Perhaps you have been in situations where the physician and the team are gathered near a bedside and the discussion for the patient’s plan of care devolves into a search for treatment suggestions due to a poor response and prognosis under the current therapy. Often it is a perceived last chance or potential option for survival of the patient. Inhaled nitric oxide (INO) is one of those interventions on the short list of “maybes” for our patients with severe acute respiratory distress syndrome (ARDS).

“One of the most exciting aspects of the practice of medicine is that it is continually evolving and changing. Faced with thousands of articles every year, a practitioner can’t help but feel overwhelmed at times. This is why the practice of evidence-based medicine is so important,” writes Kimura.1 What does the evidence lead us to conclude with respect to ARDS and INO? Is it beneficial? Is it therapeutic? Most importantly, are morbidity and mortality reduced?

The respiratory therapist is an integral member of the intensive care unit in almost every hospital in the country. We are valued members of the team and are bedside patient care advocates. In that regard, we are responsible for assessing and evaluating the therapies we apply on an ongoing basis. Use of ventilator technology, medications, and special gases must be scrutinized, and the evidence either for or against treatments and protocols should dictate our patient management approach.

Therapists who practiced prior to the last decade may remember that the treatment for closed head injuries included immediate and sustained hyperventilation. The patient’s CT scans or MRI images would show improvement and significant reduction of cerebral edema, encouraging us to conclude that we were fixing the problem. However, the final outcome was essentially unchanged when compared to nonhyperventilated patients due to several factors, including cerebral hypoxia and substantial reperfusion injury.2 With ARDS, we are again searching for opportunities to optimize our treatments.

What Is ARDS?

Acute respiratory distress syndrome is a severe, often fatal inflammatory disease of the lung that is typically characterized by a sudden onset of respiratory distress and pulmonary edema, usually in tandem with other acute medical conditions of either a pulmonary origin (infection process) or traumatic injury (chest wall trauma, motor vehicle accident, etc).3 In many cases, ARDS may be the end point of multiorgan failure due to a host of etiologies. Severely decreased lung compliance and poor oxygenation are hallmarks of this disease process. (Readers can learn about the phases of ARDS at—ed.)

Patients with ARDS are generally managed on ventilators, and strategies for treatment may include high PEEP levels and low volume ventilation. Treatments often used in neonates have been studied to discern if their efficacy can be duplicated in the adult pulmonary system. Inhaled nitric oxide is such a treatment, and we will examine it in this article.


Inhaled nitric oxide is a selective pulmonary vasodilator approved by the FDA for use in the neonatal patient population in 1999 for the treatment of persistent pulmonary hypertension of the newborn (PPHN). It has heralded in a new age in the treatment of PPHN, resulting in decreased length of stay, decreased length of ventilator days, and decreased need for extracorporeal membrane oxygenation (ECMO) therapy.4

Nitric oxide is a colorless and odorless gas that binds to the hemoglobin (Hb) and is rapidly inactivated, thus the vasodilatory effect of INO is limited to the pulmonary system. This is in contrast to the use of intravenously infused vasodilators that cause systemic vasodilatation, which can lead to circulatory compromise. Other positive effects of INO include bronchodilation, anti-inflammatory, and antiproliferative effects.4

In the nondiseased lung, a low Po2 constricts the vasculature in hypoxic areas and redirects the flow of blood to segments with better ventilation and an increased intra-alveolar Po2. Inhaled nitric oxide augments this by increasing the flow to well-ventilated segments that may in some disease processes have an elevated vasomotor tone. In contrast to intravenous vasodilators that cause dilation to all of the pulmonary vasculature including the nonventilated segments, the result is an increased shunt and lower Po2. The benefits of INO have been shown to reduce intrapulmonary shunting in patients with ARDS.4

Pharmacologically, it has been studied and shown that INO is effective in improving the circulation within the pulmonary system and that the effects are targeted to the pulmonary vasculature with minimal systemic effects.4

Based on the facts above, we might conclude that INO is another useful strategy in the treatment of ARDS. As clinicians, we must ask ourselves if these outcomes can be translated with success into the world of adult pulmonary medicine, specifically in treating ARDS, which has a 25% to 40% mortality rate.5

The fact is there are multiple processes leading up to ARDS that make its treatment a unique challenge to the health care team. Treatment must be tailored for each case, as each patient will have a unique medical background that must be taken into consideration before developing a plan of care.

Is the patient septic? Are there complicating factors, such as a history of cardiac or pulmonary disease? Is this the result of an accident in an otherwise healthy young person? A complete medical and lifestyle history must be taken into account when beginning a course of therapy for the ARDS patient.


