Pulsed Delivery of Inhaled Nitric Oxide to Patients With Primary Pulmonary Hypertension

Pulsed Delivery of Inhaled Nitric Oxide to Patients With Primary Pulmonary Hypertension* An Ambulatory Delivery System and Initial Clinical Tests Richard N. Channick, MD; John W. Newhart, CRTT; F. Wayne Johnson, RCPT; Penny]. Williams, MD; William R. Auger, MD, FCCP; Peter F. Fedullo, MD, FCCP; and Kenneth M. Moser, MD, FCCP

Background: Inhaled nitric oxide (NO) has been shown to be a selective pulmonary vasodilator in certain patients with primary pulmonary hypertension (PPH). Objectives: The purpose of this study was to design and test a system for delivery of NO to awaken, ambulatory patients with PPH and to evaluate this system in the home setting. Methods: The ambulatory delivery system consisted of a tank of 80 ppm of NO (balance N2), a modified gas-pulsing device, and nasal cannulas. The pulsing device was set to deliver NO for 0.1 sat the beginning of each inspiration. Results: Using this system, eight patients with PPH were studied with pulmonary artery catheters in place. Inhalation of NO led to significant reductions in both mean pulmonary arterial pressure (PAPm) (51±12 to 43±10 mm Hg; p=0.001) and pulmonary vascular resistance (PVR) (790±285 to 620±208 dyne·s·cm- 5; p=O.Ol). Three of the eight patients had both greater than 20% and greater than 30% decreases in PAPm and PVR, respectively. No exhaled NO or N02 was detectable in any of the eight patients. One patient was discharged home from the hospital on a regimen of inhaled NO. At 9 months, no adverse effects were noted and the system was working well. Conclusions: Pulsed delivery of inhaled NO to ambulatory patients with PPH, via nasal prongs, is feasible and, in some patients, leads to significant improvement in pulmonary hypertension. Inhaled 09NO, therefore, may have a role in the long-term treatment of patients with PPH. (CHEST 1996; 109:1545-49) Key words: inhaled nitric oxide; nasal cannulas, outpatient administration; primary pulmonary hypertension; pulsed delivery Abbreviations: CO=cardiac output; NO=nitric oxide; PAPm=mean pulmonary arterial pressure; PGI2=prostaglandin I2 (prostacyclin); PPH=primary pulmonary hypertension; PVR=pulmonary vascular resistance; SVR=systemic vascular resistance

Nitric oxide (NO), previously identified as an endothelium dependent relaxation factor, 1•2 has been shown, when delivered as an inhaled gas, to be a selective pulmonary vasodilator in patients with chronic pulmonary hypertension. 3-6 These observations have led to interest in the potential use of inhaled *From the Pulmona.rx and Critical Care Division (Drs. Channick, Williams, Auger, Fedullo, and Moser and Mr. Tohnson) and Department of Respiratory Care, (Mr. Newhart) University of California at San Diego Medical Center. This study was supported, in part, by Nellcor Puritan Bennett Corporation, Pleasanton, Calif, and Apria Healthcare. Manuscript received August 4, 1995; revision accepted November 3. Reprint requests: Dr. Channick, Pulrrwnary and Critical Care Division, UC SD Medical Center, Mail Code 8381, 200 West Arbor Dr, San Diego, CA 92103

NO as a therapeutic agent in various pulmonary hypertensive states. Practical application of NO, however, requires a safe and reliable delivery system. The purpose of this study was to design and test a system for pulsed delivery of NO via nasal cannulas to patients with primary pulmonary hypertension (PPH). Specific requirements for such a system included the following: (1) portability; (2) reliable delivery; (3) safety; and (4) conservation of delivered N 0 gas. In this report, we describe the features of our delivery system and initial clinical tests. MATERIALS AND METHODS

This study was approved by the Institutional Human Subjects Committee. Informed consent was obtained from the patients. CHEST I 109 I 6 I JUNE, 1996

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inspiration, one would expect minimal NO exhaled into the ambient air. For the short-tenn clinical tests, the delivered concentration of 80 ppm NO was achieved by blending 800 ppm NO (balance nitrogen), with N2 via a stainless steel blender (Bird Corp; Palm Springs, Calif). For the ambulatory patient, a portable source tank of 80 ppm NO (Puritan-Bennett Corp; Lenexa, Kan) was used. To monitor NO and N02 concentrations, a chemiluminescent analyzer (API Inc; San Diego) was used . In the blender studies, inspired NO was measured. In both the blender and ambulatory systems, exhaled and ambient gas were analyzed. The delivery system is shown in Figures 1 and 2.

