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Overdosing with prostacyclin in primary pulmonary hypertension
Karlman Wasserman, MD, PhDa and
Ronald Oudiz, MDb
a Division of Respiratory and Critical Care Physiology and Medicine, Harbor-UCLA Medical Center, 1000 W. Carson Street, Torrance, California 90507, USA
b Division of Cardiology, Harbor-UCLA Medical Center, 1000 W. Carson Street, Torrance, California 90507, USA
Rich and McLaughlin (1) reported excessively high rest cardiac outputs in 12 of 55 patients with primary pulmonary hypertension (PPH) treated with intravenous prostacyclin, all of whom had follow-up right heart catheterization. As they point out, the intravenous dosing of prostacyclin, which has been so helpful in increasing exercise tolerance and prolonging life in patients with PPH, is complex. The practice has been to maximize dose at the time of initiation of treatment and then to adjust the dose according to symptomatology. The average rest cardiac index was 7.4 liters/min per m2 in these patients. They proceeded to reduce the dose of prostacyclin, on the basis of repeat cardiac output and hemodynamic measurements, until they reduced the rest cardiac index to 4.0 liters/min per m2. This resulted in an average dose reduction of 39%, with virtually no change in pulmonary artery pressure. They did not report any data on the effect of the dose reduction on the patients’ exercise performance (e.g., peak oxygen consumption [ ;-1qO2] or anaerobic threshold), which is obviously the important question because exercise limitation is the major symptom in these patients.
From the Fick principle for measuring cardiac output, it is obvious that ;-1qO2 is a proxy variable of cardiac output. The dose of the drug that provides the highest peak ;-1qO2 during exercise is therefore also the dose that provides the maximally effective cardiac output response to exercise (2). The maximal cardiac output that provides effective perfusion to the tissues without developing lactic acidosis, and therefore is the sustainable level of exercise, is the anaerobic threshold, a measurement obtained by measuring carbon dioxide consumption (;-1qCO2) concurrently with ;-1qO2. The oxygen pulse (;-1qO2/heart rate), measured during the same test, is equal to the stroke volume x arteriovenous oxygen difference, and correlates well with stroke volume as measured by the direct Fick method. The slope of expired volume (;-1qE) versus ;-1qCO2 is consistently high in patients with PPH, because it reflects hypoperfusion to the ventilated lung. Thus, as recently reported by Wax et al. (3), cardiopulmonary exercise testing provides a valuable noninvasive marker that can be useful in guiding therapy.
Cardiopulmonary exercise testing provides a comprehensive, quantitative, noninvasive assessment of cardiovascular and respiratory function. In preliminary studies of sequential cardiopulmonary exercise testing in patients with PPH treated with prostacyclin, we found that a maximal benefit is achieved despite increasing dosage. The failure to improve variables of aerobic function and ventilatory efficiency in response to exercise logically sets the optimal dose.
The high rest cardiac output values reported by Rich and McLaughlin are counter to those expected in patients with PPH, and therefore the mechanism would be interesting to address. They attributed the high rest cardiac outputs to increased inotropy caused by prostacyclin. They did not provide stroke volume measurements to support this suggestion. The very flushed skin of these patients suggests another explanation. Perhaps the reduced systemic resistance decreased left ventricular afterload. This may decrease pressure in the left atrium below that of the right atrium, thereby diverting right atrial blood through a foramen ovale. The blood flow through the foramen ovale is a right to left shunt, but the high skin blood flow is functionally a left-to-right shunt.
Prostacyclin is not a selective pulmonary vasodilator. It dilates the systemic circulation as well as the pulmonary circulation. Because of the pulmonary arteriopathy in PPH, dilation of the pulmonary circulation is likely to be more limited than that of the systemic circulation. Thus, if pulmonary vascular disease limits the ability to further recruit and dilate pulmonary blood vessels beyond a certain point with an increasing dose, further dosing will just dilate the systemic circulation with no benefit to the patient. In fact, the unneeded vasodilation may be detrimental to the patient, as Rich and McLaughlin suggest.
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References
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- Rich S, McLaughlin VV. The effects of chronic prostacyclin therapy on cardiac output and symptoms in primary pulmonary hypertension. J Am Coll Cardiol. 1999;34:1184–1187[Abstract/Free Full Text]
- Stringer W, Hansen J, Wasserman K. Cardiac output estimated non-invasively from oxygen uptake (;-1qO2) during exercise. J Appl Physiol. 1997;82:908–912[Abstract/Free Full Text]
- Wax D, Garofano R, Barst RJ. Effects of long-term infusion of prostacyclin on exercise performance in patients with primary pulmonary hypertension. Chest. 1999;116:914–920[Abstract/Free Full Text]
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