Posts Tagged ‘Children’s Hospital Colorado’

Curator: Aviva Lev-Ari, PhD, RN

iNO – Clinical Trials and Meta Analysis Studies: Recent Findings

Clinical perspectives with long-term pulsed inhaled nitric oxide for the treatment of pulmonary arterial hypertension

1Department of Pediatrics and Medicine, Columbia University, New York, New York, US
2Department of Pediatrics and Medicine, Massachusetts General Hospital, Boston, Massachusetts, US
3Department of Pediatrics, University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora, Colorado, US
4Ikaria, Inc., Hampton, New Jersey, USA
Address correspondence to: Dr. Robyn J. Barst, 31 Murray Hill Road, Scarsdale, NY 10583, USA ; Email:
This article has been corrected. See Pulm Circ. 2012; 2(3): iv.


Pulmonary arterial hypertension (PAH) is a chronic, progressive disease of the pulmonary vasculature with a high morbidity and mortality. Its pathobiology involves at least three interacting pathways –
  • prostacyclin (PGI2),
  • endothelin, and
  • nitric oxide (NO).
Current treatments target these three pathways utilizing PGI2 and its analogs, endothelin receptor antagonists, and phosphodiesterase type-5 (PDE-5) inhibitors.
Inhaled nitric oxide (iNO) is approved for the treatment of hypoxic respiratory failure associated with pulmonary hypertension in term/near-term neonates. As a selective pulmonary vasodilator, iNO can acutely decrease pulmonary artery pressure and pulmonary vascular resistance without affecting cardiac index or systemic vascular resistance. In addition to delivery via the endotracheal tube, iNO can also be administered as continuous inhalation via a facemask or a pulsed nasal delivery. Consistent with a deficiency in endogenously produced NO, long-term pulsed iNO dosing appears to favorably affect hemodynamics in PAH patients, observations that appear to correlate with benefit in uncontrolled settings. Clinical studies and case reports involving patients receiving long-term continuous pulsed iNO have shown minimal risk in terms of adverse events, changes in methemoglobin levels, and detectable exhaled or ambient NO or NO2. Advances in gas delivery technology and strategies to optimize iNO dosing may enable broad-scale application to long-term treatment of chronic diseases such as PAH.
Keywords: drug, hypertension, inhalation administration, nitric oxide, pulmonary arterial hypertension, pulmonary circulation, pulmonary hypertension, pulmonary/physiopathology, pulse therapy, vasodilator agents


In summary, uncontrolled observational studies of long-term use (>1 month) of continuous pulsed iNO (as monotherapy or as part of combination therapy) in a total of 14 patients with PAH across five studies [Ref 46-48, 54,55]

have reported no significant adverse events, no elevated metHb levels, and no detectable exhaled or ambient NO or NO2. In one study, a patient experienced three episodes of severe epistaxis over two years while on a combination of pulsed iNO and epoprostenol.[46]

In a case report of a patient awaiting heart-lung transplantation, the patient experienced hypotensive bradycardia upon an attempt to wean from iNO therapy. In addition, a recurrence in hypotensive bradycardia resulted in the increase of iNO dose (40–106 ppm), followed by a decrease to 70 ppm (along with administration of bicarbonate and reintroduction of prostacyclin) after increasing metabolic acidosis.[55]

There is evidence that pulsed delivery may allow utilization of lower NO concentrations compared with continuous face mask administration, potentially minimizing the risk of associated adverse events as well as resulting in a more practical delivery system.[49]

The consensus on treatment for PAH encompasses numerous goals, the most important being to improve overall quality of life by decreasing symptoms while minimizing treatment-related side effects.[2]

Additional goals include enhancing functional capacity, i.e., exercise capacity, improving hemodynamic derangements (lowering PVR and PAP, and normalizing RAP and CO), and preventing, if not reversing, disease progression. Finally, improving survival, although certainly desirable, is rarely an end point in trials examining PAH treatment.[2]

The availability of novel treatments and the improvement in survival rates have allowed the goals of PAH therapy to expand from improving survival and preventing disease progression to also improving HRQOL.[71]

Potential advances in long-term PAH treatment, such as ambulatory iNO administration, may allow for greater improvements in HRQOL. Pérez–Peñate et al. observed that ambulatory pulsed iNO treatment did not diminish quality of life beyond the consequences of the disease itself.[47]

Eight of eleven patients who led a nonsedentary life were able to leave their home daily, with four returning to work while on long-term iNO therapy.

