A key player in the evolution of nitric oxide therapy describes the versatile compound’s past, present, and future.

MillerIn the late 1980s, after reading an abstract by Higenbottam1 on inhalation of gaseous nitric oxide, I was intrigued. As an RT, I was excited by the possible emergence of a new respiratory drug. I immersed myself in research pertaining to this gas molecule. My early quest resulted in the first review article published on inhaled nitric oxide.2 In 1992, Science magazine named nitric oxide molecule of the year.3 Tens of thousands of articles have been published on the topic. Nitric oxide was the subject of a 1998 Nobel Prize in medicine.4 Clinically, many RTs working in neonatal intensive care during the early research years experienced the rewarding feeling of administering nitric oxide and witnessing its rapid, almost miraculous results.

Despite the accolades, nitric oxide has been the cause of much confusion and controversy due to commercial and legal issues.

Research on gaseous nitric oxide began when Furchgott and Zawadzki5 showed that the relaxation of blood vessels depended on an intact endothelium. Murad et al6 showed that nitroglycerine caused blood vessels to relax, and that this was caused by the release of nitric oxide gas. Ignarro et al7 demonstrated that the relaxation of blood vessels described by Furchgott was due to a substance produced in the endothelium, which his group called endothelium-derived relaxing factor (EDRF). In 1987, Ignarro demonstrated that EDRF was, indeed, nitric oxide. In 1998, these three individuals won the Nobel Prize for their discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system.4

In 1987, Higenbottam et al8 treated seven patients exhibiting pulmonary hypertension with gaseous nitric oxide, and they showed a positive response. In 1990, following confirmation of this response, a US entity filed to patent nitric oxide for this indication; two patents were granted 6 years later. Litigation concerning nitric oxide and related devices followed, and it continues today.

Between 1988 and 1996, thousands of research studies were undertaken on the mechanism of nitric oxide therapy and how to apply it to patient care. To date, more than 50,000 papers on the subject have been published. During this period, many RTs published articles demonstrating how to deliver this unique gas safely and effectively. A number of commercial entities worked together to develop monitoring and delivery devices to support the explosion of clinical research. RTs were in the thick of this entire process. Nitric oxide was provided for research use for a reasonable price of approximately $0.11/L.9 RTs were center stage, guiding and providing expertise in gas delivery for research. Delivery of gaseous nitric oxide required finesse, and RTs were the perfect people to provide that service.

Research is showing that gaseous nitric oxide is much more than the selective pulmonary vasodilator reflected in the patents for use with reversible pulmonary hypertension. Nitric oxide is involved in almost every body system, and many potential pulmonary and extrapulmonary applications for gaseous nitric oxide fall outside the current US Food and Drug Administration (FDA) approval. For instance, gaseous nitric oxide at doses of less than 80 ppm produces an anti-inflammatory effect by reducing neutrophil adhesion, platelets, and pro-inflammatory cytokines in the circulating blood.10 Research combining gaseous nitric oxide with new modes of mechanical ventilation may result in protective strategies that could have an impact on diseases such as bronchopulmonary dysplasia and the adult respiratory distress syndrome (ARDS).11 Similar paracrine mechanisms for gaseous nitric oxide are being explored for beneficial effects on sickle-cell crisis, neurological dysfunction during cardiopulmonary bypass, and ischemia-reperfusion injuries.12-14

The role of gaseous nitric oxide in the immune system as an endogenous antimicrobial agent is also being explored. Macrophages naturally produce gaseous nitric oxide as a host-defense mechanism against microbes, but these gaseous nitric oxide supplies are often overcome and depleted during infection.15 Exogenous gaseous nitric oxide may sustain (and even enhance) the ability to defeat invading bacteria and viruses, as well as cancer cells. RTs are involved in evaluating the potential of gaseous nitric oxide to reduce and prevent ventilator-acquired pneumonias.16,17

Gaseous nitric oxide also plays a major role in the wound-healing process.18 Varying the level of gaseous nitric oxide affects collagen and collagenase levels at the wound site. It seems possible that the combination of antimicrobial attributes and vasodilatory effects with the ability to manipulate the pace of collagen formation at a wound site would be effective in promoting healing. Should research prove this to be true, burn patients (who now have high mortality and morbidity rates due to infection and keloid scarring) may greatly benefit from the topical administration of exogenous gaseous nitric oxide.

RTs were involved in many of these research projects. Much work still needs to be done to explore the role of gaseous nitric oxide for myriad potential indications in addition to its reversible vasodilatory effects. There is much that RTs could contribute toward research for these new indications, which could result in expanded and strengthened roles for RTs. Unfortunately, once commercialization of gaseous nitric oxide began, research in this arena was curtailed. In December 1998, researchers’ access to inexpensive inhaled nitric oxide stopped.

