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Inhaled Nitric Oxide Improves Oxygenation Acutely But Not Chronically in Acute Respiratory Distress Syndrome: A Randomized, Controlled Trial*
Sangeeta Mehta, MD, FRCPC*
Mitchell M. Levy, MD, FCCM‡
Nicholas S. Hill, MD, FCCP‡
Kathy Short, RRT§
James R. Klinger, MD, FCCP‡
*Department of Medicine, M
of Surgery†; Pulmonary, Sleep, and Critical Care Medicine‡;
*This work was supported in part by NIH grant # HL-02613 (JRK) and a grant from Pfizer Pharmeutical.
KEY WORDS: nitric oxide, oxygenation, acute respiratory distress syndrome, mean pulmonary artery pressure
Objective: To determine whether prolonged inhalation of nitric oxide (NO) improves cardiopulmonary hemodynamics and gas exchange in adult patients with the acute respiratory distress syndrome (ARDS).
Design: Randomized, controlled trial.
Setting: Medical and surgical intensive care units in a university affiliated hospital.
Patients: 14 patients with ARDS
Interventions: Patients were randomized to receive conventional therapy (n = 6) or conventional therapy and inhaled NO (n = 8). The study was divided into acute and chronic phases. During the acute phase, the NO group received inhaled NO at 5, 10, and 20 parts/million (ppm) for 30 minutes at each dose, and hemodynamic and arterial blood gas measurements were performed at baseline and at the end of each dosage interval. The dose of NO resulting in the highest PaO2/FiO2 was continued until the following day. During the chronic phase, dosage titration was repeated daily for 3 days (days 2 to 4) to determine the NO dose for the following 24 hours. To simulate the dosage titration in the NO group, the control group had similar measurements performed. NO was discontinued when the PaO2/FiO2 ratio was greater than 200 mm Hg on FiO2 less than 0.5.
Measurements and Main Results: During the acute phase, inhaled NO
at 5 and 10 ppm was associated with a decrease in the mean pulmonary artery
pressure (MPAP; baseline: 35 ± 2, 5 ppm: 32 ± 2, and 10 ppm: 30 ± 2 mm
Hg, P < .05
Conclusions: In patients with ARDS, NO reduces MPAP and improves oxygenation acutely but fails to improve these variables beyond 24 hours.
Acute respiratory distress syndrome (ARDS) is characterized by diffuse lung injury usually accompanied by inflammation and occlusion of the pulmonary microcirculation.1-3 These abnormalities result in pulmonary hypertension and arteriovenous shunting, which contribute to the severe hypoxemia associated with ARDS. In addition, pulmonary hypertension causes right ventricular dysfunction,4 which may impair CO and further depress oxygen delivery. Nitric oxide (NO) is an endogenous vasodilator constituitively released by vascular endothelial cells.5 Because of its high permeability to lipid membranes, NO rapidly diffuses across the endothelial basement membrane of pulmonary vessels and into adjacent vascular smooth muscle, where it interacts with soluble guanylate cyclase to raise intracellular cGMP levels and cause vasorelaxation.6
Inhalation of exogenous NO produces selective pulmonary vasodilation.7 Because of rapid inactivation through binding with hemoglobin, the vasoactive effect of inhaled NO is limited to the pulmonary circulation.8 In patients with ARDS, in addition to reducing pulmonary arterial pressure, NO administration also reduces pulmonary venous admixture as well as the alveolar-arterial oxygen difference.9 Because of its unique ability to reduce pulmonary artery pressure (PAP) while redistributing pulmonary blood flow from nonventilated to ventilated areas of the lung, NO has been advocated as an adjunctive therapy in the treatment of ARDS.10,11
In previous studies,9,11-13 NO was shown to improve oxygenation acutely in patients with ARDS. This effect is rapid, reversible and can be reproduced daily for up to 7 weeks after the initial exposure.9 The reduction in PAP has been associated with a decrease in pulmonary capillary pressure,14 an improvement in right ventricular ejection fraction, and a reduction in RV work, but is not associated with a fall in cardiac output (CO) or systemic vascular resistance (SVR).9,13,15,16 Conversely, NO has several potentially toxic effects, the most important of which appears to be its interaction with superoxide to form peroxynitrite, a potent oxidant capable of damaging a variety of biomolecules, including the lipid portion of cellular membranes.17 Hence, despite its acute beneficial effects on pulmonary hemodynamics and gas exchange, it is possible that extended NO therapy could damage alveolar epithelial cells or interfere with the healing and repair of diffuse alveolar damage.18
The purpose of this study was to determine, using a prospective, randomized controlled design, whether prolonged NO improves cardiopulmonary hemodynamics and gas exchange in adult patients with ARDS.
