Conference Proceedings: Inhaled Nitric Oxide: Delivery Systems and Monitoring

Conference Proceedings
Inhaled Nitric Oxide: Delivery Systems and Monitoring

Richard D Branson RRT, Dean R Hess PhD RRT FAARC, Robert S Campbell RRT,
Jay A Johannigman MD
Introduction
Manufacture and Storage of Nitric Oxide
Production Of NO2
Use of Absorbers/Scrubbers to Reduce NO2
Effect on FIO2
Environmental Contamination with NO/NO2 and Scavenging
Ideal NO Delivery System
Delivery Systems for Adult Mechanical Ventilators
Continuous Injection into the Inspiratory Limb (ci)
Inspiratory Phase Injection into The Inspiratory Limb (ii)
Continuous Injection into the Y-Piece (cy)
Inspiratory Phase Injection into the Y-Piece (iy)
Tracheal Injection
Premixing System (pre)
Delivery Systems for Pediatric Mechanical Ventilation
Delivery Systems for Manual Ventilators
NO Delivery with Anesthesia Ventilators
Commercial Systems for Mechanical Ventilation
I-NOvent Delivery System
NOdomo
Servo 300
Pulmonox
Delivery Systems for Spontaneous Breathing
Monitoring NO and NO2
Electrochemical Analyzers
Chemiluminescence Analyzers
Summary
[Respir Care 1999;44(3):281306] Key words: nitric oxide, NO, nitrogen dioxide, electrochemical analyzer, chemiluminescence analyzer.
Introduction
Excitement over the potential clinical applications of
inhaled nitric oxide (INO) has frequently been tempered
Richard D Branson RRT, Robert S Campbell RRT, and Jay A Johannigman MD are affiliated with the Division of Trauma and Critical Care,
Department of Surgery, University of Cincinnati, Cincinnati, Ohio. Dean
R Hess PhD RRT FAARC is affiliated with Respiratory Care Services,
Department of Anaesthesia and Critical Care, Massachusetts General
Hospital, Harvard Medical School, Boston, Massachusetts.
Correspondence: Richard D Branson RRT, Department of Surgery, University of Cincinnati, 231 Bethesda Avenue, Cincinnati, OH, 452670558. E-mail: Richard.Branson@UC.edu.
RESPIRATORY CARE MARCH 1999 VOL 44 NO 3
by the difficulties in safe and accurate INO delivery. Early

application of INO was, by necessity, accomplished using
various nonstandardized (home made) devices. NO delivery was further complicated by attempts to utilize industrial NO and nitrogen dioxide (NO2) monitors within
the bidirectional, nonconstant gas flow of a warm, humid
ventilator circuit. Techniques to safely administer NO, limit
NO2 production, monitor both NO and NO2, and prevent
environmental contamination will be required before INO
can become a routine therapy. This paper will review preparation of NO cylinders, techniques for delivery of INO,
monitoring of NO and NO2, and environmental contamination with NO and NO2.
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INHALED NITRIC OXIDE: DELIVERY SYSTEMS