NrTROGEN OXIDES ANALYZER

Clinical Tests

OXYGEN ANALVZER

VACUUM GAS SCAVENGER

FIGURE 1. NO delivery and monitoring system for short-term tests.

Delivery System The basis of the delivery system is a commercially available oxygen-pulsing device (provided by Nellcor Puritan Bennett Corporation; Pleasanton, Calif) that delivers gas via a nasal cannula for a set duration at the onset of each inspiration. The device is de mand activated, responding to a negative inspiratmy pressure of 0.5 em H20. The concentration of NO delivered with each pulse was 80 ppm. The duration of each pulse could be varied, but flow rate was constant at 10 Umin. In one patient, a dose-response relationship was dete rmined at varying pulse settings. With mixing of entrained room air, the concentration of NO delivered to the alveoli is less than 80 ppm. For example, if a patient's inspiratory flow rate is 40 Umin, the 80 ppm of pulsed NO (delivered at 10 Umin) would be diluted to approximately 20 ppm. Furthermore, as NO is being delivered only during the initial phase of

FIGURE 2. Delivery and monitoring system for ambulatory delivery of NO.

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The delivery system was tested in eight patients with PPH, whose conditions were diagnosed by standard criteria, as defmed in the National Institutes of Health PPH Registry 7 All patients had arterial and pulmonary arterial catheters inse rted. Pulmonary and systemic arterial pressures, arterial and mixed venous blood gases, and cardiac output (CO ) (thermodilution technique in triplicate) were measured at baseline and after 15 min of NO inhalation. Four patients were receiving supple mental oxygen at the time of NO inhalation. Gas exchange data were collected on the remaining four patients who were breathing room air prior to inhaled NO. In two patients, pulsed NO inhalation was continued longer than 15 min . One patient (patient 7) was delivered NO for 24 h. The other patient (pati ent 8) was ambulatory on the ward for an additional 24 h and then discharged home from the hospital with the ambulatory NO system. RESULTS

Delivery and Monitoring

The delivery device functioned without problems. NO was delivered with each breath. Neither NO nor N02 was detected in the expired gas or ambient air. The ambulatory patient had no difficulty with the portable system and was able to ambulate in the halls, eat, and bathe. This patient was discharged home from the hospital with an ambulatory system. Large, stationary tanks and small, portable tanks of NO were used to provide continuous NO inhalation. Herrwdynamic and Gas Exchange Results

Hemodynamic data at baseline and 15 min into NO inhalation for each patient are shown in Table 1. For the group as a whole, significant decreases in mean pulmonary arterial pressure (PAPm), mean right atrial pressure, and pulmonary vascular resistance (PVR) were noted dming NO inhalation. Three of the eight patients (patients 5, 6, and 7) manifested more than 20% decreases in PAPm and more than 30% decreases in PVR during NO inhalation. These patients were classified as NO "responders." No significant changes in pulmonary capillary wedge pressure, CO, or systemic vascular resistance (SVR) were noted during NO inhalation. Dose-response testing in one of the responders (patient 6) demonstrated that the minimal pulse duration required for maximal reduction in PAPm (75 to 59 mm Hg) was 0.1 s per inspiration. Among the Clinical Investigations

Table !-Hemodynamic Data at Baseline and After 15 min of Inhalation of NO Via the Pulsed Delivery Device* Patient

l. Baseline NO 2. Baseline NO 3. Baseline NO 4. Baseline NO 5. Baseline NO 6. Baseline NO 7. Baseline NO 8. Baseline NO Mean::+:SD Baseline NO