At this time, the use of INO is still on a case-by-case basis. While there is some anecdotal evidence for the use of INO in ARDS, there are relatively few benchmark studies available for review. The difference in application is largely related to the dissimilar etiologies of ARDS or acute lung injury (ALI) versus PPHN.6

In the neonate or pediatric patient with PPHN as with the adult ARDS patient, there may be no previous pulmonary factors. Thus, a disease-free lung may decompensate due to various mitigating factors of the disease process. It may be these factors that prevent INO from being the “magic bullet” in the treatment of ARDS.

The ARDS process differs from the PPHN disease process, which is generally classified into three types, depending on the possible etiology:

1. PPHN associated with pulmonary parenchymal disease, such as hyaline membrane disease, meconium aspiration, or transient tachypnea of the newborn as the cause of alveolar hypoxia

  • known as secondary PPHN or appropriate PPHN
  • alveolar oxygen tension appears to be the major determinant of pulmonary artery vasoconstriction.

2.PPHN with radiographically normal lungs and no evidence of parenchymal disease

  • frequently called persistent fetal circulation (PFC), or primary or inappropriate PPHN

3. PPHN associated with hypoplasia of the lungs

  • most often in the form of diaphragmatic hernia
  • associated with an anatomic reduction in the number of capillaries.7

In otherwise healthy newborns, most of whom have no pulmonary impairment, this process is mainly a circulatory issue, due to the diversion or shunting of pulmonary blood flow into the systemic circulation. Sepsis, a major predisposing factor in the development of ARDS, may be part of the sequelae of meconium aspiration, but is not considered a causative factor in the development of PPHN.

Most common causes attributed to the development of ARDS:

  • sepsis (bacterial infection of the blood)
  • trauma (usually blunt force trauma to the thoracic cage)
  • pulmonary infection (pneumonia or most recently H1N1 infection)

Other documented causative conditions:

  • multiple transfusions
  • near drowning in salt water
  • inhalation of toxic chemical smoke
  • aspiration of vomit
  • narcotics
  • sedatives
  • overdoses of tricyclic antidepressants
  • shock 3

ARDS can have multifactorial complicated sequelae of pulmonary events such that when and where to use INO as an adjunct therapy becomes a difficult decision for the health care provider. Mark Grzeskowiak, RRT, FAARC (manager, education and quality at Long Beach Memorial Medical Center and Miller Children’s Hospital, Long Beach, Calif), remarked, “About the only time we see patients walk away [from INO] is when we use it for diagnostic applications. They are almost always outpatients. If the patients respond [to INO,] they [will] receive drug therapy. In almost every other case [when] it [INO] was being used as rescue therapy to treat severe hypoxemia, the [critically ill] patients did not survive.”

More Studies Needed

The average adult ARDS patient has multiple medical issues to be treated, and thus far INO has been shown in clinical trials to have a transient improvement for only the first 24 hours of treatment. INO also increases the risk of renal impairment in the adult population.8

In a randomized controlled clinical trial at the University of Utah Medical Center, the investigators’ concluding statement was: “We have shown in patients with severe ARDS that INO does not produce a sustained improvement in oxygenation as compared with conventional therapy. We feel that the transient increase in Pao2/Fio2 produced by INO does not justify its routine use in ARDS. Further studies are warranted to determine whether subgroups of patients might benefit from this therapy.”4

INO has been demonstrated to be helpful only briefly in the short term, and as more advances in medicine arise, we may see the use of INO as an initial treatment in the recovery of the patient in ARDS. It is true that more studies need to be done, and we as respiratory therapists must be an integral part in the search. Respiratory therapists will learn and adapt new ways to use the tools we have to advance the care for our patients with ARDS and ALI.

Denise M. Rees, RCP, RRT-NPS, is a NICU therapist and assistant supervisor at Santa Monica-UCLA Medical Center and Orthopedic Hospital in Santa Monica, Calif. She is also adjunct faculty and clinical instructor for the East Los Angeles College and Santa Monica College Health Sciences Department. DeeAnna Serna-Flood, RRT, RCP, is a NICU therapist at Santa Monica-UCLA Medical Center and Orthopedic Hospital. For further information, contact [email protected]


  1. Kimura C. Evidence-Based Medicine. March 2003. Available at: Accessed September 1, 2010.
  2. Geraci EB, Geraci TA. Hyperventilation and head injuries. J Neurosci Nurs. 1996;6:381-7.
  3. What Is Adult Respiratory Distress Syndrome. Available at: Accessed September 1, 2010.
  4. Ichinose F, Roberts JD, Zapol WM. Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential. Circulation. 2004;109:3106-11
  5. Acute Respiratory Distress Syndrome (ARDS). Available at: Accessed September 1, 2010.
  6. 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;157:1372-80.
  7. Maycock DE. Persistent Pulmonary Hypertension of the Newborn. Available at: [removed][/removed]. Accessed September 1, 2010.
  8. Afshari A, Brok J, Moller A, Wetterslev J. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) and acute lung injury in children and adults. Cochrane Database Syst Rev. 2005;7:CD002787.