Manufacture and Storage of Nitric Oxide
Nitric oxide is one of the higher oxides of nitrogen and
until recently was regarded as a common atmospheric pollutant resulting predominately from automobile exhaust.1 6
NO is typically present in the atmosphere at concentrations of 10 100 parts per billion (ppb) and in cigarette
smoke at 400-1000 parts per million (ppm). The molecular
weight and density of NO are less than oxygen or nitrous
oxide (N2O), but greater than nitrogen.
Until recently, the most noteworthy medical interest in
NO was as a lethal contaminant of nitrous oxide cylinders.710 In 1967, Clutton-Brock described the death of 2
patients and the poisoning of a third, attributable to NO
contamination of N2O cylinders used during anesthesia.9
Acute methemoglobinemia occurred in all 3 patients, with
the development of respiratory failure resulting in the 2
deaths. NO contamination had occurred during the manufacture of N2O.
Nitric oxide is a small, diatomic, free radical that is
unstable in the ambient atmosphere. Nitric oxide is highly
soluble in lipid, reacts rapidly with oxygen (O2) to form
NO2, and is potentially toxic.13,6 10 In fact, one of the
challenges of NO manufacture and delivery is the minimization of NO2 production. NO2 is toxic at much lower
levels than NO. The Occupational Safety and Health Administration (OSHA) has set exposure limits for NO in the
workplace at 25 ppm time-weighted average for 8 hours.
OSHA exposure limits for NO2 are 5 ppm.3 The LC50 (the
concentration that causes death in 50% of laboratory animals) for NO and NO2 has been rated at 115 ppm for pure
gas (ie, 100% NO or NO2).4 However, the LC50 of an
NO/N2 gas mixture is considerably greater than 115 ppm.
For example,11 the LC50 of a 800 ppm NO/N2 gas cylinder
is:11
LC50 5 115 ppm/800 ppm 3 1,000,000 5 143,750 ppm
The production of medical grade NO poses a number of
challenges. NO had been manufactured in industrial grades
for use in welding and in the semiconductor industry for
years prior to the first medical application. NO can be
produced by reacting sulfur dioxide with nitric acid, by
reacting sodium nitrite and sulfuric acid, or by oxidation
of ammonia over a platinum catalyst at high temperatures
(. 500 C).1113 NO is then mixed with a carrier gas
(usually N2) to produce the desired NO concentration with
a minimum purity of 99%. The carrier gas could be any
inert gas, including helium. Helium/NO mixtures might
have certain advantages, but would be considerably more
expensive than NO/N2 mixtures. The final concentrations
of cylinder gases (NO and NO2) are measured by chemiluminescence analysis. The NO2 concentration in the cylinder should be , 2% of the NO concentration.
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Cylinders for NO are constructed of an aluminum alloy.

Good Manufacturing Practice standards require that medical grade cylinders undergo special preparation to maintain a precise concentration. Cylinder processing involves
multiple purgings of the interior of the cylinder with nitrogen, followed by evacuation to a minimum of 50 microns residual pressure while the cylinder is heated. Heating aids in the drying process. The presence of water and
NO can lead to the production of nitric acid, which could
damage cylinder walls. Cylinders are then filled with the
desired NO concentration and rolled at room temperature
to prevent stratification. Cylinders of NO are stable for 2
years or longer.
During early applications of INO therapy, cylinders of
400 to 2200 ppm NO were commonly provided by gas
manufacturers. Following some trial and error, it appears
that medical grade NO cylinders will contain 800 ppm.
Cylinder NO concentration would appear a rather unimportant issue, but a number of issues are at play in the
decision. The optimal concentration of NO in the cylinder
balances safety, effectiveness, and cost. Other papers in
this issue will suggest that the therapeutic range of INO is
1 80 ppm, depending of the desired effect. As such, it is
important that NO cylinders allow delivery of this range of
concentrations without causing a significant decrease in
the inspired oxygen concentration (fraction of inspired oxygen [FIO2]) or increase of the tidal volume (VT).
Lower cylinder concentrations are required for accurate
delivery of low doses of INO. Lower cylinder concentrations allow greater precision because it is easier to measure and maintain higher flows precisely, and source gas
of lower concentration requires a higher flow to achieve
the desired NO concentration. However, if high concentrations are required when using low cylinder concentrations, greater NO flow is necessary, which decreases FIO2
and increases VT. Higher source gas concentration allows
administration of a higher FIO2, because less flow from the
source tank is required to achieve the desired NO concentration. In the range described, an NO dose of 80 ppm can
be delivered at an FIO2 of 0.90. Higher cylinder concentrations of NO require less frequent cylinder changes and
might reduce the cost of INO treatment compared with
cylinders of low NO concentration. However, a higher
cylinder concentration increases the likelihood of injury to
the patient due to inadvertent dosing errors (excessive NO
delivery) and injury to personnel due to system leaks.
For institutions with a valid U.S. Food and Drug Administration (FDA) Investigational New Drug number, cylinders of NO produced in compliance with FDA pharmaceutical code of Good Manufacturing Practice are now
provided in 19 L water capacity cylinders containing 1963
L of gas at 2000 psig. These cylinders contain either 100
or 800 ppm of NO in a balance of nitrogen. For transport,
D cylinders of 100 or 800 ppm are also available. The

