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Title: Extended Therapy with Inhaled Nitric Oxide Fails to Improve Oxygenation in Patients with the Acute Respiratory Distress Syndrome: a Randomized Controlled Trial

Inhaled Nitric Oxide Improves Oxygenation Acutely But Not Chronically in Acute Respiratory Distress Syndrome: A Randomized, Controlled Trial*


Sangeeta Mehta, MD, FRCPC*

H. Hank Simms1 Simms, MD, FACS

Mitchell M. Levy, MD, FCCM

Nicholas S. Hill, MD, FCCP

William Schwartz2 Schwartz, RRT§

David Nelson2 Nelson, RRT§

Kathy Short, RRT§

James R. Klinger, MD, FCCP


*Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Canada

Departments of Surgery; Pulmonary, Sleep, and Critical Care Medicine; and Respiratory Care2Care4; Rhode Island Hospital and Brown University School of Medicine, Providence, RI


*This work was supported in part by NIH grant # HL-02613 (JRK) and a grant from Pfizer Pharmaceutical.


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 repeated measures ANOVA) and an increase in the PaO2/FiO2 ratio (baseline: 106±18, 5 ppm: 126±26, and 10 ppm: 130±25 mm Hg, P < .05 ANOVA). There were no changes in MPAP or PaO2/FiO2 in the control group during the same time period. In the chronic phase, no significant changes from baseline in MPAP or PaO2/FiO2 were observed in the NO group at days 1 through 4. In the control group however, PaO2/FiO2 increased at day 1 and remained elevated through day 4. There was no difference in PaO2/FiO2 measurements between NO and control groups on days 1 through 4 of the study, but the percentage increase from baseline was greater in the control than in the NO patients at days 2 and 3. No significant differences were observed in hemodynamic variables or PaCO2 between groups at any time point.

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.



Study Population

This study was reviewed and approved by the Rhode Island Hospital Committee for the Protection of Human Subjects, and written informed consent was obtained from all patients or their next of kin. Patients were recruited from the Medical, Surgical, and Coronary Care Units at Rhode Island Hospital, a university affiliated hospital. Patients with ARDS (defined below) were offered enrollment into the study if they were 18 years of age or older. The diagnosis of ARDS was defined as follows: (1) radiographic evidence of diffuse bilateral alveolar infiltrates, (2) pulmonary artery occlusion pressure < 18 cm H2O, and (3) PaO2/FiO2 < 200 mm Hg while mechanically ventilated with a positive end expiratory pressure (PEEP) ³ 8 cm H2O. Patients were excluded from the study if they were receiving intravenous nitroglycerin or prostacyclin, high dose corticosteroids (> 10 mg methylprednisolone per day), or unconventional modes of mechanical ventilation (such as high frequency ventilation or ventilation in the prone position) or if they had suffered a myocardial infarction within the previous 72 hours, had 2,3-DPG deficiency, or had met entry criteria for more than 5 days.


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, Alberta) before the humidifier.


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 ³>10% increase in PaO2/FiO2 compared with the baseline PaO2/FiO2 for that day was used for the next 24 hours. If a higher dose of NO did not increase PaO2/FiO2 by ³>10%, then the dose was decreased until a ³>10% drop in PaO2 was obtained. At that point, the dose of NO prior to the drop in oxygenation was used. Inhaled NO was discontinued if the PaO2/FiO2 ratio did not fall ³>10% when NO was turned off, or when the PaO2/FiO2 was > 200 mm Hg on an FiO2 < 0.5 off ofin the absence of NO. The study was terminated when the PaO2/FiO2 decreased <10% for 24 hours after discontinuing NO. Inhaled NO was discontinued prior to study termination when any of the following occurred without any other explanation: (1) systemic hypotension defined as a MAP <70 mm Hg or a drop in MAP >15 mm Hg that could not be attributed to other factors, (2) ³10% reduction in CO, (3) ³10% reduction in PaO2/FiO2, (4) inhaled NO2 >2 ppm, or (5) a methemoglobin level >3%.


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.


Patient Care

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 the NO dose titration. Patients were ventilated in the assist/control or pressure control modes, and the ventilatory mode was not changed during the study period.


Statistical Analysis

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.  Differences in mean values were A P < .05 was considered significant at P < 0.05.



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 the controls group at baseline (25.4 + 8 versus 9.3 + 1, P < .05) and throughout the 4-day study. However, there were no differences between the groups in body temperature, MAP, SVR, or other indicators of sepsis. One patient in each group was septic (defined as simultaneous hypotension and alteration in body temperature and WBC or respiratory rate) at one point during the study.


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 aton 10 ppm when compared with 5 ppm NO. There were no significant hemodynamic differences between the NO and control groups at the start of the study. There was a trend toward lower PaO2/FiO2 ratios at study entry in the control group (74 + 11 mm Hg versus 106 + 18 mm Hg), but the difference was not statistically significant (P = .19). Inhaled NO decreased MPAP and increased PaO2/FiO2 acutely (Table 2 and Figure 1). The increase in PaO2/FiO2 was not dose related. There was no significant difference in PaO2/FiO2 between 5, 10, or 20 ppm NO (Figure 1). No significant changes in MPAP or PaO2/FiO2 were observed in the control patients over the same time period. There was a strong trend toward a higher PaO2/FiO2 ratio in the NO than in the control group, but the difference did not quite reach statistically significance (130 + 25 mmHg versus 81 + 14 mm Hg, 10 ppm NO versus 60 minute time point in controls, P = .057). No changes in PVR, PAOP, SVR, CVP, CI, DO2I, or PaCO2 were observed in either group during the acute phase of the study (Table 2).


