Free
Clinical Science  |   October 1999
Unintended Inhalation of Nitric Oxide by Contamination of Compressed Air  : Physiologic Effects and Interference with Intended Nitric Oxide Inhalation in Acute Lung Injury
Author Affiliations & Notes
  • Albert Benzing, M.D.
    *
  • Torsten Loop, M.D.
  • Georg Mols, M.D.
  • Klaus Geiger, M.D.
  • *Staff Anesthesiologist. †Resident in Anesthesia. ‡Professor and Chairman, Department of Anesthesia.
Article Information
Clinical Science
Clinical Science   |   October 1999
Unintended Inhalation of Nitric Oxide by Contamination of Compressed Air  : Physiologic Effects and Interference with Intended Nitric Oxide Inhalation in Acute Lung Injury
Anesthesiology 10 1999, Vol.91, 945. doi:
Anesthesiology 10 1999, Vol.91, 945. doi:
INHALED nitric oxide (NO), a selective pulmonary vasodilator, 1,2 decreases pulmonary artery pressure (PAP) and increases arterial oxygen tension in patients with acute lung injury and acute respiratory distress syndrome. 3,4 Nitric oxide concentrations as low as 60 parts per billion (ppb) may increase arterial oxygen tension (PaO2) in persons with the acute respiratory distress syndrome. 5 
Compressed air in hospitals, drawn from the local environment, may contain variable amounts of NO as a result of air pollution. 6 Combined with pure oxygen, compressed air is used for mechanical ventilation in critically ill patients. However, the effects of such unintended inhalation of NO on pulmonary gas exchange and hemodynamics in persons with acute lung injury and acute respiratory distress syndrome have not been studied.
Therefore, we wanted to determine whether contamination of compressed air by NO affects hemodynamics and gas exchange in patients with acute lung injury and acute respiratory distress syndrome, and whether the unintended NO inhalation interferes with the therapeutic use of inhaled NO.
Patients and Methods 
During two periods of 4 and 2 weeks, respectively, concentrations of NO and nitric dioxide in the compressed air of the university hospital's central gas supply were monitored continuously by a chemiluminescent analyzer (AL 700 MED; Eco Physics, Dürnten, Switzerland) that accurately measures NO concentrations >10 ppb (data supplied by the manufacturer). Five liter per minute of compressed air were directed to the NO analyzer. Data were stored on a personal computer every 5 min.
Environmental NO concentrations were measured by chemiluminescence at a monitoring station 300 m away from the hospital. These data were obtained from the local environmental monitoring agency (UMEG GmbH, Karlsruhe, Germany).
After approval from the local ethics committee, the effect of unintentional NO inhalation on PaO2was evaluated in 15 patients with acute lung injury or acute respiratory distress syndrome. 7 The severity of lung injury was graded according to a lung injury score. 8 In nine of these patients with an indwelling pulmonary artery catheter, pulmonary hemodynamics and venous admixture were also determined. Table 1lists clinical characteristics. The lungs were ventilated with pressure control (Servo 900C; Siemens-Elema, Lund, Sweden or Evita 4, Dräger, Lübeck, Germany) at a fraction of inspired oxygen (FIO2) between 0.4 and 0.7. Patients were studied on workdays between 9 A.M. and 4 P.M.. During this period, NO concentrations in the compressed air had been highest.
Table 1. Clinical Characteristics of Patients and Pulmonary Gas Exchange 
Image not available
Table 1. Clinical Characteristics of Patients and Pulmonary Gas Exchange 
×
Inspiratory NO concentrations were measured by chemiluminescence. Pressure measurements were made at end-expiration with the patient supine using calibrated pressure transducers (Medex Novotrans II MX 860, Hilliard, OH), with zero set to ambient pressure at the midaxillary line. Pulmonary vascular resistance (PVR) and intrapulmonary venous admixture (QVA/QT) were calculated using standard formulas.
In the first 10 patients, the source of compressed air was changed from the central gas supply to a gas tank containing compressed air without NO (< 10 ppb) by disconnecting the tube for compressed air from the central gas supply and reconnecting it to the gas tank. This maneuver lasted <5 s. Ventilatory patterns remained unchanged. Measurements were made before, 15 min after change, and 15 min after return to baseline.
In addition, in the final five patients, the effects of 5 ppm inhaled NO were evaluated when the ventilator was connected to the central gas supply and to the gas tank. The source of compressed air and addition of NO were administered randomly. Nitric oxide was administered as described previously. 9 
Statistical Analysis 
Data are expressed as the mean ± SD. Data were compared by one-way analysis of variance for repeated measurements followed by the Student–Newman–Keuls test for multiple comparisons. A P  value < 0.05 was considered significant.