This study was
Inhaled nitric oxide delivery system
Nitric oxide (BOC Inc, Port Allen,
LA) at a concentration of 800 ppm in nitrogen was diluted with air by a Bird
Air Oxygen Blender (Bird Products Corp., Palm Springs, CA) and introduced into
the high-pressure air inlet of a Mallinckrodt 7200a ventilator (Lanexa, KA). In
the ventilator, the NO/air mixture was blended with O2 to obtain the
desired concentration of NO and O2 and administered to the patient
throughout the inspiratory cycle. The inspired NO and nitrogen dioxide (NO2)
concentrations were measured continuously by a Pulmonox II analyzer (Tofield,
NO Group Study Protocol—Acute Phase
Patients were randomized to receive conventional treatment or conventional treatment plus NO using a computer-generated random number sequence. Neither patients nor medical personnel were blinded to the randomization group. Patients randomized to receive NO underwent an initial dose titration at the start of the study. Prior to dose titration, FiO2 was decreased to the lowest concentration that maintained the oxygen saturation > 90%. Subsequently, FiO2 and other ventilator settings were not changed during the dose titration. Inhaled NO was initiated at 5 ppm, and the dose was doubled every 30 minutes up to 20 ppm. Arterial blood gases and hemodynamic measurements were obtained at baseline and at the end of each 30-minute interval. The dose titration was discontinued for any of the following reasons: (1) > 10% reduction in the PaO2/FiO2, (2) > 10% reduction in CO, (3) systemic hypotension defined as a mean arterial blood pressure (MAP) < 70 mm Hg or a reduction in MAP of ³ 15 mm Hg, or (4) an inhaled NO2 concentration > 2 ppm. The NO dose that produced a ³ 10% improvement in PaO2/FiO2 compared with the previously administered lower dose (or baseline) was selected as the dose for chronic administration (chronic phase). Patients were maintained on the NO dose as determined in the acute phase study until the next dose titration was performed on the following day (day 2).
NO Group Study Protocol—Chronic Phase
The dose titration protocol (5, 10,
and 20 ppm) was repeated daily for 3 days (days 2, 3, and 4), with the NO dose
for the following 24 hours adjusted as determined from the daily titration
study. The highest dose of NO that produced a
Conventional therapy group
Patients randomized to receive conventional therapy had arterial blood gases and hemodynamic measurements obtained at baseline (0 time) and 30 minute intervals X 3 (30, 60, 90 minutes) at the onset of the study and then daily to simulate the dose titration protocol in the NO group.
Lung injury score was determined at study entry.21 All patients had thermodilution pulmonary artery and radial arterial catheters in place. For the acute phase of the study, blood pressure, heart rate, PAP, pulmonary artery occlusion pressure (PAOP), CO, systemic and pulmonary vascular resistances (SVR and PVR), and arterial blood gases were recorded at study entry and at the end of each dosage interval (ie, at 0, 30, 60, and 90 minutes). For the chronic phase of the study, the above measurements were repeated daily during the NO dose titration. Daily values were calculated as the mean of all values obtained during the dose titration and any additional values recorded during the 24 hours between dose titrations. Methemoglobin levels were measured in the NO group at study entry and daily thereafter. Inspired NO2 was measured continuously.
All patient care other than the administration of NO was directed by the patient’s critical care team. Ventilator and FiO2 adjustments as well as measurement of cardiopulmonary hemodynamics and arterial blood gases could be made by the ICU team at any time other than during NO dose titration. Patients were ventilated in the assist/control or pressure control mode, and the ventilatory mode was not changed during the study period.
