LETTER TO THE EDITOR
Pulmonary vasoreactivity in PPH
Ivan M. Robbins, MDa,
Robyn J. Barst, MDa,
Richard N. Channick, MDa and
Lewis J. Rubin, MDa
a Pulmonary Hypertension Center, Vanderbilt University School of Medicine, Room T-1219, MCN, Nashville, Tennessee 37232, USA
Ivan.Robbins{at}mcmail.vanderbilt.edu
We read with interest the article by Krasuski et al. (1) titled "Inhaled Nitric Oxide Selectively Dilates Pulmonary Vasculature in Adult Patients With Pulmonary Hypertension, Irrespective of Etiology." The investigators reported that 67% of patients with primary pulmonary hypertension (PPH) and 63% of patients with secondary pulmonary hypertension had a decrease in mean pulmonary artery pressure (mPAP) of at least 20% with acute testing using inhaled nitric oxide (iNO). In contrast, the acute response rates from our institutions are much lower. Over the last year, a total of 97 adult patients with PPH were tested at our three centers. Using the same criteria as Krasuski et al. (1) to define a positive vasodilator response, we observed an overall acute response rate of only 21%. The response rate varied among institutions, ranging from 13% to 35% in the adult population. We list the number and percent with an acute response and the range of positive responses in Table 1. Although we observed a higher acute response rate in children with PPH (57%, n = 30), children are known to exhibit more pulmonary vasoreactivity than are adults (2); Krasuski et al. (1) limited their study to adults, and the youngest patient in their study was 26 years old.
Previous studies also support a lower acute response rate with iNO. Sitbon et al. (3) tested 33 patients with PPH with inhaled iNO (10 ppm) and found that only 10 (30%) had a decrease in mPAP of 20% or more. More recently, Ricciardi et al. (4) studied 17 patients with PPH and found only 2 (12%) patients had a decrease in mPAP of 20% or more with iNO (80 ppm). We are concerned that the results reported from Krasuski et al. (1) may provide misleading information to your readers and may result in empiric treatment with chronic calcium channel-blocker therapy without prior acute vasodilator testing.
Why the discrepancy between our findings and those of Krasuski et al. (1)? The reasons are unclear. All three of our institutions use iNO at a concentration of  40 ppm, similar to the concentration that Krasuski et al. (1) used in their study. Our patients received iNO using a face mask in conjunction with INOvent Delivery System (INO Therapeutics, Clinton, New Jersey), as was used by Krasuski et al. (1) study, or a pulsed delivery system (Devillbis Pulsair OMS 50, Cryo-Fab, Kenilworth, New Jersey) via nasal cannula, which has previously been shown to produce the same degree of vasodilation as that obtained with a face mask (5). Krasuski et al. (1) administered nitric oxide for 5 min before hemodynamic measurements were obtained, not significantly different from our protocols (range 5 to 10 min).
Hemodynamic instability during the course of the catheterization may account for some of the difference between ourselves and Krasuski et al. (1). The investigators do not appear to have repeated baseline hemodynamics in-between different doses of iNO, although the mPAP was very similar using 10, 20 or 40 ppm of iNO, suggesting that hemodynamic instability was not a major factor contributing to their results.
Despite the fact that the investigators' cohort represents the largest published study of acute testing with iNO in the adult population, only 18 patients had PPH. It is possible that their high percentage of acute responders is the result of a chance sampling of a group of patients with a higher rate of vasoreactivity than expected. This seems unlikely, however, as Duke is a large referral center, as are our institutions, so that one would expect sicker patients with a lower than expected rate of acute vasoreactivity to be seen there.
It is clear that large numbers of patients need to be evaluated with a standard protocol to obtain reproducible data. Presently, there is still no consensus among investigators as to what constitutes a positive acute response. Plans are underway for a multicenter study to evaluate the acute effects of iNO and to compare the results to those obtained with other agents used for acute vasodilator testing. A more important question remains unanswered: How well does a positive response to acute vasodilator testing predict long-term benefit with calcium channel-blocker therapy? Before answering that question, however, we need to be sure that we have reliably tested patients for pulmonary vasoreactivity. We strongly caution against empiric treatment with calcium channel blockers based on the assumption that most PPH patients are vasoreactive.
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References
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1. Krasuski RA, Warner JJ, Wang A, Harrison JK, Tapson VF, Bashore TM. Inhaled nitric oxide selectively dilates pulmonary vasculature in adult patients with pulmonary hypertension, irrespective of etiology. J Am Coll Cardiol. 2000;36:2204–2211[Abstract/Free Full Text]
2. Barst RJ, Maislin G, Fishman AP. Vasodilator therapy for primary pulmonary hypertension in children. Circulation. 1999;99:1197–1208[Abstract/Free Full Text]
3. Sitbon O, Humbert M, Jagot JL, et al. Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J. 1998;12:265–270[Abstract]
4. Ricciardi MJ, Knight BP, Martinez FJ, Rubenfire M. Inhaled nitric oxide in primary pulmonary hypertension: a safe and effective agent for predicting response to nifedipine. J Am Coll Cardiol. 1998;32:1068–1073[Abstract/Free Full Text]
5. Channick RN, Newhart JW, Johnson FW, et al. Pulsed delivery of inhaled nitric oxide to patients with primary pulmonary hypertension: an ambulatory delivery system and initial clinical tests. Chest. 1996;109:1545–1549[Abstract/Free Full Text]
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