An ideal drug-device for long-term PAH treatment should emphasize portability and safety features for outpatient use. Advances in iNO gas delivery technology and strategies to optimize dosing should allow for randomized controlled trials of iNO and, hopefully, may lead to broad-scale application of iNO in the treatment of chronic diseases such as PAH.[45]


Anesth Analg. 2011 Jun;112(6):1411-21. doi: 10.1213/ANE.0b013e31820bd185.
Epub 2011 Mar 3.

Inhaled nitric oxide for acute respiratory distress syndrome and acute lung injury in adults and children: a systematic review with meta-analysis and trial sequential analysis.

Afshari ABrok JMøller AMWetterslev J.


Department of Anesthesiology, Rigshospitalet, University of Copenhagen, Anestheisa, Juliane Marie Centre, Copenhagen, 2100, Denmark.



Acute hypoxemic respiratory failure, defined as acute lung injury and acute respiratory distress syndrome, are critical conditions associated with frequent mortality and morbidity in all ages. Inhaled nitric oxide (iNO) has been used to improve oxygenation, but its role remains controversial. We performed a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials (RCTs). We searched CENTRAL, Medline, Embase, International Web of Science, LILACS, the Chinese Biomedical Literature Database, and CINHAL (up to January 31, 2010). Additionally, we hand-searched reference lists, contacted authors and experts, and searched registers of ongoing trials. Two reviewers independently selected all parallel group RCTs comparing iNO with placebo or no intervention and extracted data related to study methods, interventions, outcomes, bias risk, and adverse events. All trials, irrespective of blinding or language status were included. Retrieved trials were evaluated with Cochrane methodology. Disagreements were resolved by discussion. Our primary outcome measure was all-cause mortality. We performed subgroup and sensitivity analyses to assess the effect of iNO in adults and children and on various clinical and physiological outcomes. We assessed the risk of bias through assessment of trial methodological components. We assessed the risk of random error by applying trial sequential analysis.


We included 14 RCTs with a total of 1303 participants; 10 of these trials had a high risk of bias. iNO showed no statistically significant effect on overall mortality (40.2%versus 38.6%) (relative risks [RR] 1.06, 95% confidence interval [CI] 0.93 to 1.22; I² = 0) and in several subgroup and sensitivity analyses, indicating robust results. Limited data demonstrated a statistically insignificant effect of iNO on duration of ventilation, ventilator-free days, and length of stay in the intensive care unit and hospital. We found a statistically significant but transient improvement in oxygenation in the first 24 hours, expressed as the ratio of Po₂ to fraction of inspired oxygen (mean difference [MD] 15.91, 95% CI 8.25 to 23.56; I² = 25%). However, iNO appears to increase the risk of renal impairment among adults (RR 1.59, 95% CI 1.17 to 2.16; I² = 0) but not the risk of bleeding or methemoglobin or nitrogen dioxide formation.


iNO cannot be recommended for patients with acute hypoxemic respiratory failure. iNO results in a transient improvement in oxygenation but does not reduce mortality and may be harmful.


Clinical Policy Bulletin:

Nitric Oxide, Inhalational (INO) Number: 0518

Aetna Policy

      Aetna considers inhaled nitric oxide (INO) therapy medically necessary as a component of the treatment of hypoxic respiratory

      failure in term and near-term (born at 34 or more weeks of gestation) neonates when both of the following criteria are met:

  •                         Neonates do not have congenital diaphragmatic hernia; and
  •                         When conventional therapies such as administration of high concentrations of oxygen, hyperventilation, high-frequency
  •                         ventilation, the induction of alkalosis, neuromuscular blockade, and sedation have failed or are expected to fail.

