Current issues and trends in Respiratory therapy
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Inhaled Nitric Oxide Delivery Systems for Mechanically Ventilated and Nonintubated Patients: A Review
Stefano Gianni, Ryan W Carroll, Robert M Kacmarek,y and Lorenzo Berra
Introduction
Nitric Oxide Generators and Delivery Systems
Cylinder-Based Systems
Electricity-Generated NO
Chemical NO Generator
NO-Releasing Solutions
NO-Releasing Nanoparticles
Summary
Nitric oxide (NO) is a biologically active molecule approved for the treatment of pulmonary hypertension
in newborn patients. Commercially available NO delivery systems use pressurized cylinders as the source
of NO and a sensor to control the concentrations of NO and nitrogen dioxide (NO2) delivered. Cylinder-
based delivery systems are safe and widely used around the world, but they are bulky, expensive, and
reliant on a robust supply chain. In the past few years, novel NO generators and delivery systems have
been developed to overcome these limitations. Electric NO generators produce NO from ambient air
using high-voltage electrical discharge to ionize air, which leads to the formation of NO, NO2, and ozone
(O3). A scavenging system is incorporated to reduce the concentration of the toxic byproducts generated
in this type of system. NO can also be generated by the reduction of NO2 by ascorbic acid or released
from liquid solutions or solid nanoparticles. The development of easy-to-use, safe, and portable NO deliv-
ery systems may enable the delivery of NO in the out-patient setting or at home. Furthermore, non–cyl-
inder-based NO generators reduce the cost of NO production and storage and may therefore make NO
delivery feasible in low-resource settings. Here we review commercially available systems that can gener-
ate and administer inhalable NO. Key words: nitric oxide; nitrogen dioxide; respiratory therapy; inhala- tion. [Respir Care 2021;66(6):1021–1028. © 2021 Daedalus Enterprises]
Introduction
Nitric oxide (NO) gas is a molecule that plays a pivotal
role in many physiological processes. In the cardiovascu-
lar system, NO is released by the endothelial cell and acts
as a vascular smooth muscle relaxant to induce systemic
and pulmonary vasodilation.1 Because NO is rapidly inac-
tivated by the reaction with oxyhemoglobin, inhaled NO
acts as a pure pulmonary vasodilator with negligible sys-
temic hemodynamic effects.2 In 1999, the U.S. Food and
Drug Administration (FDA) approved gaseous inhaled
NO for the treatment of “term and near-term (> 34 weeks)
neonates with hypoxic respiratory failure associated with
clinical or echocardiographic evidence of pulmonary
hypertension where it improves oxygenation and reduces
the need for extracorporeal membrane oxygenation.”3,4 In
addition to its pulmonary vasodilator effect, NO displays
a mild bronchodilator effect5 as well as antithrombotic6-7
and anti-inflammatory effects.8
In adult patients with ARDS, NO reduces pulmonary
artery pressure and improves ventilation-perfusion match-
ing.9-11 Moreover, NO reduces pulmonary vascular resist-
ance in patients with COPD12,13 and chronic pulmonary
hypertension.14,15
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NO is normally produced by healthy endothelium and, in
the presence of intravascular hemolysis, is rapidly inacti-
vated by its reaction with free hemoglobin,16 inducing
systemic and pulmonary vasoconstriction. The potent pul-
monary vasodilator effect of inhaled NO has been demon-
strated to treat the systemic and pulmonary vasocon-
striction induced by free hemoglobin.17 Cardiopulmonary
bypass induces intravascular hemolysis, releasing hemoglo-
bin and subsequently scavenging endogenous NO, leading
to intrarenal vasoconstriction and causing post-cardiac sur-
gery kidney injury. A recent randomized controlled trial
demonstrated that the perioperative administration of NO
reduces the incidence of acute kidney injury in cardiac sur-
gery subjects.18 Furthermore, NO displays a broad antimi-
crobial effect against bacteria,19 fungi,20 and viruses,21
especially if administered at high concentrations (> 100 parts per million [ppm]).22-25 The antimicrobial properties of
high-concentration NO are now being tested in several clini-
cal trials (ClinicalTrials.gov registration NCT02498535,
NCT04685720, NCT04606407, NCT04305457).
