Inhaled Nitric Oxide

POLICY NUMBER

A.8.01.37

DESCRIPTION

Inhaled nitric oxide (INO) is a natural vasodilator and has been studied for a variety of types of respiratory failure. Most commonly, it is used as an initial treatment for neonates with hypoxic respiratory failure to improve oxygenation and reduce the need for invasive extracorporeal membrane oxygenation. It is also proposed as a treatment for premature infants, critically ill children, and adults with respiratory failure, as well as in the postoperative management of children undergoing repair of congenital heart disease and patients after lung transplantation to prevent or reduce reperfusion injury.

Hypoxic Respiratory Failure

Hypoxic respiratory failure may result from respiratory distress syndrome, persistent pulmonary hypertension, meconium aspiration, pneumonia, or sepsis.

TreatmentTreatment typically includes oxygen support, mechanical ventilation, and induction of alkalosis, neuromuscular blockade, or sedation.

Extracorporeal membrane oxygenation is an invasive technique that may be considered in neonates when other therapies fail. Inhaled nitric oxide is both a vasodilator and a mediator in many physiologic and pathologic processes. Inhaled nitric oxide has also been proposed for use in preterm infants less than 34 weeks of gestation and in adults.

Also, there are several potential uses in surgery. One is the proposed use of inhaled nitric oxide to manage pulmonary hypertension after cardiac surgery in infants and children with congenital heart disease. In congenital heart disease patients, increased pulmonary blood flow can cause pulmonary hypertension. Cardiac surgery can restore the pulmonary vasculature to normal, but there is the potential for complications, including post-operative pulmonary hypertension, which can prevent weaning from ventilation and is associated with substantial morbidity and mortality. Another potential surgical application is the use of inhaled nitric oxide in lung transplantation to prevent or reduce reperfusion injury.

In 1999, INOmax™ (Ikaria) was cleared for marketing by the U.S. Food and Drug Administration through the 510(k) process for the following indication: “INOmax, in conjunction with ventilatory support and other appropriate agents, is indicated for the treatment of term and near-term (>34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension.” In 2015, Mallinckrodt acquired Ikaria.

In 2014, Advanced Inhalation Therapies received orphan drug designation for its proprietary formulation of nitric oxide as an adjunctive treatment of cystic fibrosis.

In 2019, Genosyl® (nitric oxide for inhalation; Vero Biotech, LLC) received FDA approval to "improve oxygenation and reduce the need for extracorporeal membrane oxygenation in term and near-term (>34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension." In April 2021, the GENOSYL DS Nitric Oxide Delivery System was recalled due to a software issue that leads to errors in the delivery of nitric oxide. For impacted devices, the issue was corrected with the release of Software 2.2.4.

In 2020, the FDA granted emergency expanded access for INOpulse (Bellerophon Therapeutics) inhaled nitric oxide delivery system for treating COVID-19.

POLICY

Inhaled nitric oxide may be considered medically necessary as a component of treatment of:

• Hypoxic respiratory failure in neonates born at more than 34 weeks of gestation.

Other indications for inhaled nitric oxide are investigational, including, but not limited to:

• Treatment of premature neonates born at less than or equal to 34 weeks of gestation with hypoxic respiratory failure;

• Treatment of adults and children with acute hypoxemic respiratory failure;

• Postoperative use in adults and children with congenital heart disease;

• In lung transplantation, during and/or after graft reperfusion.  

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Inhaled nitric oxide appears to be of greatest benefit to neonates born at more than 34 weeks for whom primary or secondary pulmonary hypertension is a component of hypoxic respiratory failure.

The benefit of inhaled nitric oxide appears limited in term or near-term infants whose hypoxic respiratory failure is due to diaphragmatic hernia, unless there is associated pulmonary hypertension.

The following criterion for hypoxic respiratory failure has been reported:

• An oxygenation index of at least 25 on 2 measurements made at least 15 minutes apart.

(The oxygenation index [OI] is calculated as the mean airway pressure times the fraction of inspired oxygen divided by the partial pressure of arterial oxygen times 100. An OI of 25 is associated with a 50% risk of requiring extracorporeal membrane oxygenation [ECMO] or dying. An OI of 40 or more is often used as a criterion to initiate ECMO therapy.)

If ECMO is initiated in near-term neonates, inhaled nitric oxide should be discontinued because there is no benefit to combined treatment.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

8/27/2007: Policy added.

11/15/2007: Policy approved by MPAC.

9/11/2008: Policy reviewed, no changes.

07/15/2010: Policy reviewed; no changes.

09/23/2011: Policy description updated. The medically necessary statement was changed from “34 or more weeks of gestation” to “more than 34 weeks of gestation” for consistency with FDA approval of the technology. The investigational statement on premature neonates was changed from “less than 34 weeks” to “less than or equal to 34 weeks.” Added the use of this technology in adults and children with acute hypoxemic respiratory failure and postoperative management of pulmonary hypertension in children with congenital heart disease to the investigational policy statement. The title was changed to “Inhaled Nitric Oxide” to reflect the expanded scope of the policy. Deleted ICD-9 code 765.27 from the Covered Codes table.

01/09/2013: Deleted postoperative management of pulmonary hypertension in children with congenital heart disease from the investigational policy statement. Added criteria to the policy guidelines regarding hypoxic respiratory failure and benefits of inhaled nitric oxide.

01/22/2014: Policy reviewed; no changes. 

11/14/2014: Policy reviewed; description updated. Policy statement unchanged.

08/26/2015: Code Reference section updated for ICD-10.

05/26/2016: Policy number A.8.01.37 added. Policy Guidelines updated to add medically necessary and investigative definitions.

07/20/2016: Policy description updated regarding potential surgical applications using inhaled nitric oxide. Investigational policy statement reformatted to list criteria. Added postoperative use in adults and children with congenital heart disease and in lung transplantation, during and/or after graft reperfusion to the investigational policy statement.

06/14/2017: Policy description updated. Policy statements unchanged.

06/19/2018: Policy description updated regarding the proposed use of inhaled nitric oxide. Policy statements unchanged. Policy Guidelines updated regarding the oxygenation index for ECMO therapy.

06/10/2019: Policy reviewed; no changes.

07/08/2020: Policy description updated. Policy statements unchanged.

08/24/2021: Policy reviewed. Policy statements unchanged. Policy Guidelines updated regarding the benefit of inhaled nitric oxide. Changed "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

06/22/2022: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to change "individuals" to "neonates born at more than 34 weeks."

07/17/2023: Policy description updated regarding devices. Policy statements unchanged.

06/14/2024: Policy reviewed; no changes.

08/14/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross & Blue Shield Association Policy # 8.01.37

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of the is document.

Covered Codes

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