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Dr. Barst is Associate Professor of Pediatrics and Medicine at Columbia University College of Physicians and Surgeons, New York, NY.
Correspondence to: Robyn J. Barst, MD, 3959 Broadway BH262N, New York, NY 10032
A cardinal rule in medicine is to "do no harm." As physicians, we are constantly asking ourselves what the overall risk/benefit ratio is for every therapeutic intervention we consider for our patients. In addition, consideration of any therapeutic modality is based on our knowing the natural history of the condition untreated, with our weighing the advantages vs disadvantages of adding therapeutic interventions (whether medical or surgical). Ricciardi et al report in this issue of CHEST (see page 1218) using echocardiographic parameters to predict an adverse response with an acute trial of nifedipine in patients with primary pulmonary hypertension. Acute vasodilator testing for patients with primary pulmonary hypertension was first reported in the mid 1970s following favorable experiences with vasodilator therapy for systemic hypertension. With the advent of vasodilators (such as hydralazine), physicians looked to these vasodilators with potential promise for their patients with primary pulmonary hypertension. Unfortunately, several of the earliest experiences with acute vasodilator testing resulted in fatalities using agents with a relatively long half-life, eg, hydralazine, in whom minimal if any active pulmonary vasoreactivity existed, ie, postmortem histopathology revealed severe fixed pulmonary vascular disease with little medial hypertrophy in the pulmonary arterioles. The administration of a relatively long-acting vasodilator in patients with advanced disease resulted in significant systemic vasodilatation with little if any pulmonary vasodilatation and subsequently cardiogenic shock. Based on this early experience, we "stepped back" and readdressed the cardinal rule to "do no harm" in medicine.
Unfortunately, the natural history of primary pulmonary hypertension untreated has a 5-year survival of at best 34%.1 The 5-year survival is most likely < 34% since the National Institutes of Health (NIH) Registry Series included anticoagulation in some patients, which has been demonstrated to improve survival,2 3 as well as calcium channel blockade therapy in some patients (although we do not know from the NIH Registry Series whether or not the patients treated with calcium channel blockade were patients in whom acute pulmonary vasoreactivity existed; chronic calcium channel blockade has only been shown to be efficacious for acute responders).3 4 5
The standard of care for primary pulmonary hypertension currently includes chronic calcium channel blockade if acute pulmonary vasoreactivity is demonstrated with acute vasodilator testing.3 4 5 This occurs in approximately 20 to 25% of adults and 40% of children. For the remainder, ie, 75 to 80% of the adults and 60% of the children, continuous IV infusion of prostacyclin is used. Chronic prostacyclin has been shown to improve quality of life, exercise capacity, pulmonary and systemic hemodynamics as well as survival.6 Although patients as well as their physicians prefer oral calcium channel blockade as opposed to IV prostacyclin, the decision needs to be based on safety and efficacy as opposed to a preference for route of administration of the vasodilator agent, ie, oral vs IV.
Ricciardi et al looked at echocardiographic parameters that appear to be useful in predicting who may or may not have an adverse response with acute calcium channel blockade testing. Their data demonstrate that diminished left ventricular size and leftward ventricular septal bowing are associated with systemic arterial hypotension following acute calcium channel blockade testing. The authors recommend using these echocardiographic parameters to select patients for whom a trial of nifedipine should be avoided. Unfortunately, the authors do not present the data for the patients’ acute hemodynamic responses with inhaled nitric oxide or adenosine testing prior to the trial of nifedipine, although they state in their manuscript that 20 of the 23 patients did undergo acute testing with either inhaled nitric oxide or adenosine. The importance of knowing this information is based on several studies demonstrating that acute calcium channel blockade testing is safe if a favorable response occurs with prior administration of IV prostacyclin, inhaled nitric oxide, or IV adenosine.3 4 5 A positive or favorable acute response is defined as a significant decrease in mean pulmonary artery pressure, as opposed to a decrease in pulmonary vascular resistance only. This is particularly important when using IV prostacyclin as the agent for vasodilator testing, since pulmonary vascular resistance decreases in most patients, even if there is not a significant decrease in pulmonary artery pressure. Whether this is due to a positive inotropic effect of prostacyclin increasing cardiac output remains unknown. In our experience, we have only observed systemic arterial hypotension with acute calcium channel blockade testing in patients in whom there was no significant decrease in pulmonary artery pressure with acute testing using IV prostacyclin or inhaled nitric oxide. In the experience of Ricciardi et al with 20 of 23 patients who underwent acute testing with either IV adenosine or inhaled nitric oxide and 22 of 23 patients received a trial of nifedipine, one wonders what the acute response with adenosine or nitric oxide was in the 5 patients in whom systemic arterial hypotension occurred following the first dose of nifedipine (group 1, which also included the 1 patient who was not tested with nifedipine based on the patient’s initial hemodynamic parameters revealing significant right heart failure). If one knew that the acute response with acute testing with adenosine or nitric oxide did not demonstrate a favorable response, one could have predicted a lack of a favorable response with nifedipine testing, thereby avoiding the nifedipine trial with a possible adverse response and serious consequences in this group of patients. Furthermore, one does not know if the two patients who received the trial of nifedipine and were not tested with adenosine or nitric oxide prior to the nifedipine test were in the group that developed systemic hypotension (group 1). It is for these reasons that much has been written in the medical literature strongly recommending acute vasodilator testing with a short-acting potent pulmonary vasodilator, eg, IV prostacyclin, inhaled nitric oxide, or IV adenosine prior to consideration of a trial of calcium channel blockers.3 4 5
It is not surprising that the authors observed that the association between the echocardiographic variables associated with systemic hypotension following a trial of nifedipine was less significant when controlling for pulmonary vascular resistance. Although pulmonary vascular resistance is a calculated parameter, it correlates (inversely) with acute pulmonary vasoreactivity with acute vasodilator testing using IV prostacyclin.5 A higher pulmonary vascular resistance suggests lack of an acute responsiveness. Unfortunately, the correlation is not 100% accurate; and therefore, unless a patient is in significant right heart failure, we recommend testing an individual patient with a short-acting vasodilator agent, eg, IV prostacyclin, inhaled nitric oxide, or IV adenosine, as opposed to assuming that all patients with right heart failure will only be candidates for chronic IV prostacyclin, as opposed to chronic calcium channel blockade by oral administration.
The authors’ findings remain important and are useful to add to our armamentarium of noninvasive tests assessing the severity of an individual patient’s disease, which is extremely helpful in determining risk/benefit considerations prior to performing invasive procedures such as cardiac catheterization. Previous studies have demonstrated that exercise tests (both the 6-min walk that evaluates exercise endurance, as well as progressive cycle ergometry measuring exercise tolerance)6 7 correlate with severity of disease in patients with primary pulmonary hypertension and the risk of invasive procedures (such as cardiac catheterization) in these high-risk patients. If the authors performed either a 6-min walk or progressive cycle ergometry tests with their patients prior to the trial of nifedipine, it would be interesting to know whether these exercise studies were useful in predicting their results, ie, systemic hypotension following the trial of nifedipine testing. Regardless, Dr. Ricciardi’s study gives us additional information to help us critically weigh risk/benefit concerns as we individualize the evaluation and therapeutic approach for our patients.
References
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