The increased spectrum of pathologies treated with NO
gas has urged innovators and industries to find solutions to
produce versatile, inexpensive, and readily available NO
delivery systems for in-hospital, out-patient, and home use.
While offering novel solutions, companies are also focusing
on the safety of delivery systems. The main safety issue of
high-dose inhaled NO delivery is the generation of nitrogen
dioxide (NO2). When NO and oxygen (O2) mix in a gaseous
environment, NO2 is formed spontaneously by the following
reaction: NO þ NO þ O2 ! NO2 þ NO2. The speed of NO2 production has a first-order dependence on O2 concen-
tration and a second-order dependence on NO concentration
with a time constant of 1:1960:11 � 10�11=PPM � s.26 Inhaled NO reacts with water and generates nitric acid
(pH 1.0), causing chemical lesions to the bronchial mu-
cosa. Therefore, to avoid pulmonary injury, the Amer-
ican Conference of Governmental Industrial Hygienists
established a limit of 3 ppm NO2 in an 8-h time weighted av-
erage and 5 ppm as a short-term exposure limit.27 More con-
servatively, the National Institute for Occupational Safety
and Health recommends a short-term exposure limit of 1
ppm.27 It is therefore imperative that any NO delivery system
reduces the delivered NO2 levels below the safety thresholds.
In this review we will describe the systems currently devel-
oped to administer inhaled NO to patients (Table 1).
Nitric Oxide Generators and Delivery Systems
Cylinder-Based Systems
Cylinder-based systems represent the vast majority of com-
mercially available NO delivery systems. (Table 2). Pressurized
cylinders contain various concentrations of NO buffered with
an inert gas (ie, not containing oxygen) such as nitrogen (N2) to
avoid the generation of NO2 within the cylinder.
The N2/NO pressurized cylinder is connected to a flow-
regulated injector that delivers a set NO flow and therefore
the target NO concentration into the inspiratory arm of a re-
spiratory circuit. A central processing unit continuously
measures the gas flow delivered to the patient (ie, from a ven-
tilator) and regulates the NO flow from the pressurized cylin-
der in real time. The targeted NO concentration is obtained
by maintaining the ratio between the NO flow from the pres-
surized cylinder and the total gas flow delivered to the
patient. The NO administration can be continuous throughout
the respiratory cycle or synchronized with ventilation. All
commercially available NO delivery systems are able to con-
tinuously measure NO, NO2, and O2 concentrations through
an electrochemical sensor cell.28 The schema of a cylinder-
based NO delivery system is summarized in Figure 1.
Specific cylinder-based delivery systems that should be
highlighted are the INODD (Novoteris, Garden Grove,
California) and the INOpulse (Bellerophon Therapeutics,
Warren, New Jersey). The INODD is, up to now, the only
commercially available cylinder-based system designed to
deliver high-dose NO (160 ppm) and is currently employed
in a trial testing the safety and efficacy of 160 ppm NO on
multi-resistant bacterial lung infection and in subjects with
coronavirus disease-2019 (COVID-19) (NCT03331445).
The INOpulse is a portable system designed to deliver
NO in an ambulatory/home environment using a 0.16-L
mini-cylinder as the NO source. The INOpulse delivers a
set pulsed volume of NO at the beginning of each breath
via a special nasal cannula connected to the device.
Consequently, the INOpulse delivers a constant dose of NO
over time (expressed in mg/kg/h)12 that is independent of minute ventilation and inspiratory flow. In spontaneously
breathing patients, the administration of a pulsed NO dose
has 2 potential advantages. First, a pulsed NO dose can be
Drs Gianni and Berra are affiliated with the Department of Anaesthesia,
Critical Care and Pain Medicine, Massachusetts General Hospital,
Boston, Massachusetts. Dr Carroll is affiliated with the Department of
Pediatrics, Massachusetts General Hospital, Boston, Massachusetts.
Dr Kacmarek was affiliated with Respiratory Care Department,
Massachusetts General Hospital, Boston, Massachusetts. All authors are
affiliated with Harvard Medical School, Boston, Massachusetts.