PAPm, mmHg

RAPm, mmHg

CO, Umin

PCWP, mmHg

PVR, dyne·s·cm- 5

MAP, mmHg

SVR, dyne·s·cm- 5

51 47 33 29 41 35 49 45 33 75 59 56 44 60 53

7 2 1 1 5 5 4 3 21 17 16 14 13 8 10 9

5.7 5.7 3.8 4.4 6.7 7.5 3.7 3.4 2.1 2.2 5.7 6.2 5.3 6.0 4.9 5.2

10 10 5 6 9 9 10 10 9 9 7 8 8 8 10 7

577 522 579 415 378 277 850 821 1,385 881 949 658 728 483 821 708

100 91 88 95 87 80 95 93 111 100 102 95 92 70 87 97

1,305 1,249 1,798 1,715 968 800 1,984 2,111 3,461 3,046 1,218 1,045 1,199 1,181 1,265 1,354

51::+::12 43::+::101

9::+::6.6 6.6::+::5.61

4.7::+::1.4 4.9::+::1.7

8.5::+::1.8 8.3::+::1.3

790::+::285 620::+::2081

95::+::8 90::+::10

45

1,688::+::763 1,624::+::701

*RAPm=mean right atrial pressure; MAP=mean arterial pressure; PCW=pulmonary capillary wedge pressure. tp=O.OOl NO compared with baseline. lp=0.01 NO compared with baseline.

nonresponders at the 0.1-s pulse duration, increasing pulse duration did not lead to additional hemodynamic responses. Gas exchange data for the four patients breathing room air prior to NO inhalation are shown in Table 2. For the group, no significant change in gas exchange parameters occurred during NO inhalation. However, Pa02 did increase in three of four patients. Safety Parameters

In addition to the absence of any measurable exhaled NO or N02, methemoglobin levels did not change significantly during short-term NO inhalation. Patients noted no adverse symptoms. The first outpatient, after 9 months of NO inhalation, has reported no adverse symptoms. Methemoglobin levels in this patient have not changed (0.4% at baseline, 0.3% at 35 weeks). No exhaled or ambient NO or N02 has been detected in the patient's home. DISCUSSION

In this study, we have reported details of an NO delivery system that is practical for ambulatory patients. We have demonstrated the reliability of this system in the clinical setting. Finally, we have demonstrated safety and feasibility of the system in eight patients with PPH and, in three patients, we have demonstrated marked reduction in PAPm and PVR with very short NO pulses. One patient was discharged home from the hospital on a regimen of inhaled NO

delivered via this system and is currently at 36 weeks of continuous NO inhalation. The on-demand nature of the system is ideally suited for ambulatory NO delivery for several reasons. First, NO can be delivered easily via nasal cannula. The device is extremely sensitive to small inspiratory efforts. Second, NO delivered via short pulses during the early phase of inspiration has the theoretical advantage of increasing the amount of NO delivered to the alveoli, thus increasing the fraction of NO that is absorbed by the lungs. We have previously demonstrated that, when delivered throughout the inspiratory cycle, approximately 25% of inhaled NO will return in the expiratory gas. 8 In an "open" system, such as occurs when patients are breathing via nasal cannulas, NO would, therefore, be released into the ambient air, a potential safety concern. With our system, which delivers a pulse of NO at the beginning of inspiration, there was no measurable NO in the exhaled gas, suggesting complete absorption. Finally, compared with continuous flow, the short pulsing of NO utilizes less gas. Although 80 ppm of N 0 is delivered through the device with each pulse, the actual concentration of NO delivered to the alveoli is less. The exact concentration will depend on the patient's inspiratory flow rate. In the three patients who were responders, a pulse setting providing an NO pulse ofO.l sat the beginning of each inspiration resulted in significant decreases in pulmonary arterial pressures and PVR. It is possible that the "ideal" pulse setting may vary among individual paCHEST /109/6/ JUNE, 1996

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Table 2-Gas Exchange Data at Baseline and During Pulsed NO in Patients Breathing Flo2 of0.21* Patient 4. Baseline