Values shown are mean + SEM.
One-way repeated measures analysis of variance was used to compare values at
different time points within groups. When statistically significant differences
were measured, pairwise multiple comparisons were made using the
Student-Newman-Keuls method. Differences in mean values between groups at the
same time point were measured using unpaired t-tests.
Between July 1994 and April 1995,
14 patients were enrolled in the study; 8 were randomized to conventional
treatment with inhaled NO, and 6 to conventional treatment alone. The clinical
characteristics of the patients are shown in Table 1. At study entry, there
were no significant differences in age or length of time that the patients had
met the study criteria for ARDS prior to enrollment. Both groups had similar
lung injury scores (table 1). Other organ failure existed in all patients
except for 1 patient in the control group. The mean WBC was significantly
higher in the group that received NO than in control
Acute Response to Nitric Oxide
During the acute phase of the
study, all 8 patients randomized to NO received the 5 and 10 ppm doses. Four of
the 8 patients did not receive 20 ppm NO during the dose titration because they
had no significant improvement in PaO2/FiO2
Chronic Response to Nitric Oxide
During the chronic phase, the
administered dose of NO was always 10 ppm or less, except in 2 patients who
received 20 ppm on day 2 of the study. In the NO group, the initial significant
improvement in PaO2/FiO2 was no longer apparent by day 1
(Figure 2), and mean PaO2/FiO2 for all patients given NO
fell from a peak of 130 + 25 mm Hg (10 ppm) to 115 + 17 mm Hg
(day 1). No change from baseline in MPAP, PaO2/FiO2 ratio
or any of the other hemodynamic variables was
Because of the variability in baseline PaO2/FiO2 within and between groups, changes in PaO2/FiO2 ratios were normalized to baseline measurements (Figure 3). Compared to the control group, there was a trend toward a greater percent increase in PaO2/FiO2 in patients given 5 and 10 ppm NO acutely (Figure 3, panel on left), but the difference was not statistically significant. By day 2, the percent improvement from baseline in PaO2/FiO2 was greater in the controls than in patients given NO (P < .05, Figure 3, panel on right). No significant differences between groups were observed for percent changes from baseline in PEEP or PIP (data not shown).
Hospital mortality in both groups was 50%. Patients died of multisystem organ failure. In the NO group, 3 of the 4 patients that died were still being treated with NO at the time of death. They died after 2, 4, and 29 days of NO. The other patient met the oxygenation criteria for discontinuation after 4 days of NO but died of complications of a bowel infarction 12 days after NO cessation. One patient in the NO group was switched to high frequency ventilation on day 2 because of worsening gas exchange on NO. The other survivors in the NO group received NO for, 5, 5, and 11 days. Deaths in the control group occurred 7, 25, and 68 days after study entry.
There were no complications during delivery of NO. NO2 levels did not exceed 2 ppm. Methemoglobin levels remained in the normal range, except in 1 patient whose baseline methemoglobin level was elevated at 3.8% prior to NO and declined to 2.2% while NO was continued over the subsequent 3 days.
In the present study, we used a randomized, prospective design to determine whether long-term NO therapy improved cardiopulmonary hemodynamics and oxygenation in adults with ARDS. As demonstrated by other investigators,9,12-16 we found that inhaled NO lowered PAP and increased PaO2/FiO2 acutely. However, in patients that received inhaled NO, neither PAP or PaO2/FiO2 were significantly changed from baseline levels at days 1 through 4 of therapy. In contrast, control patients had no changes in cardiopulmonary hemodynamics or oxygenation during the acute phase of the study, but PaO2/FiO2 improved during the chronic phase.
The reason for the
lack of a sustained improvement in oxygenation in patients given inhaled NO is
not known. It is unlikely that the patients in our NO group were unresponsive
to NO or were given inadequate doses of NO during the chronic phase of the study.