Dr Gianni has disclosed no conflicts of interest. Dr Carroll has disclosed
a relationship with Unitaid. Dr Kacmarek had disclosed relationships
with Medtronic, Orange Med, Medtronic, and Venner Medical. Dr Berra
has disclosed relationships with the NIH, iNO Therapeutics, Praxair,
Masimo, and the Mercatus Center of George Mason University.
†Deceased.
Correspondence: Lorenzo Berra MD, Massachusetts General Hospital,
Harvard Medical School, 55 Fruit St, Boston, MA 02141. E-mail:
DOI: 10.4187/respcare.08856
INHALED NITRIC OXIDE DELIVERY SYSTEMS
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precisely delivered using a nasal cannula without the need
for a snug, tight-fitting mask, improving patient comfort in
an ambulatory or home setting. Second, the brief pulse of
NO minimizes the amount of drug dispensed and reduces
the environmental exhaust.29
Clinical trials are ongoing to test the efficacy of pulsed
inhaled NO for the treatment of pulmonary hypertension
associated with interstitial lung disease (NCT02734953),
COPD,12 and sarcoidosis (NCT03727451). A phase 3 clini-
cal trial (NCT02725372) testing the effect of pulsed inhaled
NO in subjects with symptomatic pulmonary arterial hyper-
tension was stopped for futility. Furthermore, there are 2
phase 3 clinical trials under way to test whether the admin-
istration of NO through INOpulse can reduce mortality and
acute respiratory failure in spontaneously breathing sub-
jects with COVID-19 (NCT04421508 and NCT04388683).
Table 2. Technical Characteristics of Cylinder-Based NO Delivery Systems
System What Is Set NO Delivery Concentration Range,
ppm NO Injector Flow Sensor
INOMax (Mallinkrodt) NO concentration Synchronized, continuous 0–80 Reusable Reusable
NOxBOXi (Praxair) NO concentration Synchronized, continuous 0–80 Single use Single use
SoKINOX (Air Liquide) NO concentration Synchronized, continuous 0–80 Single use Single use
AeroNOx 2.0
(International
Biomedical)
NO flow Continuous Depends on NO/N2 cyl-
inder concentration
and set flow
Single use Single use
NO-A (EKU) NO concentration Synchronized, continuous 0–100 Single use Single use
NOXTEC 1000 (ITC) NO concentration Continuous 0–100 Single use Single use
NOx plus (Zysense) NO flow Continuous Depends on NO/N2 cyl-
inder concentration
and set flow
Reusable Reusable
The operator can set the desired NO concentration or the NO flow necessary to achieve it. The NO delivery can be continuous (ie, the system maintains a stable NO concentration throughout the respira-
tory cycle) or synchronized with ventilation (ie, the system delivers an NO flow proportional to the inspiratory flow delivered by the ventilator). All the delivery systems use an electrochemical cell sensor
to measure NO and NO2 concentration.
NO ¼ nitric oxide NO2 ¼ nitrogen dioxide ppm ¼ parts per million
Table 1. Summary of the Available Nitric Oxide Delivery Systems
Manufacturer Product Market Release
Cylinder-based systems
Mallinckrodt INOMax DSIR North America, Europe, Australia
Praxair NOxBOXi North America, Europe
EKU NO-A Europe, Asia
Air Liquide Healthcare SoKINOX North America, Europe, Australia
Ingenierı́a y Técnicas Clı́nicas NOXTEC Europe
Novoteris INODD Research use only (NCT02498535)
International Biomedical Aeronox North America, Europe
Zysense NOx plus North America, Europe, South America
Bellerophon INOpulse Research use only (NCT03267108, NCT04421508, NCT03727451, NCT02652429)
Electric NO systems
Third Pole Therapeutics eNOX-200 Under development
Beyond Air LungFit Research use only (NCT04685720, NCT04397692, NCT04606407)
Chemical-based NO systems
Vero Biotech Genosyl Ds United States of America
Nu-Med plus Clinical Unit Under FDA approval
NO-releasing solutions
SaNOtize NORS Research use only (NCT04163978, NCT04443868, NCT04337918)
Nanoparticle NO technology
NMB Therapeutics NanoNOx Under development
Vast Therapeutics TBD Under development
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Systems that utilize cylinder-based delivery are the more
widely available NO delivery systems, with > 450,000 patients treated worldwide.30 They are safe and reliable and
can deliver a wide range of NO concentrations by simply
changing the flow from the NO cylinder. There are 2 main
disadvantages of cylinder-based delivery systems: (1) pres-
surized gas cylinders require an extensive supply chain, in-
ventory at the hospital, and trained personnel to connect
cylinders to ventilators or noninvasive respiratory systems;
(2) cylinder-based NO therapy is expensive for institutions
themselves,31 with the average charge for providing NO ther-
apy for 5 d to a newborn patient with persistent pulmonary
hypertension being � $14,000.30 These factors greatly reduce the feasibility of NO gas in several settings, such as
referral hospitals, out-patient clinics, in the home, and in
low-resource settings.