Results 
Nitric oxide and nitric dioxide concentrations in the compressed air of the hospital's central gas supply ranged from < 10 ppb for NO and nitric dioxide to 1,270 ppb NO and 670 ppb nitric dioxide and were highest on workdays between 9 A.M. and 4 P.M. (fig. 1). During this time, NO concentrations exceeded 80 ppb 40% of the time. These concentrations were comparable to the environmental NO concentrations (fig. 1).
Fig. 1. Mean hourly nitric oxide (NO) concentrations in the hospital's compressed air and in ambient air at each weekday. Environmental NO concentrations were measured at a monitoring station located 300 m away from the hospital. Although NO concentrations in the compressed air were less than the environmental NO concentrations, the time courses of the NO concentrations were comparable. 
Fig. 1. Mean hourly nitric oxide (NO) concentrations in the hospital's compressed air and in ambient air at each weekday. Environmental NO concentrations were measured at a monitoring station located 300 m away from the hospital. Although NO concentrations in the compressed air were less than the environmental NO concentrations, the time courses of the NO concentrations were comparable. 
Fig. 1. Mean hourly nitric oxide (NO) concentrations in the hospital's compressed air and in ambient air at each weekday. Environmental NO concentrations were measured at a monitoring station located 300 m away from the hospital. Although NO concentrations in the compressed air were less than the environmental NO concentrations, the time courses of the NO concentrations were comparable. 
×
Replacement of the hospital-supplied compressed air by tank-supplied NO-free compressed air decreased PaO2by 10 ± 5%(table 1), and increased PVR and QVA/QTby 13 ± 7% and 4 ± 3%, respectively (table 2).
Table 2. Effect of Contamination of Hospital's Compressed Air by Nitric Oxide on Gas Exchange and Hemodynamics in Nine Patients with ALI and ARDS 
Image not available
Table 2. Effect of Contamination of Hospital's Compressed Air by Nitric Oxide on Gas Exchange and Hemodynamics in Nine Patients with ALI and ARDS 
×
Adding 5 ppm inspiratory NO to hospital-supplied compressed air did not affect PaO2/FIO2, and PVR. In contrast, when added to gas-tank supplied NO-free compressed air, it increased PaO2/FIO2by 16 ± 11% and decreased PVR by 14 ± 8%(table 3).
Table 3. Interaction of Unintended and Intended Nitric Oxide Inhalation in Five Patients with ALI and ARDS 
Image not available
Table 3. Interaction of Unintended and Intended Nitric Oxide Inhalation in Five Patients with ALI and ARDS 
×
Discussion 
These results show that even in nonindustrial regions such as Freiburg, Germany, compressed air contains clinically effective NO concentrations. In patients with acute lung injury and acute respiratory distress syndrome, such unintended NO inhalation may increase PaO2and decrease PAP and PVR. The unintended NO inhalation makes the therapeutic use of inhaled NO less effective.
Nitric oxide is an air pollutant that originates from various sources. During combustion at high temperatures, such as in car engines, nitrogen is oxidized to NO. Nitric oxide is an unstable radical that is oxidized to nitric dioxide in the presence of oxygen. 10 The estimated half-life of 100 ppb NO in air is 506 h, and the estimated half-life of 500 ppb NO in air is 101 h. It is, therefore, stable enough to reach the lungs of mechanically ventilated patients via  hospital-supplied compressed air.
Nitric oxide concentrations were highest on workdays, which is probably related to car traffic. Although NO concentrations in the hospital's compressed air were less than environmental NO concentrations at a monitoring station 300 m away from the hospital, the time courses of the NO concentrations were comparable.
Several European cities have reported environmental NO concentrations as high as 991 ppb (Copenhagen, Denmark), 11 1,045 ppb (Düsseldorf, Germany), 12 600 ppb (Berlin, Germany), 13 and 498 ppb (Innsbruck, Austria). 14 Nitric oxide concentrations correlated with car traffic and working days and correlated inversely with wind intensity. 14 
In our study, NO concentrations in compressed air exceeded 80 ppb on weekdays between 9 A.M. and 4 P.M. nearly half of the time. At an FIO2of 0.4, 80 ppb NO in compressed air results in an inspired NO concentration of 60 ppb. Nitric oxide may improve oxygenation and decrease PVR at concentrations as low as 50 to 150 ppb. 5,15–17 In one of our patients, withdrawal of just 63 ppb NO decreased PaO2. In a study of the effects of unintended NO inhalation in 11 patients after cardiac surgery and in one patient after renal transplantation, the PaO2decreased by 10.5 ± 7.8% when the compressed air was substituted for by a mixture of pure nitrogen and oxygen with a similar FIO2. 18 However, maintaining an identical FIO2in this way may be difficult. Changing the source of compressed air of the ventilator as we did reliably prevents any change in FIO2.