NO 8. Baseline NO 7. Baseline NO 6. Baseline NO Mean:!: SO Baseline NO

Pv02, mmHg

a-v02, mL02flOO mL Blood

7.39 7.42 7.42 7.39 7.39

40 41 39 37 37 35 34 37

4.5 5.1 4.6 4.:3 6.4 .5.2 6.2 5.5

7.41:!::0.04 7.42:!::0.03

38:!::2.7 38:!::2.5

5.4:!::1.0 .5.0:!::0.5

Pa02, mmHg

PaC02 mmHg

78 86 65 65 57 61 58 59

26 26 34 33 30 30 31 31

7.4.5 7.46

65:!::10 68:!::12

30:!::3 30:!::3

pH

7.37

*Fio 2 =fraction of inspired oxygen; Pv02=mixed venous pressure of oxygen; a-v02=arterial-venous oxygen content difference.

tients. What the long-term pulse duration should be in patients who are nonresponders short term is unclear. However, based on the data from this study, an "arbitrary" setting of 0.1 s per pulse seems reasonable. The findings of significant improvement in pulmonary hypertension observed in these patients in the absence of systemic hemodynamic changes are similar to findings previously reported in patients given N 0 via face mask9 and indicate that short pulsing of N 0 results in physiologic responses comparable to continuous inhalation. Vesal and coworkers 10 have recently reported similar results using NO in thromboxane analogue-induced pulmonary hypertension in pigs. The therapeutic potential of long-term NO inhalation in patients with PPH is suggested by several previous observations. Rich and coworkers 11 have demonstrated that sustained reduction in pulmonary arterial pressures in patients treated with oral calcium channelblocking agents is associated with an excellent 5-year survival in patients with PPH. Unfortunately, approximately 75% of patients with PPH do not achieve a hemodynamic response of this magnitude. Recently, continuous IV prostaglandin I2 (PGh; prostacyclin) has been demonstrated to improve exercise capacity and survival in a long-term trial (up to 18 months). 12 The long-term improvement in hemodynamics and exercise capacity observed in these patients was independent of the short-term hemodynamic response to PGI 2. It has been speculated that PGI2 may be exerting a beneficial effect via mechanisms other than pulmonary vasodilation. These include the antiplatelet properties ofPGI2 or the inhibition of smooth muscle cell proliferation. Although efficacious in many patients, potential disadvantages of long-term PGI2 infusion include difficulty with the delivery system, catheter infections, and untoward symptoms. It has been shown that NO also has potent antiplatelet13,14 and anti-smooth muscle proliferative properties.15 Therefore, the possibility exists that long-term inhalation of NO will, as with PGI2, exert beneficial 1548

effects independent of short-term hemodynamic responses. Previous studies have demonstrated that the shortterm hemodynamic effects of inhaled NO in patients with PPH are similar to those produced by PGI2.9J 6 Inhaled NO produced no systemic hemodynamic effects, in contrast to significant reductions in mean arterial pressure and SVR and increases in CO consistently observed during incremental PGI 2 infusion. It has been speculated that such increases in CO in the absence of reductions in pulmonary arterial pressures may actually increase right ventricular wall stress. However, long-term increases in CO may improve exercise tolerance. Based on these prior observations and our preliminary findings in this study, we discharged one patient home from the hospital with the ambulatory NO system. After 36 weeks, no adverse effects have been noted and the delivery system is functioning well. Two additional outpatients are currently undergoing NO therapy. However, determination of the efficacy and safety oflong-term outpatient administration of NO in patients with PPH awaits further data. Questions that are currently being addressed in patients undergoing outpatient NO therapy include the following. (1) Does long-term inhaled NO therapy improve survival and/or exercise tolerance? (2) What are the long-term effects of inhaled NO on pulmonary arterial pressures and cardiac output; are they independent of short-term effects? (3) Does long-term NO therapy have any systemic effects, eg, platelet function? (4) Can both NO and oxygen be provided via the pulsed delivery system? ACKNOvVLEDGMENTS: The authors thank Diane Mcintyre and Katie Kinninger for their technical assistance in this study. REFERENCES

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