Electricity-Generated NO
Electricity-generated NO systems use high-voltage elec-
trical discharges to generate NO from air or another gas
mixture (Fig. 2). The application of an electric potential
between 2 electrodes ionizes air (or other gas mixture),
causing an electron flow from the cathode to the anode.
Gas Inlet
Gas Pump Flow sensor
Ca(OH)� scavenger 0.22-�m filter
Sparking chamber
Gas Outlet
Gas Pump Flow sensor
Ca(OH)� scavenger 0.22-�m filter
Fig. 2. Schema of a nitric oxide electric generator. Ca(OH)2 ¼ calcium hydroxide.
Set NO concentration
CPU Flow sensor
Sensors
NO NO� O�
Ventilator Patient
N O
ta nk
Flow regulator
Fig. 1. Schema of a cylinder-based NO delivery system. NO ¼ nitric oxide; NO2 ¼ nitrogen dioxide; CPU ¼ central processing unit.
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The frequent electron collisions due to the high current
raise the temperature between the 2 electrodes up to 10,000
Kelvin, causing the dissociation of N2 and O2 into a plasma
state and the subsequent generation of NO, NO2, and ozone
(O3). Air flows used are in the range of 0.9–4.5 L/min. The
NO and NO2 production increase with frequency of
the sparking pulse, increase with greater atmospheric pres-
sure, and decrease with increasing air flow.32,33
Because NO electric generators produce both NO and
NO2, it is imperative to minimize the NO2/NO ratio to
achieve more efficient and safer NO production. One of the
main determinants of the NO2/NO ratio is the temperature of
the plasma: the higher the plasma temperature, the lower the
NO2/NO ratio. The plasma temperature is dependent on the
capacitance of the pulse-forming capacitor (increasing with
the increase in capacitance, up to 20nF), and on the current
running through the sparker (plasma temperature increases
from 900 to 1130 K as the current increases from 600 to
1,400 ampere).34 The NO2/NO ratio is also dependent on the
inter-electrode gap: increasing the inter-electrode gap from
1.0 to 7.5 mm decreases the NO2/NO ratio from 0.12 to 0.09.
Namihira et al35 measured how NO production is affected by
variations of O2 + N2 gas mixture using an NO electric gen-
erator with the following settings: 1.5 L/min of total gas flow
and pulse frequency of 3 Hz. The highest NO production
was observed with an FIO2 of 0.26. The NO2/NO ratio was
also found to be dependent on the electrode material, ranging
from 0.13 for tungsten to 0.05 for iridium, across an array of
metals (ie, tungsten > carbon > nickel > iridium). To administer pure NO, it is critical to remove the
byproducts such as NO2, ozone (O3), and brass particles
emitted by the electrode during arc discharges. Because
NO2 is continuously produced whenever oxygen and NO
are mixed, a system that removes NO2 from the outlet of
the NO generator is always necessary, and 2 mechanisms
can be used: the catalytic conversion of NO2 into NO, and
the selective adsorption of NO2.
There are 4 primary methods to convert NO2 into NO.
One method is to use a molybdenum wire33,36 or a mol-
ybdenum powder filter that can convert NO2 into NO
when heated to � 870 Kelvin through the reaction 3NO2 þ Mo ! 3NO þ MoO3, Namihira et al33 reported a decrease of NO2 concentration from 138 ppm to 48
ppm accompanied by an increase of NO concentration
from 455 ppm to 540 ppm when employing this reaction.