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 seen observed in the NO group over the 4-day period (Table 3, Figure 2). In contrast, the PaO2/FiO2 ratio increased by day 1 in the control group compared with baseline and remained elevated for the study duration (Figure 2). No significant differences in any of the hemodynamic or gas exchange measurements was observed between groups at any time point. There were also no significant differences in mean airway pressure oras assessed by PEEP; however, and peak inspiratory pressure (PIP) was significantly higher in the NO group on days 1 and 2 (Table 4).

       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.


DISCUSSION add discussion of difference in PIP

       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 thate have been found to be effective and have been used by other investigators.

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.

       Our 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 levels. 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 oxygenO2 could be in contact for prolonged periods of time. A rebound phenomenon in which PaO2/FiO2 falls abruptly when NO is interrupted after long-term administration has also been described20 and has been attributed to inhibition of endothelial NO-synthase by exogenous NO.28 This phenomenon resulted in precipitous declines in oxygenation in at least 1 of our patients during transient discontinuation of NO. Other putative toxic effects of NO include a mutagenic effect through DNA deamination,29 impaired surfactant function,30 and increased free radical formation17. Emphysematous lesions in the lung after inhalation of 20 ppm of NO for 6 weeks has been reported in healthy rats,31 suggesting that long-term NO may also damage normal lung tissue.

       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.

       Studies 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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21.    Rossaint R, Gerlach H, Schmidt-Ruhnke H, et al: Efficacy of inhaled nitric oxide in patients with severe ARDS. Chest 107:1107-1115, 1995.

22.    Dellinger RP, Zimmerman JL, Taylor RW, et al and the inhaled nitric oxide in ARDS study group. Effects of inhaled nitric oxide in patients with the acute respiratory distress syndrome: Results of a randomized phase II trial. Crit Care Med 26:15-23, 1998.

23.    Troncy E, Collet J-P, Shapiro S, et al: Inhaled nitric oxide in acute respiratory distress syndrome. Am J Respir Crit Care Med 157:1483-1488, 1998.

24.    Day RW, Allen EM, Witte MK: A randomized, controlled study of the 1 hour and 24 hour effects of inhaled nitric oxide therapy in children with acute hypoxemic respiratory failure. Chest 112:1324-1331, 1997.

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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             Ventilator

                                            to ARDS                         (days)              Score                    Failure                          Mode

Control Group

               42       F             Tricyclic overdose                2                  3.3                            Ileus, liver                        PC

               60       F             Ovarian abscess, Sepsis               5             3.3                            CNS                        


               34       M            DKA, pneumonia                       1             3                               None                              PC

               78       M            AAA Repair                             1             3.7                         Kidney                           AC

               63       M            Pancreatitis                               3                  4                            Kidney                           AC

               66       M            Total colectomy                       3             4                               DIC, Fungemia         AC/PC

Mean   57 ± 7 yrs                                              3.3 ±  1       3.3 ±  0.2


Nitric Oxide Group

               26       M            Pneumonia                               1                  3.3                            DIC                                PC

               34       M            Fournier's gangrene                2                  3.7                            Ileus                          PC

               66       F             Bowel infarction                2                  2.7                         Kidney                           AC

               59       M            Mediastinitis                            4                  3                               Liver                         AC

               32       M            MVA/Pneumonia                     5                  2.3                            Ileus                          AC

               19       F             Hodgkin’s disease                   4                  3                               DIC, Ileus                       PC

               69       F             Pneumonia                               1                  2.7                         Kidney, CNS, BM        AC

               34       M            Pneumonia                               1                  4                               Liver, Kidney, DIC          PC

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.

BM = bone marrow, AC = assist/control, PC = pressure controlCNS = central nervous system, DKA = diabetic ketoacidosis, AAA = abdominal aortic aneurysm, DIC = disseminated intravascular coagulation, MVA = motor vehicle accident.


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. , ppm = parts per million.

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.

Table 4. Airway PressuresChronic Phase

Control Group                              Baseline      Day 1              Day 2        Day 3              Day 4

      N                                             6                6                      6                      6                            6

      PEEP (cm H2O)          11.7     ±      .5   12.0      ±    1.2       10.5     ±      1.4       9.6      ±    1.3       10.7     ±      .67

      PIP (cm H2O)                35.4     ±      2.4 34.3      ±    2.3*           32.8     ±      2.3*           34.5     ±      2.6       37.2     ±      2.0

      Paw (cm H2O)                21.3     ±      2.2 21.0      ±    3.0       19.1     ±      3.2       19.5     ±      3.2       20.8     ±      3.2


Nitric Oxide Group

      N                                             8                8                      6                      7                            5

      PEEP (cm H2O)                10.8     ±      .31 11.1      ±    .70       10.6     ±      .68       10.9     ±      .7         10.1     ±      .9

      PIP (cm H2O)                41.6     ±      1.7 45.4      ±    1.8       44.7     ±      2.7       41.3     ±      4.1       37.9     ±      3.6

      Paw (cm H2O)                21.8     ±      1.4 24.8      ±    2.4       24.6     ±      3.1       24.3     ±      3.0       20.3     ±      3.9


Values are mean + SEM. PEEP = positive end-expiratory pressure, PIP = peak inspiratory pressure, Paw = mean airway pressure.

*P < .05 compared with NO group on corresponding day.

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