As an RT, I had realized that a device other than a large chemiluminescence analyzer was needed to monitor gaseous nitric oxide dosing and aberrant nitrogen dioxide levels. With the help of my friends and family, we conceived and built a small bedside analyzer with alarms for clinical research. Soon, other researchers and RTs wanted to use the device, and I decided to commercialize the first dual nitric oxide/nitrogen dioxide display analyzer. I did not patent the analyzer because it would have slowed research in the field.

In December 1999, nitric oxide as a new drug for use in neonates with persistent pulmonary hypertension of the newborn (PPHN) was approved. Once approval was granted, the price of gas rose to approximately $6/L, bringing the cost of treating a newborn with this gas from $200 to almost $12,000, with a minimum charge of $3,000 to open the tank of gas for any application.19 This discouraged many researchers from exploring other applications of nitric oxide. The FDA approval that was granted covers only a single indication. There is, however, much valid research to be done outside this area.

RTs have played a significant role in the emergence of nitric oxide, one of the most amazing messenger molecules ever to be discovered. Commercially, we have struggled, but I am confident that we will work out our problems. There is plenty of room for a win-win solution in the commercial arena. I believe this because I think that great discoveries in medicine such as gaseous nitric oxide survive commercial and legal challenges. History is still unfolding for this molecule, and I predict that RTs have not seen the last of their involvement with gaseous nitric oxide.

Chris Miller, PhD(c), BA, RRT, is founder, Pulmonox Medical Inc, Edmonton, Alberta, Canada.

1. Higenbottam TW, Pepke-Zaba J, Scott JP, Woolman P, Coutts C, Wallwork J. Inhaled endothelium-derived relaxing factor (EDRF) in pulmonary hypertension (PPH) [abstract]. Am Rev Respir Dis. 1988;137(4):107.
2. Miller CC, Miller JWR. Pulmonary vascular smooth-muscle regulation: the role of inhaled nitric oxide gas. Respir Care. 1992;37:1175-1185.
3. Culotta E, Koshland DE. NO news is good news. Science. 1992;258:1862-1865.
4. Nobel e-Museum. Nobel prize in physiology or medicine 1998. Available at: http://www.nobel.se/medicine/laureates/1998/illpres/index.html. Accessed August 31, 2003.
5. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373-376.
6. Arnold WP, Mittal C, Katsuki S, Murad F. Nitric oxide activates guanylate cyclase and increases guanosine 3’:5’-monophosphate levels in various tissue preparations. Proc Natl Acad Sci USA. 1977;74:3203-3207.
7. Ignarro LJ, Buga GM, Wood KS, Byrnes RE, Chaudhuri G. Endothelium–derived relaxing factor produced and released from artery and vein in nitric oxide. Proc Natl Acad Sci USA. 1987;84:9265-9269.
8. Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 1991;338:1173-1174.
9. Hill W. Health Canada is now regulating nitric oxide (NO). Important lessons from the USA and Europe [editorial]. Canadian Journal of Respiratory Therapists. 2002;38:4.
10. Gianetti J, Bevilacqua S, De Caterina R. Inhaled nitric oxide: more than a selective pulmonary vasodilator. Eur J Clin Invest. 2002;32:628-635.
11. Mehta S, McDonald R, Hallett DC, Lapinsky SE, Aubin M, Stewart TE. Acute oxygenation response to inhaled nitric oxide when combined with high-frequency oscillatory ventilation in adults with acute respiratory distress syndrome. Crit Care Med. 2003;31(2):383-389.
12. Clinical Trials.com. Nitric oxide therapy for patients with sickle cell anemia and secondary pulmonary hypertension. Available at: http://www.clinicaltrials.gov/ct/ show/NCT00023296?order=4. Accessed August 31, 2003.
13. Joe Beckman. Nitric oxide and superoxide in cerebral ischemic injury. UAB Anesthesiology, Contracts and Grants. Available at: http://www.anes.uab.edu/ GRANTS.HTM. Accessed August 31, 2003.
14. Adrie C, Bloch KD, Moreno PR, et al. Inhaled nitric oxide increases coronary artery patency after thrombolysis. Circulation. 1996;94:1919-1926.
15. Fang FC. Nitric Oxide and Infection. New York: Kluwer Academic/Plenum Publishers; 1999.
16. Dukelow AM, Weicker S, Karachi TA, et al. Effects of nebulized diethylenetetraamine-NONOate in a mouse model of acute Pseudomonas aeruginosa pneumonia. Chest.2002;122(6):2127-2136.
17. Jean D, Maitre B, Tankovic J, et al. Beneficial effects of nitric oxide inhalation on pulmonary bacterial clearance. Crit Care Med. 2002;30(2):442-447.
18. Witte MB, Barbul A. Role of nitric oxide in wound repair. Am J Surg. 2002;183:406-412.
19. Smith I. Saving lives at what cost? RT. February/March 2000:69-73.