Another method utilizes ascorbic acid loaded on silica
gel pellets (see Chemical NO Generators). A third
method is to have barium oxide (BaO) react with NO2,
producing NO according to the following reaction:
3NO2 þ BaO ! BaðNO3Þ2 þ NO. The fourth method involves calcium hydroxide (Ca(OH)2), which is capable
of selectively reacting with NO2 though the following
reaction37: CaðOHÞ2 þ NO2 þ NO ! CaðNO2Þ2 þ H2O. Yu et al38 reported a reduction of NO2 levels between
70% and 90% using a scavenger containing Ca(OH)2,
when using both in-line and offline electric plasma
generators.
An electrical discharge can also produce ozone (O3) as a
potential toxic by-product. O3 can be detected in the output
arm of the generator and ranges from 10 ppm32 to 18 parts
per billion (ppb).38 The U.S. Environmental Protection
Agency dictates that O3 levels must be kept below 0.07
ppm (70 ppb). O3 is removed (< 0.1 ppb) by bubbling the gas through water32 or by using a Ca(OH)2 filter.
38
Brass and platinum nanoparticles can be generated from
the etching of the electrode material during electric dis-
charges and may be present in the unfiltered gas. A high-ef-
ficiency particulate (HEPA) air filter can remove the metal
particles from the NO generated by electrical discharge.39
The generation of NO from air using pulsed electrical
discharges is a growing field of research, and a handful of
companies are building NO generators and delivery sys-
tems using this technology. The FDA approval process for
these devices is ongoing. The opportunity to generate NO
from air without the need for expensive and bulky gas cyl-
inders is promising and could make NO widely available in
underrepresented regions, both domestically and abroad.
Electric NO generators, when compared to cylinder-
based delivery systems, have 2 potential limitations: NO
production and safety. Because the NO production
decreases when the air flowing through the sparker
increases, the NO generated may not be sufficient to main-
tain the desired NO concentration (eg, in the setting of a
patient receiving NO through a mechanical ventilator deliv-
ering high minute ventilation). Another limitation of the
electric NO generators is the higher risk of safety issues
compared to cylinder-based delivery systems. In case of a
system malfunction (ie, damage to the HEPA filter or to the
Ca(OH)2 scavenger), the device may deliver unmeasured
toxic products such as metal brass particles or ozone (O3).
Chemical NO Generator
In 2011 Lovich et al40 described the generation of NO
from the reduction of NO2 using ascorbic acid. The authors
developed a cartridge composed of a thermoplastic struc-
ture wherein powdered ascorbic acid and silica gel are
adhered to the inside of a solid tube. The pores in the silica
gel provide a matrix in which ascorbic acid and NO2 react
at high efficiency. NO2 flows through the inlet of this car-
tridge and is directed to the tube margins, where it per-
meates radially through the wall of a tube of ascorbic
acid/silica gel particles imbedded in the thermoplastic
structure, ultimately yielding NO. The authors reported the
complete conversion of NO2 (80 ppm) into NO with an out-
put NO2 concentration < 1 ppm (0.6–0.8 ppm using 1 car- tridge with FIO2 of 1.0).
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In a subsequent manuscript, Lovich et al41 described an
NO generator and delivery system based on this concept.
NO generation follows a 2-step process: the first step is the
generation of NO2 from the vaporization of liquid dinitro-
gen tetroxide (N2O4), and the second step is the conversion
of NO2 to NO using the previously described ascorbic acid
cartridge (Fig. 3).
Liquid N2O4 is contained in a 2-mL evaporation chamber;
the walls of this chamber are stainless steel and transmits
heat to the contained liquid N2O4 to promote the formation
of gaseous NO2. Then the NO2 flows through a capillary
tube of defined cross-sectional area and length and is mixed
with air or nitrogen before entering the reactor cartridge and
being converted to purified NO. Consequently, NO produc-
tion is regulated only by the evaporation chamber tempera-
ture and by cross-sectional area and length of the capillary
tube linking the N2O4 reservoir to the manifold. For a fixed
resistance and for a fixed carrier stream flow, the pressure
and the generated NO2 concentration are directly propor-
tional. The authors reported that the natural logarithm of the
NO2 concentration in the carrier stream is linearly related to
the inverse of the temperature.
