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Inhaled Nitric Oxide

Policy Number: MP-440

Latest Review Date: June 2021

Category: Therapy                                                                 

Policy Grade: B

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.

DESCRIPTION OF PROCEDURE OR SERVICE:

Inhaled nitric oxide (INO), a treatment for neonates who have hypoxic respiratory failure, is intended to improve oxygenation, reduce mortality rates, and reduce the need for invasive extracorporeal membrane oxygenation (ECMO). It is also proposed as a treatment for premature infants, critically ill children, adults with respiratory failure, in the postoperative management of children undergoing repair of congenital heart disease and in lung transplantation to prevent or reduce reperfusion injury.

Hypoxic Respiratory Failure

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

Treatment

Treatment consists of oxygen support, mechanical ventilation, and induction of alkalosis, neuromuscular blockade, or sedation.

Extracorporeal membrane oxygenation (ECMO) is an invasive technique that may be considered in neonates when other therapies fail. Inhaled nitric oxide (INO) is both a vasodilator and a mediator in many physiologic and pathologic processes. INO 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 INO 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 postoperative pulmonary hypertension, which can prevent weaning from ventilation and is associated with substantial morbidity and mortality. Another potential surgical application is the use of INO in lung transplantation to prevent or reduce reperfusion injury.

KEY POINTS:

This policy includes literature found via MEDLINE search through March 30, 2021.

Summary of Evidence

For individuals who are neonates and are term or near-term at birth and have hypoxic respiratory failure who receive inhaled nitric oxide (INO), the evidence consists of randomized controlled trials (RCTs) and a systematic review. Relevant outcomes are overall survival, hospitalizations, resource utilization, and treatment-related morbidity. Evidence from RCTs and a meta-analysis support the use of INO in term or near-term infants. Pooled analyses of RCT data have found that INO leads to a significant reduction in the need for extracorporeal membrane oxygenation (ECMO) and in the combined outcome of ECMO or death. The evidence is sufficient to determine qualitatively that the technology results in an improvement in the net health outcome.

 

For individuals who are neonates and are premature at birth and have hypoxic respiratory failure who receive INO, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, hospitalizations, resource utilization, and treatment-related morbidity. A large number of RCTs have evaluated INO for premature neonates, and most trials have reported no significant difference on primary end points such as mortality and bronchopulmonary dysplasia (BPD). Meta-analyses of these RCTs have not found better survival rates in patients who receive with INO compared with a control intervention. Most meta-analyses did not find other outcomes e.g., BPD and intracranial hemorrhage were improved by INO. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome..

For individuals who have acute hypoxemic respiratory failure (non-neonates) who receive INO, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival, hospitalizations, resource utilization, and treatment-related morbidity. A large number of RCTs have evaluated INO for treatment of acute hypoxemic respiratory failure. Meta-analyses of these RCTs have not found that INO significant reduces mortality or shortens the duration of mechanical ventilation. There is some evidence from a meta-analysis of 4 RCTs and from a cohort study that INO may be associated with an increased risk of renal impairment in patients with acute respiratory distress syndrome (ARDS). The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have congenital heart disease who underwent heart surgery who receive INO, the evidence consists of RCTs and a systematic review. Relevant outcomes are overall survival, hospitalizations, resource utilization, and treatment-related morbidity. Evidence from a number of small RCTs and a systematic review of these trials did not find a significant benefit for INO on mortality and other health outcomes in the postoperative management of children with congenital heart disease. There is less evidence on INO for adults with congenital heart disease. One RCT found that treatment with INO did not improve of postoperative outcomes in adults with congestive heart failure. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have lung transplant who receive INO, the evidence consists of RCTs and a systematic review. Relevant outcomes are overall survival, hospitalizations, resource utilization, and treatment-related morbidity. Several small RCTs have evaluated INO after lung transplantation and have not found statistically significant improvement in health outcomes. A systematic review of RCTs and observational studies concluded that there is insufficient evidence to support routine use of INO after lung transplant. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

PRACTICE GUIDELINES AND POSITION STATEMENTS

Pediatric Academic Society

In April 2019, the Pediatric Academic Society convened a workshop regarding the role of INO in infants born preterm. The controversy surrounding its use in this patient population was reviewed by established experts in the field. The experts at the workshop concluded that the "rate of INO use in the infant born preterm is not declining, despite the publication of RCTs and related consensus statements that discourage its routine use due to lack of evidence for bronchopulmonary dysplasia prevention." These experts stated that "none of these studies or recommendations are based on its role in the management of persistent primary hypertension of the newborn in infants born preterm." In this setting, "extensive case series, guidelines, and others recommend the selective use of INO in infants born preterm with documented persistent primary hypertension of the newborn physiology as a contributing cause of hypoxemia, as best confirmed by echocardiography."