The magnitude of the NO-induced decrease in PAP and improvement in PaO2/FiO2
observed during the acute phase of the study are consistent with those reported
by other investigators.9,13,15,20 Furthermore, NO was temporarily
discontinued each day of the study and PaO2/FiO2 levels
fell > 10%, suggesting that despite the lack of continued improvement in
oxygenation, the patients in the NO group remained responsive to NO. In the
present study, the administered NO dose was always between 5 and 10 ppm, except
in 2 patients who received 20 ppm on day 2 of the study. The percent increase
in PaO2/FiO2 in both of these patients was greater than
the mean improvement observed in the NO group. Gerlach and colleagues11
noted that PaO2 improved significantly at an NO dose of 0.1 ppm and
deteriorated at doses above 10 ppm. Lowson et al13 also found no
further improvement in oxygenation at doses of NO greater than 10 ppm.
Furthermore, in 2 previous studies suggesting long-term benefit of NO in
patients with ARDS, the average daily doses were 18 and 11.5 ppm, respectively,9,21
and in other randomized controlled trials of ARDS, the doses of NO ranged from
1.25 to 80 ppm22 or averaged 5.623 and 14 ppm24.
Thus, the dose of NO used in this study is similar to doses th
The small number of patients in this study makes it difficult to draw definitive conclusions about the efficacy of extended NO therapy in ARDS. Using data published from an earlier report,23 the present study was adequately powered to have a 90% probability of detecting an increase in PaO2/FiO2 of 64 mm Hg or greater with a P value of < .05. Thus, it is possible that there may have been a significant but smaller improvement in PaO2/FiO2 that was undetected by our study. However, our findings suggest that the magnitude of the acute improvement in oxygenation in response to inhaled NO is not sustained during extended NO therapy for ARDS.
findings are similar to other randomized controlled trials of inhaled NO in
adults with acute lung injury22-27 and lend support to the
hypothesis that inhaled NO is unlikely to improve outcome in adults with ARDS,
despite acute improvements in oxygenation and pulmonary hemodynamics. Our
findings differ from the results of previous trials in that we found a
significantly greater increase in oxygenation in controls than in patients
receiving NO (Figure 3). A deleterious effect of chronic inhaled NO has not
been reported previously. However, there are several potential adverse effects
of NO that could worsen oxygenation or prevent repair of acutely injured lung.
NO2 causes acute lung injury and its formation is well documented
during inhaled NO therapy in patients receiving high FiO2. Although
exhaled NO2 levels were closely monitored and were below toxic
levels throughout the study, local concentrations of this compound may have
been much higher in poorly perfused areas of ventilated lung where NO and
On the other hand, it is possible that the greater increase in oxygenation in the control patients was the result of less severe ARDS in those patients rather than any deleterious effect of NO. Despite the similarity of the lung injury score at the time of study entry, 2 of the control patients had a greater than 100% increase in PaO2/FiO2 within 48 hours of study entry. By day 3, all 5 patients remaining in the control group had an increase in PaO2/FiO2 that was greater than 40%, as opposed to only 2 of 6 patients in the NO group. Other investigators32 have noted that inhaled NO is less effective at improving oxygenation in septic patients with ARDS. Although we found no difference in the number of patients that met criteria for sepsis between groups, the WBC was significantly higher in the NO group, and a greater number of the patients that were randomized to receive NO had pneumonia (4/8 versus 1/6 in the control group). Finally, PIP was greater in the NO group than in control patients on days 1 and 2, suggesting greater severity of lung injury. Thus, the smaller increase in oxygenation in patients receiving NO than controls may have been due to differences in their underlying diseases.
evaluating the use of inhaled NO in neonates with hypoxic respiratory failure
have shown very promising results, with improvements in oxygenation and reduced
requirements for extracorporeal oxygenation.33,34 Unfortunately,
randomized controlled trials in adults with ARDS have failed to show any
improvement in outcome. Benefit is suggested by a trend toward a reduction in
ventilator days in 2 of the studies,22,23 and a reduction in the
development of severe respiratory failure in patients with acute lung injury.26
At present, the available data does not support the long-term use of inhaled NO
in adults with ARDS. However, inhaled NO in combination with other strategies
such as prone positioning and high-frequency oscillatory ventilation may prove
to be useful.35
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Figure 1. Acute phase of the study. During the acute phase, the NO group received inhaled NO at 5, 10, and 20 ppm NO, with the dose increased at 30-minute intervals. PaO2/FiO2 ratios were determined at baseline and at the end of each interval, and are plotted in the panel on the right. Patients in the control group (panel on the left) had PaO2/FiO2 ratios determined at baseline and at 30-minute intervals (30, 60, 90 minutes) to simulate the dose titration protocol in the NO group. Open triangles are individual patients in each group, and solid triangles are group means. *P<.05 compared with baseline by repeated measures ANOVA for 8 patients that received 5 and 10 ppm NO during the dose titration. **P<.05 compared with all other time points by repeated measures ANOVA for 4 patients that received 5, 10, and 20 ppm.