Table 1.
Characteristics of a Storage Room for Nitric Oxide

Cylinders
Well ventilated to prevent accumulation of NO . 25 parts per

million and reduction of oxygen concentration ,18%
A means of securing cylinders
Temperature conditions below 120 F
A means of securing the area to avoid unauthorized use
Cylinders should be transported secured to a cart designed for
moving cylinders
Cylinders should not be transported without a protective cap
Full and empty cylinders should be segregated
NO 5 nitric oxide. (From Reference 11, with permission.)
Compressed Gas Association (CGA) 626 valve outlet has

been specifically designated for medical applications of
INO to prevent inadvertent connection with another cylinder gas.
Storage and transport standards for NO/N2 cylinders are
governed under CGA standards for any medical gas cylinder (Table 1). NO/N2 mixtures do not support combustion and are not flammable. Because the gas is oxygen-free
(to prevent the production of NO2), NO/N2 mixtures are
classified as asphyxiating. Accidental cylinder evacuation
into a closed space (closet or storage room) poses the risk
of hypoxic breathing conditions because of the reduction
in ambient oxygen concentration. Gas storage rooms for
NO/N2 cylinders must be well ventilated to maintain an
FIO2 . 0.18 in the case of a cylinder leak.
Materials compatible with NO include Teflon, silicone,
nickel, aluminum, and stainless steel. Cylinder pressure
regulators for NO are constructed from stainless steel. In
our experience, plastic oxygen delivery tubing and rubber
high-pressure hoses have not shown signs of deterioration
when exposed to clinically relevant NO concentrations.
When a cylinder regulator is attached to the NO/N2 cylinder, oxygen in the regulator mixes with NO, creating
NO2. Between uses, NO2 may also accumulate in the regulator. Prior to connection to a high pressure hose, the
regulator should be adequately purged. This can be accomplished by cracking the cylinder, as is often done to
remove dust and debris of cylinder outlets.
One concern with NO delivery through humidified systems is the production of nitric acid:
2 NO 1 O2 3 2 NO2
2 NO2 1 H2O 3 2 HNO3 1 NO
We are unaware of damage to any respiratory care equipment due from exposure to NO, NO2, or HNO3, although
this has been suggested as a possibility.13 Krebs et al measured the nitrate/nitrite content of water from humidifiers
used in ventilator circuits following 12 hours of NO delivery. They reported that the level of nitrates/nitrites was
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MONITORING
higher than the amount permitted for drinking water.14

However, they did not provide the measured concentrations. Westfelt et al measured the pH of deionized water
washed through hygroscopic heat and moisture exchangers following NO delivery, and found no evidence of acid
accumulation.15 This methodology may be suspect, because the media of these devices are treated by a salt
(lithium or calcium chloride).
At least one group has described the delivery of NO to
the intensive care unit (ICU) via a pipeline system, similar
to that used for air and oxygen. Whiteley et al used a
conventional gas supply system to provide NO to an 18bed unit.16 The authors suggest that the pipeline may prevent complications secondary to exhaustion of cylinders,
such as rebound pulmonary hypertension and hypoxemia.
Whiteley et al report no adverse events or problems with
NO2 production in the pipeline system.
Pinsky et al have described the inadvertent delivery of
NO at therapeutic doses through a hospitals air system.17
These authors measured the NO level in the hospitals
compressed air system over a period of days, and found
that NO levels varied with ambient air levels (which should
be expected) and exceeded 1 ppm at one institution. They
also reported extremely high levels (5 6.5 ppm) over a
period of 5 days, associated with welding near the air
intake of the compressed gas system. To our knowledge,
these results have not been reproduced at other institutions.
Production of NO2
From a safety standpoint the most important consideration for NO delivery systems is the production of NO2.
NO2 is produced spontaneously from the reaction of NO
and O2.510,16,1725 Although OSHA has set safety limits
for NO2 at 5 ppm,3 reports of airway reactivity20,26 29 and
parenchymal lung injury25,30 have been reported with inspired NO2 concentrations of # 2 ppm. Based on this
information, NO delivery systems should maintain NO2
levels as low as possible, with , 1 ppm appearing to be an
obtainable goal.22 Because NO2 is an atmospheric pollutant, its toxic pulmonary effects have been investigated in
many studies.31 Animal studies evaluating the parenchymal effects of high levels of NO2 (. 10 ppm) have reported pulmonary edema, hemorrhage, changes in surface
tension properties of surfactant, reduction in number of
alveoli, and death.10,3234 Other studies have shown that
NO2 at concentrations as low as 2 ppm produced alveolar
cell hyperplasia, altered surfactant hysteresis, changes in
the epithelium of the terminal bronchiole, and loss of cilia.6,25 In humans, 2.3 ppm NO2 was shown to affect alveolar permeability.35 Several studies have reported increased
airway responsiveness to NO2 at # 2 ppm.25,36,37 NO2 may
remain in the lungs for prolonged periods because it reacts
with water to produce nitric acid and undergoes irrevers-
283