      Note: Use of INO therapy for more than 4 days is subject to medical necessity review.

      Aetna considers the diagnostic use of INO medically necessary as a method of assessing pulmonary vaso-reactivity in persons

      with pulmonary hypertension.

      Aetna considers INO therapy experimental and investigational for all other indications because of insufficient evidence in the

      peer-reviewed literature, including any of the following:

                        Acute bronchiolitis; or

                        Acute hypoxemic respiratory failure in children (other than those who meet the medical necessity criteria above) and in adults; or

Adult respiratory distress syndrome or acute lung injury; or

Post-operative management of pulmonary hypertension in infants and children with congenital heart disease; or

Premature neonates (less than 34 weeks of gestation); or

Prevention of ischemia-reperfusion injury/acute rejection following lung transplantation; or

Treatment of persons with congenital diaphragmatic hernia; or

Treatment of vaso-occlusive crises or acute chest syndrome in persons with sickle cell disease (sickle cell vasculopathy).



NO is naturally produced in the body by the enzyme NO synthase, which converts L-arginine to L-citrulline and NO in the presence of oxygen and certain cofactors. Both constitutive and inducible forms of NO synthase are present in endothelium and various other tissues.39–,41 NO has several important physiological roles, including involvement in smooth muscle relaxation, neurotransmission, host defense responses, and platelet function. NO produced by the vascular endothelium causes local vasodilatation, thereby regulating vasomotor tone. Circulating NO is present in only picomolar amounts and is rapidly inactivated by reaction with hemoglobin. Because of this short circulating half-life (3–5 seconds), inhalation of subtoxic levels of NO causes vasodilatation of the pulmonary vasculature with little or no systemic vasodilatation. Therapeutic administration of NO by inhalation thus provides a means of selectively lowering pulmonary arterial blood pressure, potentially improving hemodynamic status and gas exchange.11–13,15,17,18,23

Inhaled NO has been widely studied in adults with pulmonary hypertension and acute lung injury, and it is currently approved by the Food and Drug Administration for treatment of hypoxic respiratory failure in neonates with pulmonary hypertension. Three potential hazards associated with inhaled NO therapy are recognized:

(1) direct pulmonary toxic effects of NO,

(2) pulmonary toxic effects due to NO2 produced by oxidation of NO, and

(3) development of methemoglobinemia.

Studies of exposure to toxic levels of NO and NO2 in various species indicated that high concentrations of these gases can be lethal. Pulmonary edema, hypoxemia, acidosis, and hypotension developed in dogs exposed to 0.5% to 2% NO or NO2, and most animals died within 7 to 50 minutes of exposure.42 In rats, inhaled NO2 concentrations of 127 ppm were lethal within 30 minutes in 50% of animals (LC50).43 The LC50 in primates exposed to NO2 for 30 to 60 minutes is 100 to 200 ppm.43 Methemoglobinemia is detectable by measurement of blood levels of methemoglobin and is manifested clinically as cyanosis and hypoxia. Methemoglobinemia developed in animals exposed to high concentrations of NO or NO2, although not uniformly. In one instance, a methemoglobin level of 1.00 developed in a dog exposed to 2% NO for 50 minutes.42

In humans, NO at 10 to 20 ppm can cause irritation of the eyes and nose, 25 ppm can be irritating to the respiratory tract and cause chest pain, 50 ppm can cause pulmonary edema, and 100 ppm can be fatal.1,4