Pediatric Pulmonary Hypertension Network

In 2016, The Pediatric Pulmonary Hypertension Network (a network of clinicians, researchers, and centers) published recommendations for use of INO in premature infants with severe pulmonary hypertension. Key recommendations are:

“(1) INO therapy should not be used in premature infants for the prevention of BPD [bronchopulmonary dysplasia], as multicenter studies data have failed to consistently demonstrate efficacy for this purpose.

(2) INO therapy can be beneficial for preterm infants with severe hypoxemia that is primarily due to PPHN [persistent pulmonary hypertension of the newborn] physiology rather than parenchymal lung disease, particularly if associated with prolonged rupture of membranes and oligohydramnios.

(3) INO is preferred over other pulmonary vasodilators in preterm infants based on a strong safety signal from short- and long-term follow-up of large numbers of patients from multicenter randomized clinical trials for BPD prevention….”

National Institutes of Health

The National Institutes of Health (2011) published a consensus development conference statement on INO for premature infants, which was based on the Agency for Healthcare Research and Quality‒sponsored systematic review of the literature, previously described. Conclusions included:

“Taken as a whole, the available evidence does not support use of INO (inhaled NO) in early-routine, early-rescue, or later-rescue regimens in the care of premature infants of <34 weeks’ gestation who require respiratory support.”

“There are rare clinical situations, including pulmonary hypertension or hypoplasia, that have been inadequately studied in which INO may have benefit in infants of <34 weeks’ gestation. In such situations, clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties.”

“There are rare clinical situations, including pulmonary hypertension or hypoplasia, that have been inadequately studied in which INO may have benefit in infants of <34 weeks’ gestation. In such situations, clinicians should communicate with families regarding the current evidence on its risks and benefits as well as remaining uncertainties.”

American Heart Association/American Thoracic Society

The American Heart Association and American Thoracic Society (2015) published guidelines on the management of pediatric pulmonary hypertension. Relevant recommendations related to INO included:

  • "Inhaled nitric oxide (iNO) is indicated to reduce the need for extracorporeal membrane oxygenation (ECMO) support in term and near-term infants with persistent pulmonary hypertension of the newborn (PPHN) or hypoxemic respiratory failure who have an oxygenation index that exceeds 25 (Class I; Level of evidence A)."
  • "iNO can be beneficial for preterm infants with severe hypoxemia that is due primarily to PPHN physiology rather than parenchymal lung disease, particularly if associated with prolonged rupture of membranes and oligohyramnios (Class IIa; Level of evidence B)."

American Academy of Pediatrics

In 2014, the American Academy of Pediatrics provided the following recommendations on the use of INO in premature infants (Table 1).

Table 1. Guidelines on Use of INO for Premature Infants

Recommendation

QOE

GOR

“Neither rescue nor routine use of iNO improves survival in preterm infants with respiratory failure.”

A

Strong

“The preponderance of evidence does not support treating preterm infants who have respiratory failure with iNO for the purpose of preventing/ameliorating BPD, severe intraventricular hemorrhage, or other neonatal morbidities.”

A

Strong

“The incidence of cerebral palsy, neurodevelopmental impairment, or cognitive impairment in preterm infants treated within iNO is similar to that of control infants.”

A

NR

BPD: bronchopulmonary dysplasia; GOR: grade of recommendation; INO: inhaled nitric oxide; NR: not reported; QOE: quality of evidence.

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS

Use of inhaled nitric oxide is not a preventive service.