ible reactive absorption by the pulmonary epithelial lining
fluid.38 Exhaled NO2 therefore may not be a sensitive
indicator of toxic pulmonary levels. Although antioxidants
present in the lung fluids protect normal individuals from
the effects of breathing 2 ppm NO2,7 we keep the NO2 as
low as possible, because its effects in an injured lung (eg,
acute respiratory distress syndrome [ARDS]) are unknown.
The extent of conversion of NO to NO2 is determined
by the residence time of NO with O2 and is accelerated by
increased NO concentration and high FIO2.5,8,18,19,22,23,31
The conversion rate of NO to NO2 is determined by the O2
concentration, the square of the NO concentration, and the
residence time of NO with O2. The kinetics of this relationship are described in the following equation:20,22
d[NO]/dt 5 k z [O2] z [NO]2
where [NO] is the NO concentration, [O2] is the oxygen
concentration, and t is time. Because [O2] is typically much
greater than [NO], it is assumed that [O2] remains constant. It is also assumed that all of the conversion of NO is
to NO2. Integration of the latter equation yields:
1/[NOt] - 1/[NO0] 5 k z [O2] z t
where [NOt] is the NO concentration after a residence time
t, [NO0] is the initial NO concentration, [O2] is the O2
concentration, and k is the rate constant for conversion of
NO. The difference between [NOt] and [NO0] is the [NO2].
In 1963 Glasson and Tuesday reported the value of k as
1.573 10-9 ppm-2min-1 at 23 C and one atmosphere.20
This rate constant was determined under static dry conditions, however, which might differ from dynamic systems
such as adult mechanical ventilation. Nishimura found a
rate constant of 1.463 10-9 ppm-2min-1 when NO was
blended with N2 before entering the ventilator (Fig. 1), and
that it increased eight-fold, to 1.173 10-8 ppm-2min-1, when
NO was blended with air before introduction into the ventilator.22 Aida et al28 found that the rate constant was smaller
at 37 C than at 25 C, but that it was not affected by
humidity. At clinically relevant doses (# 20 ppm), the
production of NO2 in breathing systems becomes considerably less problematic (see Fig. 1).
In breathing systems, NO2 concentration is greater with
increased NO concentration, higher FIO2, or lower minute
E.18,19,22,23 The NO2 delivered to the patient is
ventilation V
also greater for ventilators with a higher internal volume
(eg, Siemens Servo 900C) than those with a lower internal
volume (eg, Puritan Bennett 7200ae), because the higher
internal volume increases the residence time between NO
and O2.22,39 41
Losa et al found NO2 concentrations of up to 3.5 ppm at
a minute ventilation of 5.0 L/min, FIO2 of 0.37, and NO of
50 ppm using the Servo 900C.39 These authors suggested
that when using the low pressure gas inlet of the Servo
900C, the factors effecting NO2 concentrations include
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NO, FIO2, minute volume, and total gas flow into the machine relative to minute volume. These findings support
the work of Nishimura et al,22 as the minute volume and
total gas flow conspire to alter the residence time. As
minute volume falls, gas in the inspiratory reservoir of the
Servo 900C, at the desired working pressure (40 70 cm
H2O), produces NO2 quickly with increasing NO and FIO2
concentrations.
Limiting NO2 production should be paramount in the
design of any NO delivery system. Previous work suggests
that limiting residence time and using the lowest effective
NO dose are 2 simple techniques toward achieving this
goal. When high FIO2 and high NO concentrations are
required, mixing NO with N2, as opposed to compressed
air, can also be useful when delivering gases prior to the
ventilator.22
Use of Absorbers/Scrubbers to Reduce NO2
Numerous investigators have used carbon dioxide (CO2)
absorbers to scrub NO2 from the inspiratory limb of the
ventilator circuit.8,15,26,42 47 These investigations are difficult to compare because of the differences in experimental
protocols and types of absorbents. Absorbents commonly
used in anesthesia for CO2 removal vary in volume and
use materials including calcium dihydroxide, sodium hydroxide, potassium hydroxide, potassium permanganate,
and other color indicators. The components of these materials should be recorded by investigators to allow comparisons.
Stenqvist et al42 evaluated the effectiveness of soda lime
to absorb NO2, and reported that 3 ppm NO2 decreased to
less than 1 ppm after passing through the absorber. These
authors also found that the NO2 absorbing properties of
soda lime lasted approximately 72 hours. Westfelt et al
found that a soda lime absorber reduced mean NO2 values
from 4.7 ppm to 1.8 ppm.15
Weiman et al43 compared 3 kinds of absorbers, and
found NO2 absorption rates of 15% for Sodasorb, 24% for
Dragersorb, and 34% for Sofnolime. The material with the
highest potassium hydroxide (KOH) content had the greatest absorption properties. These investigators also tested 2
special preparations with KOH levels of 3.0% weight per
weight and 7.3% weight per weight. They found that NO2
removal rates increased to 44% and 47%, respectively.
The presence of excess KOH may lead to caking of the
absorbent when humidified gases are used. In fact, it has
been reported that humidification reduces NO2 absorption
by soda lime,43 but this may be due to an increase in NO2
production because of the added dead space and residence
time created by the humidification chamber. Ishibe et al
suggested that soda lime (Sodasorb and Wako lime-A)
was capable of completely eliminating NO2 concentration
up to 40 ppm from the inspiratory limb.44 They also found
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MONITORING
Fig. 1. Time required to generate 2 ppm NO2 using rate constant published by Nishimura et al.22 Top. NO concentrations up to 80 ppm.
Note that at a high NO concentration very little time is required to generate significant NO2. Bottom: NO concentrations in the clinically
relevant range up to 20 ppm. Note that when the NO concentration is less than 10 ppm a relatively long time is required to generate
significant NO2 concentrations. (From Reference 22, with permission.)
equimolecular reductions in NO, but only in the presence