Legally permissible exposure limits for NO and NO2 have been issued by the Occupational Safety and Health Administration. For NO, this threshold is 25 ppm (30 mg/m3), averaged over an 8-hour work shift.10 This value corresponds to the threshold limit value promulgated by the American Conference of Governmental Industrial Hygienists.2 Adherence to this limit is thought to provide adequate protection against methemoglobinemia and other toxic effects. Concentrations of 100 ppm and higher (30-minute mean) are deemed to be an immediate threat to life and health by the National Institute for Occupational Safety and Health.44 The Occupational Safety and Health Administration ceiling limit for NO2 is 1 ppm (1.8 mg/m3), and this limit is not to be exceeded at any time during the work shift.10 The threshold limit for TWA concentration of NO2 issued by the American Conference of Governmental Industrial Hygienists is 3 ppm,2 and the National Institute for Occupational Safety and Health requires that NO2exposures not exceed 1 ppm.10,44

These threshold values are thought to represent maximum concentrations to which nearly all workers can be exposed on a regular basis without adverse effects. Nevertheless, evidence suggests that lower levels of exposure can have deleterious effects. For example, irreversible emphysematous changes to the lungs occurred in beagles exposed to 0.6 ppm NO2 for 16 h/d for 68 months and then to clean air for 32 to 36 months.45 In a study of exposure of humans to NO at 1.0 ppm, small but significant increases in airway resistance occurred in half the subjects.46 Similarly, inhalation of NO2 at 0.7 to 2 ppm for 10 minutes increased airflow resistance in healthy subjects.1 Exposure to NO2 at 2.3 ppm for 5 hours reportedly altered alveolar permeability in humans.47 Brief exposure to NO2 levels as low as 0.4 ppm may augment the response to challenge with specific allergens, and exposure to 0.1 to 0.5 ppm may affect pulmonary function in patients with asthma or chronic obstructive lung disease.1,5,7,48,49

Limited information is available on occupational exposure to NO in the healthcare setting. Using stationary chemiluminescence monitoring, Mourgeon et al50 determined ambient concentrations of NO and NO2 in the main corridor of an ICU. They found that mean ambient NO concentrations within the ICU were 0.237 ppm (SD 0.147 ppm) during the therapeutic use of inhaled NO at 5 ppm or less in 1 or more patients and 0.289 ppm (SD 0.147 ppm) during times when inhaled NO therapy was not used. The institution where this study50 was performed is located on a main street in Paris, and Mourgeon et al concluded that the ICU corridor values were entirely dependent on prevailing outdoor concentrations. Markhorst et al51 examined ambient levels of NO and NO2 in well-ventilated and poorly ventilated pediatric ICU rooms in which administration of inhaled NO at 20 ppm was simulated. As in the study by Mourgeon et al, sampling was done from a stationary position (in the study by Markhorst et al, 65 cm from the high-frequency oscillator used) at a height of 150 cm. During the simulation, maximum NO and NO2levels were 0.462 and 0.064 ppm, respectively. Phillips et al52 used occupational hygiene techniques similar to those we used to examine exposure levels in medical personnel during administration of inhaled NO to 6 patients in a pediatric ICU. In all instances, TWA concentrations were less than the limits of detection for the assay used. The patients’ sizes and minute volumes were not specified, although 3 of the patients were classified as neonatal.

▪ Nitric oxide therapy does not appear to expose nurses to excessive levels of nitric oxide or nitrogen dioxide during routine patient care in the ICU.

We examined the occupational exposure of ICU nurses to NO during NO therapy at delivery levels of 5 and 20 ppm in adult patients with acute respiratory distress syndrome. The maximum TWA exposures in our study were 0.45 ppm for NO and 0.28 ppm for NO2, well below the legally permissible exposure limits mandated by the Occupational Safety and Health Administration, and the involved nurses reported no respiratory or other signs or symptoms. The maximum outdoor background concentrations of NO and NO2 in our county during the periods of study ranged from 0.006 to 0.030 ppm for NO and 0.018 to 0.090 ppm for NO2. For comparison, the primary national ambient air quality standard issued by the Environmental Protection Agency is 0.053 ppm (100 μg/m3), calculated as an annual arithmetic mean.53 We did not assess methemoglobin levels in the nurses; however, methemoglobinemia did not develop in the treated patients. Marked methemoglobinemia is uncommon in patients treated with inhaled NO at concentrations similar to those used in our study.11,12,15,16,18,23