At the time of this writing, the only FDA-approved NO
delivery system that uses this technology is the Genosyl DS
(Vero Biotech, Atlanta, Georgia).42 This system can deliver
NO at a concentration of 20 ppm with NO2 concentration
< 2 ppm. The main advantage of this device is the reduced device size and weight compared to cylinder-based delivery
systems. Despite being more portable, the Genosyl DS
shares the same drawback of the cylinder-based delivery
systems: the need for an extensive production and supply
chain to allow widespread use.
NO-Releasing Solutions
NO-releasing solutions are liquid solutions that, when
exposed to specific conditions, can produce and release
NO. Stenzler et al43 patented the use of a solution composed
of an NO-releasing compound (such as sodium nitrite) and
a water- or saline-based solution. The production and
release of NO is dependent on the pH of the solution: if the
pH is > 4, the production of NO is negligible; with pH val- ues < 4, the production of NO increases in a pH-dependent manner. Consequently, the solution is kept in a “dormant”
state at a pH > 4, which allows it to be easily prepared, stored, and transported without losing any appreciable
amount of NO gas. Then, for administration, the solution is
activated by adding citric acid monohydrate, driving the
pH < 4.44 Interestingly, the NO produced (generating NO2 that, reacting with the aqueous solution produced nitric
acid) keeps the pH of the solution < 4, auto-maintaining the NO release.
The NO production from the described NO-releasing so-
lution is dependent on the concentration of sodium nitrite
(NaNO2) and on the pH of the solution. The authors
described an NO production of up to 300 ppm (in the pres-
ence of a continuous air flow of 3 L/min) from 64 mL of a
60 mM NaNO2 solution.
The target clinical use of this technique is the use of
high-dose NO to treat topical infections (eg, bacteria,
fungi, and viruses). In addition, phase 1 and phase 2 trials
are ongoing to test the efficacy of intranasal administra-
tion of a NO-releasing solution for the treatment of
COVID-19 (NCT04337918) and chronic bacterial sinusi-
tis (NCT04163978).
Set a NO concentration
Heated water bath
N�O�
NO� NO
Sensors
NO NO� O�
Patient
Ascorbic acid cartridge
CPU
Fig. 3. Schema of the Genosyl DS NO generator and delivery system. NO ¼ nitric oxide; NO2 ¼ nitrogen dioxide; N2O4 ¼ dinitrogen tetroxide; CPU ¼ central processing unit.
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NO-Releasing Nanoparticles
A NO-releasing nanoparticle consists of a small particle
(measured in nanometers) that contains either NO or an
inactive NO precursor in a stable form that, when applied
to the target tissue, releases NO in a controlled manner.
Friedman et al45 reported that NO can be efficiently gener-
ated by the conversion of nitrites enclosed in a solid matrix
(derived from trehalose glass or hydrogel/glass composite).
The nitrites are stable in dry form, and NO is released from
the solid matrix when exposed to moisture. The pattern of
NO released from the nanoparticle is dependent on the
composition of the matrix: a glassy matrix releases NO
more rapidly than does a hydrogel/glass matrix.
Like the NO-releasing solutions described above, NO-
releasing nanoparticles have been used to topically admin-
ister antimicrobial doses of NO (eg, treatment of cutaneous
bacterial or mycotic infection). Furthermore, the nanopar-
ticles, due to their small diameter, could potentially be
delivered through an aerosol directly into the lung.46
Further preclinical and clinical trials are needed to address
the safety and the efficacy of this new NO delivery system.
Summary
NO gas is used worldwide for the treatment of neonates
with hypoxic respiratory failure and pulmonary hyperten-
sion. The growing interest in administering high-dose NO
for its antimicrobial effect19-21 poses a major challenge to
the available NO generation and delivery systems both in
terms of cost and safety. In recent years, an effort has been
made, both by researchers and biomedical and pharmaceu-
tical companies, to create NO delivery systems that are
more portable and easier to use. These technological
advancements will allow the use of gaseous NO outside the
hospital (ie, for patients with COPD or primary pulmonary
hypertension). Furthermore, the newly designed NO gener-
ators, by reducing NO production and storage costs, will
make NO administration feasible in low-resource settings.
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