KEY WORDS:

Inhaled Nitric Oxide, Treatment of Respiratory Failure, Nitric Oxide, Inhaled, Respiratory Failure, INOmax™, INO

APPROVED BY GOVERNING BODIES:

In 1999, INOmax™ (Ikaria®, Clinton, NJ) was approved by the FDA 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 (Dublin, Ireland) 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 2020, FDA granted emergency expanded access for INOpulse (Bellerophon Therapeutics) inhaled nitric oxide delivery system for treating COVID-19.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING:

CPT Codes:

There is not a specific CPT code.

This service is usually billed on the hospital bill with revenue code 412 for inhalation services.  The physician component is included in critical care services.

REFERENCES:

  1. Adhikari NK, Dellinger RP, Lundin S, et al. Inhaled nitric oxide does not reduce mortality in patients with acute respiratory distress syndrome regardless of severity: systematic review and meta-analysis. Crit Care Med. Feb 2014; 42(2):404-412.
  2. Afshari A, Brok J, Moller AM et al.  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.  Anesth Analg 2011; 112(6):1411-1421.
  3. American Academy of Pediatrics. Use of inhaled nitric oxide.  Pediatrics 2000; 106(2 pt 1):344-345.
  4. Askie LM, Ballard RA, Cutter G, et al.  Inhaled nitric oxide in preterm infants:  A systematic review and individual patient data meta-analysis.  BMC Pediatr 2010; 10:15.
  5. Askie LM, Ballard RA, Cutter G, et al. Inhaled nitric oxide in preterm infants: an individual-patient data meta-analysis of randomized trials. Pediatrics 2011; 128(4):729-739.
  6. Barrington KJ, Finer N, Pennaforte T, et al. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. Jan 05 2017; 1:CD000399.
  7. Barrington KJ, Finer N, Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev. Jan 03 2017; 1:CD000509.
  8. Bizzaro M, Gross I.  Inhaled nitric oxide for the postoperative management of pulmonary hypertension in infants and children with congenital heart disease.  Cochran Database Syst rev 2005; (4):CD005055.
  9. Bizzarro M, Gross I, Barbosa FT. Inhaled nitric oxide for the postoperative management of pulmonary hypertension in infants and children with congenital heart disease. Cochrane Database Syst Rev. 2014; 7:CD005055.
  10. Botha P, Jeyakanthan M, Rao JN, et al. Inhaled nitric oxide for modulation of ischemia-reperfusion injury in lung transplantation. J Heart Lung Transplant. Nov 2007; 26(11):1199-1205.
  11. Bronicki RA, Fortenberry J, Schreiber M, et al. Multicenter randomized controlled trial of inhaled nitric oxide for pediatric acute respiratory distress syndrome. J Pediatr. Feb 2015; 166(2):365-369 e361.
  12. Cole FS, Alleyn C, Barks JD et al. NIH consensus development conference statement: inhaled nitric oxide therapy for premature infants. Pediatrics 2011; 127(2):363-369.
  13. Dellinger RP, Trzeciak SW, Criner GJ, et al. Association between inhaled nitric oxide treatment and long-term pulmonary function in survivors of acute respiratory distress syndrome. Crit Care 2012; 16(2):R36.
  14. Donohue PK, Gilmore MN, Cristofalo E et al. Inhaled nitric oxide in preterm infants: a systematic review. Pediatrics 2011; 127(2):e414-422.
  15. Durrmeyer X, Hummler H, Sanchez-Luna M et al. Two-year outcomes of a randomized controlled trial of inhaled nitric oxide in premature infants.  Pediatrics 2013:132(3):e695-703.
  16. Finer NN and Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2006; (4):CD000399.
  17. Gebistorf F, Karam O, Wetterslev J, et al. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst Rev. Jun 27 2016(6):CD002787.
  18. Golombek SG, Young JN. Efficacy of inhaled nitric oxide for hypoxic respiratory failure in term and late preterm infants by baseline severity of illness: a pooled analysis of three clinical trials. Clin Ther 2010; 32(5):939-948.
  19. Greenough A, Decobert F, Field D, et al. Inhaled nitric oxide (iNO) for preventing prematurity-related bronchopulmonary dysplasia (BPD): 7-year follow-up of the European Union Nitric Oxide (EUNO) trial. J Perinat Med. Sep 07 2020; 49(1): 104-110.
  20. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
  21. Kinsella JP, Cutter GR, Steinhorn RH, et al. Noninvasive Inhaled Nitric Oxide Does Not Prevent Bronchopulmonary Dysplasia in Premature Newborns. J Pediatr. Jul 22 2014.
  22. Kinsella JP, Steinhorn RH, Krishnan US, et al. Recommendations for the use of inhaled nitric oxide therapy in premature newborns with severe pulmonary hypertension. J Pediatr. Mar 2016; 170:312-314.
  23. Kumar P, Committee on F, Newborn, et al. Use of inhaled nitric oxide in preterm infants. Pediatrics. Jan 2014; 133(1):164-170.
  24. Lakshminrusimha S, Kinsella JP, Krishnan US, et al. Just Say No to iNO in Preterms-Really?. J Pediatr. Mar 2020; 218: 243-252.
  25. Mercier J-C, Hummler H, Durrmeyer X et al.  Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomized controlled trial.  Lancet 2010; 376(9738): 346-354.
  26. Potapov E, Meyer D, Swaminathan M, et al. Inhaled nitric oxide after left ventricular assist device implantation: a prospective, randomized, double-blind, multicenter, placebo-controlled trial. J Heart Lung Transplant. Aug 2011; 30(8):870-878.
  27. Ruan SY, Wu HY, Lin HH, et al. Inhaled nitric oxide and the risk of renal dysfunction in patients with acute respiratory distress syndrome: a propensity-matched cohort study. Crit Care. Nov 30 2016; 20(1):389.
  28. Tavare AN, Tsakok T. Does prophylactic inhaled nitric oxide reduce morbidity and mortality after lung transplantation? Interact Cardiovasc Thorac Surg. Nov 2011; 13(5):516-520.
  29. Walsh MC, Hibbs AM, Martin CR, et al. Two-year neurodevelopmental outcomes of ventilated preterm infants treated with inhaled nitric oxide. J Pediatr 2010; 156(4):556-561.e1.
  30. Wang J, Cong X, Miao M, et al. Inhaled nitric oxide and acute kidney injury risk: a meta-analysis of randomized controlled trials. Ren Fail. Dec 2021; 43(1): 281-290.
  31. Yang Y, Feng Y, Zhou XG, et al. Inhaled nitric oxide in preterm infants: An updated meta-analysis. J Res Med Sci. 2016; 21:41.