In the simulation study of Markhorst et al,51 ambient NO concentrations were measured at distances of 15 to 200 cm from a high-frequency oscillator, yielding levels ranging from 1.2 to 0.4 ppm. Our measurements yielded similar results (see Figure); however, in our study, NO levels at the ventilator exhaust port were nearly 10 times higher (9.2 ppm) than those 15 cm away (1.0 ppm). NO concentrations decreased rapidly; the mean was about 0.030 ppm in the area between 0.6 m from the ventilator and 0.6 m outside the patient’s room. For comparison, in homes with gas cooking stoves, ambient NOx levels of 0.025 to 0.075 ppm are typical.9

A number of factors determine the concentrations of NO and NO2 to which personnel are exposed during the therapeutic use of inhaled NO. These include the concentration of NO delivered to the patient, the patient’s minute volume, room size, room ventilation, and whether special ventilator exhaust routing or chemical scavenging devices are used. Baseline ambient levels of NO and NO2 depend on outdoor environmental factors such as proximity to motor vehicle traffic or heavy industry, climate, wind, and sky clarity.50Depending on the mode of administration, the actual concentration of NO delivered to a patient can fluctuate from the intended level. Continuous delivery during the entire respiratory cycle can produce more atmospheric contamination than does sequential administration limited to the inspiratory phase.54 The amount of NO2 formed during NO therapy varies according to the concentrations of oxygen and NO delivered, the time the 2 gases remain in contact, total gas flow, and minute volume.55 Thus, higher fractions of inspired oxygen will lead to increased formation of NO2 during inhaled NO therapy.

Because of differences in minute volume, therapeutic administration of inhaled NO to adult patients will result in substantially greater release of NO than will administration to infants or children. For example, to achieve a delivered NO concentration of 20 ppm, the required flow from a 1000-ppm NO source varies from 20 mL/min for a minute volume of 1 L/min to more than 200 mL/min for a minute volume of 11 L/min19 (our patients’ minute volumes exceeded 11 L/min). Simultaneous treatment of multiple patients in the same room or unit might increase exposure levels. The time spent by healthcare providers in the patient’s room and their average exposure distance from the ventilator exhaust port are also important factors. Room ventilation is clearly a factor. Ventilation in our negative-pressure isolation rooms exceeded that mandated by the Centers for Disease Control and Prevention (ie, ≥6 air changes per hour for existing rooms and ≥12 air changes per hour where possible and in new hospital construction).56 Our study design did not allow analysis of the effects of any of these factors; however, the methods we used provide data for real-world examples of ICU nurses caring for typical adult patients receiving inhaled NO. These techniques also constitute the standard method for evaluations of occupational exposure to toxic gases. Studies in which these methods are used, but involving larger samples of nurses and patients in various settings, would allow better definition of variance and the effects that factors such as room ventilation have on exposure to ambient NO and NO2.

In summary, we found that inhaled NO therapy at doses up to 20 ppm does not appear to pose a risk of excessive occupational exposure to NO or NO2 to healthcare workers during the routine delivery of critical care nursing in typical adult ICU settings. These findings lend support to the occupational safety of this therapeutic modality.


