial Pressure)/Cardiac Output.2
In their patients whose mean pulmonary artery pressure (in mm Hg) and cardiac output (in liters per minute) were fixed, NO increased left atrial pressure (LAP), decreasing PVR in the above equation. The authors, previously observing patients without left ventricular assist devices, reported that NO increased left atrial pressure and left ventricular filling pressure while it decreased stroke volume index, a negative inotropic effect.3 In the present study, the increased left atrial pressure also resulted from increased left ventricular filling pressure. The above standard equation for PVR omits Poiseuille’s factor for the radius of the tubes and calculates decreased PVR independent of the radius of blood vessels.
In other patients, assisted by left ventricular assist devices as NO was inhaled, left ventricular assist device output was increased, thereby increasing the denominator to give a lower calculated PVR, again without invoking vasodilation.
What prevents NO from dilating pulmonary blood vessels in patients who have severe heart failure is the high blood concentration of norepinephrine in this condition.4 Hare previously reported that the rise in left atrial pressure resulting from NO was greatest in the patients who had the worst left ventricular failure.3 These were also the patients who had the highest blood levels of norepinephrine4 and were most susceptible to further ventricular impairment.
The observations in this article are valuable. However, instead of showing that inhaled NO dilated pulmonary blood vessels and thereby gave beneficial hemodynamic effects, this study showed that NO impaired the ventricular contractions in these patients. The authors had it right the first time.3
- Copyright © 1998 by American Heart Association
Hare JM, Shernan SK, Body SC, Graydon E, Colucci WS, Couper GS. Influence of inhaled nitric oxide on systemic flow and ventricular filling pressure in patients receiving mechanical circulatory assistance. Circulation. 1997;95:2250–2253.
Grossman W. In: Braunwald E, ed. Heart Disease. Philadelphia, Pa: WB Saunders; 1992:194.
Hare JM, Loh E, Craeger MA, Colucci WS. Nitric oxide inhibits the contractile response to β-adrenergic stimulation in humans with left ventricular dysfunction. Circulation. 1995;92:2198–2203.
Flow, therefore, is proportional to radius to the fourth power given fixed tube length and fluid viscosity, and in the absence of “vasodilation” or decreased vascular tone, flow increases must be compensated for by an increased pressure gradient. In the intact vasculature, increases in flow reflect, to a large extent, dilatation of distal arterioles, also termed resistance vessels.R1 R2 In some circuits, notably the pulmonary, recruitment of collapsed arterioles may also contribute to increases in flow in the proximal conduit vessels.R3 This mechanism, in the absence of an increase in pressure gradient, would also be considered vasodilation because effective radius has increased.
In our study, we measured total flow and the pressure gradient across the pulmonary circuit. Although we had the unique ability to control the total blood flow in our patients using the left ventricular assist device (LVAD), we did not control pulmonary arterial or left atrial pressures. Total blood flow was maintained constant (fixed LVAD mode) or allowed to respond to changes in vascular distribution (automatic LVAD mode). The comparison in our study was between the same patients with either fixed or variable blood flow. Variables such as circulating catecholamines were controlled for in the study design because the same patients were studied consecutively.
In our study, mean pulmonary arterial pressures did not increase with either fixed or variable flow. Transpulmonary gradient narrowed only in patients with fixed flow and was due to a rising left atrial pressure. The best explanation for an increase in blood flow that is not associated with an increase in transpulmonary gradient or pulmonary arterial pressure is vasodilation (as observed in the automatic-mode group). Similarly, transpulmonary gradient lowering with fixed pulmonary arterial pressure and blood flow also reflects vasodilation (as observed in the fixed-mode group). If ventricular impairment were the explanation for the rising left atrial pressure in patients in the fixed mode, this would have been associated with a concomitant rise in pulmonary arterial pressure and a fixed transpulmonary gradient.
Thus, we concluded, as we did in our previous study,R4 that NO is a pulmonary vasodilator in patients with severe heart failure. Although selective pulmonary vasodilation is beneficial in LVAD patients who can respond with increased systemic flow, it may not be beneficial in heart failure because of the increased left atrial pressure.
Cooper, CJ, Landzberg, MJ, Anderson TJ, Charbonneau F, Creager MA, Ganz P, Selwyn AP. Role of nitric oxide in the local regulation of pulmonary vascular resistance in humans. Circulation. 1996;93:266–271.
Grossman W. Clinical measurement of vascular resistance and assessment of vasodilator drugs. In: Grossman W, Baim DS, eds. Cardiac Catheterization, Angiography and Intervention. 4th ed. Philadelphia, Pa: Lea & Febiger; 1991:143–151.
Hakim TS, Michel RP, Chang HK. Partitioning of pulmonary vascular resistance in dogs by arterial and venous occlusion. Am J Physiol. 1982;52:710–715.
Loh EH, Stamler JS, Hare JM, Loscalzo J, Colucci WS. Cardiovascular effects of inhaled nitric oxide in patients with left ventricular dysfunction. Circulation. 1994;90:2780–2785.