POLICY HISTORY:

Medical Policy Group, July 2010 (3)

Medical Policy Administration Committee, July 2010

Available for comment July 23-September 6, 2010

Medical Policy Panel, July 2011

Medical Policy Group, August 2011 (2): Description, Policy, Key Points, References updated

Medical Policy Administration Committee, September 2011

Available for comment September 22 through November 7, 2011

Medical Policy Group, August 2013 (2): 2013 Updates to Description, Key Points and References

Medical Policy Panel, October 2013

Medical Policy Group, December 2013 (2): No change in policy statement.  Key Points and References updated with literature review through August 2013.  Old references to Clinical Trials removed. 

Medical Policy Panel, October 2014

Medical Policy Group, October 2014 (3):  2014 Updates to Description, Key Points & References; no change in policy statement

Medical Policy Panel, May 2016

Medical Policy Group, May 2016 (7): Updates to Description, Key Points and References. Policy section: added use of INO in lung transplantation during and/or after graft reperfusion as investigational.

Medical Policy Panel, May 2017

Medical Policy Group, May 2017 (7): Updates to Description, Key Points and References. No change in Policy Statement.

Medical Policy Panel, May 2018

Medical Policy Group, June 2018 (7): Updates to Key Points and References. No change in Policy Statement.

Medical Policy Panel, May 2019

Medical Policy Group, June 2019 (3): 2019 Updates to Description, Key Points and Practice Guidelines and Position Statements. No changes to policy statement or intent. No new References added.

Medical Policy Panel, May 2020

Medial Policy Group, June 2020 (5): Updates to Key Points, Approved by Governing Bodies, Practice Guidelines and Position Statements. No changes to Policy Statement.

Medical Policy Panel, May 2021

Medical Policy Group, June 2021 (5): Updates to Description, Key Points, Practice Guidelines and Position Statements, and References. No change to Policy Statement.

 

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

 

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

 

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.