Figure 2. Chronic phase of the study. Mean PaO2/FiO2 ratios in the NO group (right panel) and the control group (left panel) over the following 4 days are plotted. Time 0 represents baseline measurements. Open triangles are individual patients in each group, and solid triangles are group means. *P<.05 by repeated measures ANOVA.
Figure 3. Improvements in PaO2/FiO2 in the acute and chronic phases of the study expressed as percent increase in PaO2/FiO2 compared with baseline PaO2/FiO2. Open circles represent NO group means, and solid circles represent control group means. At baseline, N=8 for NO group, and N=6 for control group. Ns for the remaining time points are presented in parentheses on the figure. *P<.05 compared with NO group at equivalent time points. Values are mean ± SEM.
Table 1. Clinical Characteristics of the Patients at Study Entry
Age Sex Condition Predisposing ARDS Lung
Injury Other Organ
to ARDS (days) Score Failure
42 F Tricyclic overdose 2 3.3 Ileus, liver
60 F Ovarian abscess, Sepsis 5 3.3 CNS
34 M DKA,
pneumonia 1 3 None
78 M AAA
Repair 1 3.7 Kidney
63 M Pancreatitis 3 4 Kidney
66 M Total colectomy 3 4 DIC, Fungemia
Mean 57 ± 7 yrs 3.3 ± 1 3.3 ± 0.2
Nitric Oxide Group
26 M Pneumonia 1 3.3 DIC
34 M Fournier's gangrene 2 3.7 Ileus
66 F Bowel infarction 2 2.7 Kidney
59 M Mediastinitis 4 3 Liver
32 M MVA/Pneumonia 5 2.3 Ileus
19 F Hodgkin’s disease 4 3 DIC, Ileus
69 F Pneumonia 1 2.7 Kidney,
34 M Pneumonia 1 4 Liver, Kidney, DIC
Mean 42 ± 7 yrs 2.5 ± 0.6 3.1 ± 0.2
Means ± SEM. There were no significant differences between the 2 groups at study entry.
= bone marrow,
Table 2. Hemodynamic and Arterial PaCO2 Measurements—Acute Phase
Control Group Baseline 30 Min 60 Min 90 Min
N 6 6 6 5
MPAP (mm Hg) 31 ± 2 30 ± 2 33 ± 2 30 ± 1
PVR (dyne sec/cm5) 172 ± 21 160 ± 40 203 ± 84 197 ± 14
PAOP (mm Hg) 16 ± 2 17 ± 2 16 ± 1 17 ± 1
MAP (mm Hg) 72 ± 4 73 ± 4 77 ± 4 72 ± 4
SVR (dyne sec/cm5) 673 ± 113 586 ± 238 808 ±233 625 ± 42
CVP (mm Hg) 14 ± 1 13 ± 1 14 ± 1 15 ± 1
CI (L/min/m2) 3.7 ± 0.3 3.5 ± 0.5 3.5 ± 0.6 3.8 ± 0.1
DO2I (mL/min/m2) 422 ± 23 420 ± 30 418 ± 29 437 ± 25
PaCO2 (mm Hg) 41 ± 6 39 ± 4 40 ± 3 41 ± 4
Nitric Oxide Group
N 8 8 8 4
MPAP (mm Hg) 35 ± 2 a 32 ± 2 a 30 ± 2 a 32 ± 3
PVR (dyne sec/cm5) 197 ± 38 167 ± 24 174 ± 29 169 ± 30
PAOP (mm Hg) 16 ± 1 16 ± 1 15 ± 1 16 ± 1
MAP (mm Hg) 82 ± 8 76 ± 7 75 ± 6 73 ± 10
SVR (dyne sec/cm5) 654 ± 97 684 ± 136 687 ± 137 775 ± 143
CVP (mm Hg) 15 ± 1 14 ± 1 14 ± 1 14 ± 1
CI (L/min/m2) 4.6 ± 0.4 4.2 ± 0.4 4.2 ± 0.3 4.1 ± 0.4
DO2I (mL/min/m2) 585 ± 77 550 ± 75 545 ± 58 554 ± 32
PaCO2 (mm Hg) 42 ± 10 40 ± 8 39 ± 8 40 ± 11
Values are mean + SEM, a indicates P < .05 by repeated measures ANOVA.