In our patients, withdrawal of the unintended NO inhalation increased PAP and PVR, in contrast to a previous study that showed no effect on PAP. 18 However, baseline PAP was less than in our patients (25 ± 8 mmHg vs.  34 ± 5 mmHg). The NO-induced decreases in PAP and PVR are more pronounced when baseline PAP and PVR are high. 4,17,19,20 
Contamination of compressed air in a hospital's central gas supply in industrial regions is more pronounced than in our hospital. Nitric oxide concentrations up to 6.5 ppm NO have been measured in compressed air of other hospitals. 6 In industrial regions, critically ill patients possibly inhale NO during longer periods and at higher concentrations than in our hospital.
We found minimal effects of intentional inhalation of 5 ppm NO on oxygenation and pulmonary hemodynamics when added to hospital-supplied compressed air, but significant effects when added to tank-supplied NO-free compressed air. This is consistent with previous reports showing that patients responding positively to low inhaled concentrations of NO (i.e.  , 50–250 ppb) show little further improvement with higher concentrations. 5,15 Similarly, the response to NO is more favorable during severe than during less severe hypoxemia. 21 Because severe hypoxemia requires a high FIO2, inspired gas contains little or no compressed air and, therefore, little or no NO. In this situation, the response to an intentional NO inhalation may be favorable because there was no preceding unintended inhalation of NO. Because measurement of low NO concentrations requires chemiluminescence and is not possible by electrochemical cells, unintended NO inhalation may not be detected readily in studies using electrochemical cells to measure NO.
Different responses to inhaled NO at different days, 21,22 and seemingly contradictory findings regarding the incidence of rebound phenomena after the sudden withdrawal of therapeutic NO inhalation, 23–26 may be related in part to varying NO concentrations in the compressed air.
Our findings may have implications for prospective randomized studies on the effects of inhaled NO in patients with acute lung injury and acute respiratory distress syndrome. In such studies, care must be taken that patients in the control group are not exposed to inhaled NO by contamination of the hospital's compressed air.
The authors thank H.-J. Priebe, M.D., for critically reviewing the manuscript and the local environmental monitoring agency (UMEG GmbH, Karlsruhe, Germany) for providing data regarding ambient nitric oxide concentrations.
References 
References 
Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Wallwork J: Inhaled nitric oxide as a cause of selective pulmonary vasodilation in pulmonary hypertension. Lancet 1991; 338: 1173–4
Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM: Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991; 83: 2038–47
Rossaint R, Falke KJ, López F, Slama K, Pison U, Zapol WM: Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 1993; 328: 399–405
Bigatello LM, Hurford WE, Kacmarek RM, Roberts JD, Zapol WM: Prolonged inhalation of low concentrations of nitric oxide in patients with severe adult respiratory distress syndrome. A NESTHESIOLOGY 1994; 80: 761–70
Gerlach H, Pappert D, Lewandowski K, Rossaint R, Falke KJ: Long-term inhalation with evaluated low doses of nitric oxide for selective improvement of oxygenation in patients with adult respiratory distress syndrome. Intensive Care Med 1993; 19: 443–9
Pinsky MR, Genc F, Lee KH, Delgado E: Contamination of hospital compressed air with nitric oxide. Chest 1997; 111: 1759–63
Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, LeGall JR, Morris A, Spragg R: The American and European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149: 818–24
Murray JF, Matthay MA, Luce JM, Flick MR: An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 1988; 138: 720–3
Benzing A, Bräutigam P, Geiger K, Loop T, Beyer U, Moser E: Inhaled nitric oxide reduces transvascular albumin flux in patients with acute lung injury. A NESTHESIOLOGY 1995; 83: 1153–61
Glasson WA, Tuesday CS: The atmospheric thermal oxidation of nitric oxide. J Am Chem Soc 1963; 85: 2901–4
Raaschou-Nielsen O, Nielsen ML, Gehl J: Traffic-related air-pollution: Exposure and health effects in Copenhagen street cleaners and cemetery workers. Arch Environ Health 1995; 50: 207–13
Pfeffer HU: Ambient air concentrations of pollutants at traffic-related sites in urban aereas of North Rhine-Westphalia, Germany. Sci Total Environ 1994; 146: 263–73