  1. Beard RR. Inorganic compounds of oxygen, nitrogen, and carbon. In: Clayton GD, Clayton FE, eds. Patty’s Industrial Hygiene and Toxicology. 3rd ed. Vol. 2C. New York, NY: John Wiley & Sons; 1982:4053–4139.
  2. Documentation of the Threshold Limit Values for Chemical Substances in the Workroom Environment. 4th ed. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists Inc; 1980.
  3. Budavari S, O’Neil MJ, Smith A, Heckelman PE, Kinneary JF, eds. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. 12th ed. Whitehouse Station, NJ: Merck; 1996:1131.
  4. Sittig M. Handbook of Toxic and Hazardous Chemicals and Carcinogens. 3rd ed. Park Ridge, NJ: Noyes Publications; 1991:1201–1203, 1217–1219.
  5. Lipsett M. Oxides of nitrogen and sulfur. In: Sullivan JB Jr, Krieger GR, eds.Hazardous Materials Toxicology: Clinical Principles of Environmental Health.Baltimore, Md: Williams & Wilkins; 1992:964–972.
  6. Clayton GD. Air pollution. In: Clayton GD, Clayton FE, eds. Patty’s Industrial Hygiene and Toxicology. 4th ed. New York, NY: John Wiley & Sons; 1991:195–258.
  7. Lipsett MJ, Shusterman DJ, Beard RR. Inorganic compounds of carbon, nitrogen, and oxygen. In: Clayton GD, Clayton FE, eds. Patty’s Industrial Hygiene and Toxicology. New York, NY: John Wiley & Sons; 1994: 4523–4643.
  8. Modrak JE, Frampton MW, Utell MJ. Community air pollution: what a pulmonologist should know. Clin Pulm Med. 1997;4:266–272.
  9. Samet JM, Marbury MC, Spengler JD. Health effects and sources of indoor air pollution: part I. Am Rev Respir Dis. 1987;136:1486–1508.
  10. Occupational Safety and Health Administration, US Department of Labor. OSHA Regulated Hazardous Substances: Health, Toxicity, Economic and Technological Data. Vol. 2. Park Ridge, NJ: Noyes Data Corp; 1990:1419–1421, 1437–1440.
  11. Krafft P, Metnitz PGH, Fridrich P, Krenn CG, Hammerle AF, Steltzer H. Impact of inhaled nitric oxide on cardiopulmonary performance and outcome of ARDS patients: a literature review. Clin Intensive Care. 1997;8:27–32.
  12. Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med. 1998;26:15–23.
  13. Michael JR, Barton RG, Saffle JR, et al. Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS. Am J Respir Crit Care Med.1998;157:1372–1380.
  14. The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med.1997;336:597–604.
  15. Okamoto K, Hamaguchi M, Kukita I, Kikuta K, Sato T. Efficacy of inhaled nitric oxide in children with ARDS. Chest. 1998;114:827–833.
  16. Johannigman JA, Davis K Jr, Campbell RS, Luchette F, Hurst JM, Branson RD. Inhaled nitric oxide in acute respiratory distress syndrome. J Trauma. 1997;43:904–909.
  17. Johannigman JA, Davis K Jr, Miller SL, et al. Prone positioning and inhaled nitric oxide: synergistic therapies for acute respiratory distress syndrome. J Trauma. 2001;50:589–595.
  18. Gerlach H, Rossaint R, Pappert D, Falke KJ. Time-course and dose-response of nitric oxide inhalation for systemic oxygenation and pulmonary hypertension in patients with adult respiratory distress syndrome. Eur J Clin Invest. 1993;23:499–502.
  19. Young JD, Dyar OJ. Delivery and monitoring of inhaled nitric oxide. Intensive Care Med. 1996;22:77–86.
  20. Cuthbertson BH, Galley HF, Webster NR. Effect of inhaled nitric oxide on key mediators of the inflammatory response in patients with acute lung injury. Crit Care Med. 2000;28:1736–1741.
  21. Hoehn T, Krause MF. Response to inhaled nitric oxide in premature and term neonates. Drugs. 2001;61:27–39.