MPAP = mean pulmonary artery
pressure, PVR = pulmonary vascular resistance, PAOP = pulmonary artery
occlusion pressure, MAP = mean arterial pressure, SVR = systemic vascular
resistance, CVP = central venous pressure, CI = cardiac index, DO2I
= oxygen delivery index, PaCO2 = arterial carbon dioxide tension
Table 3. Hemodynamic and Arterial PaCO2 Measurements—Chronic Phase
Control Group Baseline Day 1 Day 2 Day 3 Day 4
N 6 6 6 5 4
MPAP (mm Hg) 31 ± 2 32 ± 2 31 ± 2 32 ± 2 31 ± 2
PVR(dyne sec/cm5) 172 ± 21 186 ± 29 257 ± 59 220 ± 39a 208 ± 36
PAOP (mm Hg) 16 ± 2 17 ± 1 16 ± 0.4 14 ± 1 15 ± 2
MAP (mm Hg) 72 ± 4 72 ± 3 87 ± 6 89 ± 9a 77 ± 2
SVR (dyne sec/cm5) 673 ± 113 818 ± 133 904 ± 230 796 ± 152 745 ± 70
CVP (mm Hg) 14 ± 1 15 ± 1 14 ± 1 13 ± 1 13 ± 1
CI (L/min/m2) 3.7 ± 0.3 3.5 ± 0.3 3.6 ± 0.5 3.9 ± 0.4 3.8 ± 0.4
DO2I (ml/min/m2) 422 ± 23 427 ± 26 431 ± 45 471 ± 48 467 ± 59
PaCO2 (mm Hg) 41 ± 6 38 ± 4 39 ± 6 37 ± 5 41 ± 6
Nitric Oxide Group
N 8 8 8 4 6
MPAP (mm Hg) 35 ± 2 31 ± 2 32 ± 2 30 ± 2 30 ± 1
PVR(dyne sec/cm5) 197 ± 38 181 ± 26 179 ± 24 191 ± 28 168 ± 25
PAOP (mm Hg) 16 ± 1 16 ± 1 16 ± 1 15 ± 1 15 ± 1
MAP (mm Hg) 82 ± 8 79 ± 7 75 ± 4 74 ± 3 83 ± 4
SVR (dyne sec/cm5) 654 ± 97 707 ± 116 756 ± 113 749 ± 94 692 ± 71
CVP (mm Hg) 15 ± 1 14 ± 1 16 ± 1 14 ± 2 14 ± 1
CI (L/min/m2) 4.6 ± 0.4 4.2 ± 0.4 4.3 ± 0.5 4.0 ± 0.4 4.6 ± 0.4
DO2I (mL/min/m2) 585 ± 77 542 ± 64 537 ± 73 543 ± 74 615 ± 43
PaCO2 (mm Hg) 42 ± 10 40 ± 8 42 ± 9 38 ± 3 38 ± 4
Values are mean + SEM, a indicates that P < .05 compared with baseline, MPAP = mean pulmonary artery pressure, PVR = pulmonary vascular resistance, PAOP = pulmonary artery occlusion pressure, MAP = mean arterial pressure, SVR = systemic vascular resistance, CVP = central venous pressure, CI = cardiac index, DO2I = oxygen delivery index, PaCO2 = arterial carbon dioxide tension.
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