Friebe A, Malkewitz J, Schultz G, Koesling D: Positive effects of pollution? Nature 1996; 382: 120
Wagner E: Impacts on air pollution in urban areas. Environmental Management 1994; 18: 759–65
Lu Q, Mourgeon E, Law-Koune JD, Roche S, Vézinet C, Abdennour L, Vicaut E, Puybasset E, Diaby M, Corriat P, Rouby JJ: Dose-response curves of inhaled nitric oxide with and without almitrine in nitric oxide responding patients with acute respiratory distress syndrome. A NESTHESIOLOGY 1995; 83: 929–43
Puybasset L, Rouby JJ, Mourgeon E, Stewart TE, Cluzel P, Arthaud M, Poete P, Bodin L, Korinek AM, Viars P: Inhaled nitric oxide in acute respiratory failure: Dose-response curves. Intensive Care Med 1994; 20: 319–27
Lowson SM, Rich GF, McArdle P, Jaidev J, Morris GN: The response to varying concentrations of inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesth Analg 1996; 82: 574–81
Lee KH, Tan PSK, Rico P, Delgado E, Kellum JA, Pinsky MR: Low levels of nitric oxide as contaminant in hospital compressed air: Physiologic significance? Crit Care Med 1997; 25: 1143–6
Puybasset L, Rouby JJ, Murgeon E, Clouzel P, Souhilt Z, Law-Koune JD, Stewart T, Devilliers C, Lu Q, Roche S, Kalfon P, Vincent E, Viars P: Factors influencing cardiopulmonary effects of inhaled nitric oxide in acute respiratory failure. Am J Respir Crit Care Med 1995; 152: 318–28
Rich GF, Murphy GD, Roos CM, Johns RA: Inhaled nitric oxide. Selective pulmonary vasodilation in cardiac surgical patients. A NESTHESIOLOGY 1993; 78: 1028–35
Treggiari-Venzi M, Ricou B, Romand JA, Suter P: The response to repeated nitric oxide inhalation is inconsistent in patients with acute respiratory distress syndrome. A NESTHESIOLOGY 1998; 88: 634–41
Lundin S, Nathorst Westfelt U, Stenqvist O, Blomqvist H, Lindh A, Berggren L, Arvidsson S, Rudberg U, Frostell CG: Response to nitric oxide inhalation in early acute lung injury. Intensive Care Med 1996; 22: 728–34
Chiche JD, Canivet JL, Damas P, Joris J, Lamy M: Inhaled nitric oxide for hemodynamic support after postpneumonectomy ARDS. Intensive Care Med 1995; 21: 675–8
Lavoie A, Hall JB, Olson DM, Wylan ME: Life-threatening effects of discontinuing inhaled nitric oxide in severe respiratory failure. Am J Respir Crit Care Med 1996; 153: 1985–7
Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner G, Davis K, Hyers TM, Papadakos P: Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: Results of a randomized phase II trial. Crit Care Med 1998; 26: 15–23
Troncy E, Collet JP, Shapiro S, Guimond JG, Blair L, Ducruet T, Francoeur M, Charbonneau M, Blaise G: Inhaled nitric oxide in acute respiratory distress syndrome. A pilot randomized controlled study. Am J Respir Crit Care Med 1998; 157: 1483–8
Fig. 1. Mean hourly nitric oxide (NO) concentrations in the hospital's compressed air and in ambient air at each weekday. Environmental NO concentrations were measured at a monitoring station located 300 m away from the hospital. Although NO concentrations in the compressed air were less than the environmental NO concentrations, the time courses of the NO concentrations were comparable. 
Fig. 1. Mean hourly nitric oxide (NO) concentrations in the hospital's compressed air and in ambient air at each weekday. Environmental NO concentrations were measured at a monitoring station located 300 m away from the hospital. Although NO concentrations in the compressed air were less than the environmental NO concentrations, the time courses of the NO concentrations were comparable. 
Fig. 1. Mean hourly nitric oxide (NO) concentrations in the hospital's compressed air and in ambient air at each weekday. Environmental NO concentrations were measured at a monitoring station located 300 m away from the hospital. Although NO concentrations in the compressed air were less than the environmental NO concentrations, the time courses of the NO concentrations were comparable. 
×
Table 1. Clinical Characteristics of Patients and Pulmonary Gas Exchange 
Image not available
Table 1. Clinical Characteristics of Patients and Pulmonary Gas Exchange 
×
Table 2. Effect of Contamination of Hospital's Compressed Air by Nitric Oxide on Gas Exchange and Hemodynamics in Nine Patients with ALI and ARDS 
Image not available
Table 2. Effect of Contamination of Hospital's Compressed Air by Nitric Oxide on Gas Exchange and Hemodynamics in Nine Patients with ALI and ARDS 
×
Table 3. Interaction of Unintended and Intended Nitric Oxide Inhalation in Five Patients with ALI and ARDS 
Image not available
Table 3. Interaction of Unintended and Intended Nitric Oxide Inhalation in Five Patients with ALI and ARDS 
×