  22. Tworetzky W, Bristow J, Moore P, et al. Inhaled nitric oxide in neonates with persistent pulmonary hypertension [letter]. Lancet. 2001;357:118–120.
  23. Journois D, Pouard P, Mauriat P, Malhère T, Vouhé P, Safran D. Inhaled nitric oxide as a therapy for pulmonary hypertension after operation for congenital heart defects. J Thorac Cardiovasc Surg. 1994;107:1129–1135.
  24. Gothberg S, Edberg KE. Inhaled nitric oxide to newborns and infants after congenital heart surgery on cardiopulmonary bypass: a dose-response study.Scand Cardiovasc J. 2000;34:154–158.
  25. Solina AR, Ginsberg SH, Papp D, et al. Dose response to nitric oxide in adult cardiac surgery patients. J Clin Anesth. 2001;13:281–286.
  26. Ardehali A, Hughes K, Sadeghi A, et al. Inhaled nitric oxide for pulmonary hypertension after heart transplantation. Transplantation. 2001;72:638–641.
  27. Ardehali A, Laks H, Levine M, et al. A prospective trial of inhaled nitric oxide in clinical lung transplantation. Transplantation. 2001;72:112–115.
  28. Crerar-Gilbert A, Boots R. Use of inhaled nitric oxide in pulmonary embolism.Anaesth Intensive Care. 1999;27:412–414.
  29. Gladwin MT, Schechter AN, Shelhamer JH, et al. Inhaled nitric oxide augments nitric oxide transport on sickle cell hemoglobin without affecting oxygen affinity. J Clin Invest. 1999;104:937–945.
  30. Rabkin DG, Sladen RN, DeMango A, Steinglass KM, Goldstein DJ. Nitric oxide for the treatment of postpneumonectomy pulmonary edema. Ann Thorac Surg.2001;72:272–274.
  31. Nakagawa TA, Johnston SJ, Falkos SA, Gomez RJ, Morris A. Life-threatening status asthmaticus treated with inhaled nitric oxide. J Pediatr. 2000;137: 119–122.
  32. Perez-Penate G, Julia-Serda G, Pulido-Duque JM, Gorriz-Gomez E, Cabrera-Navarro P. One-year continuous inhaled nitric oxide for primary pulmonary hypertension. Chest. 2001;119:970–973.
  33. Jones C. Inhaled nitric oxide: are the safety issues being addressed? Intensive Crit Care Nurs. 1998;14:271–275.
  34. Goldman AP, Cook PD, Macrae DJ. Exposure of intensive-care staff to nitric oxide and nitrogen dioxide [letter]. Lancet. 1995;345:923–924.
  35. Kalweit S. Inhaled nitric oxide in the ICU. Crit Care Nurse. August 1997;17: 26–32.
  36. Bathe D, Berssenbrugge A, Kohlmann T, Montgomery F. Monitoring accuracy for the measurement of nitric oxide in the 0 to 80 ppm range [abstract]. Crit Care Med. 1996;24:A103.
  37. Guidelines for Protecting the Safety and Health of Health Care Workers.Washington, DC: US Dept of Health and Human Services, National Institute for Occupational Safety and Health, Division of Standards Development and Technology Transfer; 1988:2–9. DHHS (NIOSH) publication 88–119.
  38. Nitrogen dioxide and nitric oxide. In: Eller PM, Cassinelli ME, eds. NIOSH Manual of Analytical Methods. 4th ed. Washington, DC: US Dept of Health and Human Services, National Institute for Occupational Safety and Health, Division of Physical Sciences and Engineering; 1994:(6014)1–4. DHHS (NIOSH) publication 94–113.
  39. Stuehr DJ, Griffith OW. Mammalian nitric oxide synthases. Adv Enzymol Relat Areas Mol Biol. 1992;65:287–346.
  40. Kobzik L, Bredt DS, Lowenstein CJ, et al. Nitric oxide synthase in human and rat lung: immunocytochemical and histochemical localization. Am J Respir Cell Mol Biol. 1993;9:371–377.
  41. Gaston B, Drazen M, Loscalzo J, Stamler JS. The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med. 1994;149:538–551.
  42. Greenbaum R, Bay J, Hargreaves MD, et al. Effects of higher oxides of nitrogen on the anaesthetized dog. Br J Anaesth. 1967;39:393–404.
  43. Harris LR, Sarvadi DG. Synthetic polymers. In: Clayton GD, Clayton FE, eds.Patty’s Industrial Hygiene and Toxicology. 4th ed. Vol. 2, part E. New York, NY: John Wiley & Sons; 1991:3673–4005.
  44. Criteria for a Recommended Standard: Occupational Exposure to Oxides of Nitrogen (Nitrogen Dioxide and Nitric Oxide). Washington, DC: US Dept of Health and Human Services, National Institute for Occupational Safety and Health; 1976:2. DHHS (NIOSH) publication 76–149.
  45. Hyde D, Orthoefer J, Dungworth D, Tyler W, Carter R, Lum H. Morphometric and morphologic evaluation of pulmonary lesions in beagle dogs chronically exposed to high ambient levels of air pollutants. Lab Invest. 1978;38:455–469.
  46. Kagawa J. Respiratory effects of 2-hr exposure to 1.0 ppm nitric oxide in normal subjects. Environ Res. 1982;27:485–490.
  47. Rasmussen TR, Kjaergaard SK, Tarp U, Pedersen OF. Delayed effects of NO2 exposure on alveolar permeability and glutathione peroxidase in healthy humans.Am Rev Respir Dis. 1992;146:654–659.
  48. Tunnicliffe WS, Burge PS, Ayres JG. Effect of domestic concentrations of nitrogen dioxide on airway responses to inhaled allergen in asthmatic patients.Lancet. 1994;344:1733–1736.
  49. Morrow PE, Utell MJ, Bauer MA, et al. Pulmonary performance of elderly normal subjects and subjects with chronic obstructive pulmonary disease exposed to 0.3 ppm nitrogen dioxide. Am Rev Respir Dis. 1992;145:291–300.
  50. Mourgeon E, Levesque E, Duveau C, et al. Factors influencing indoor concentrations of nitric oxide in a Parisian intensive care unit. Am J Respir Crit Care Med. 1997;156:1692–1695.
  51. Markhorst DG, Leenhoven T, Uiterwijk JW, Meulenbelt J, van Vught AJ. Occupational exposure during nitric oxide inhalational therapy in a pediatric intensive care setting. Intensive Care Med. 1996;22:954–958.
  52. Phillips ML, Hall TA, Sekar K, Tomey JL. Assessment of medical personnel exposure to nitrogen oxides during inhaled nitric oxide treatment of neonatal and pediatric patients. Pediatrics. 1999;104:1095–1100.
  53. Sixth Annual Report of the Council on Environmental Quality. Washington, DC: Environmental Protection Agency; 1975. Publication 040-000-00337-1.
  54. Mourgeon E, Gallart L, Umamaheswara Rao GS, et al. Distribution of inhaled nitric oxide during sequential and continuous administration into the inspiratory limb of the ventilator. Intensive Care Med. 1997;23:849–858.
  55. Losa M, Tibballs J, Carter B, Holt MP. Generation of nitrogen dioxide during nitric oxide therapy and mechanical ventilation of children with a Servo 900C ventilator. Intensive Care Med. 1997;23:450–455.

Guidelines for preventing transmission of Mycobacterium tuberculosis in health-care facilities. Centers for Disease Control and Prevention. MMWR Recomm Rep.1994;43(RR-13):1–132.

Exposure of Intensive Care Unit Nurses to Nitric Oxide and Nitrogen Dioxide During Therapeutic Use of Inhaled Nitric Oxide in Adults With Acute Respiratory Distress Syndrome

1.  Mohammed A. Qureshi, MD,

2. Nipurn J. Shah, MD,

3. Carol W. Hemmen, RN, BSN

4. Mary C. Thill, RN, MSN and

5. James A. Kruse, MD

Am J Crit Care March 2003 vol. 12 no. 2 147-153



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