of NO2. That is, if NO2 was reduced by 4 ppm, then NO
would also be reduced by 4 ppm. Ishibe et al concluded
that soda lime is effective in eliminating NO2, but that NO
monitoring should be performed downstream from the absorber to account for the NO absorption.
The absorption to NO and NO2 by soda lime may require the combination of KOH, calcium hydroxide (CaOH),
and sodium hydroxide (NaOH). The chemical reaction proposed by Weimann et al43 is:
4NO 1 4NO2 1 4NaOH 1 2Ca(OH) 1 4 KOH 3
2NaNO2 1 2NaNOs 1 Ca(NO3) 2 1 2KNO2 1 2KNO3
1 4H2O
The use of a soda lime canister in the inspiratory limb
does pose several potential problems during mechanical
ventilation. These include increased resistance of the breathing circuit, increased risk of system leaks (because of more
connection sites), increased circuit compressible volume,

more difficulty triggering the ventilator, and alteration of
inspiratory flow waveforms. Charcoal can be used to absorb NO2, but it also absorbs significant amounts of NO.42,48
Table 2 compares the data on use of absorbers to reduce
NO2 concentrations in the ventilator circuit.49
Effect on FIO2
Introduction into the ventilator circuit of any gas that is
void of oxygen will diminish the FIO2. This is true of NO,
as well as other therapeutic gases such as helium. The
reduction in FIO2 is a function of the NO dose delivered to
the patient and the NO concentration of the source gas. For
example, if the patient dose is 5 ppm and the source gas is
800 ppm, then the FIO2 will be reduced by about 0.5%.11
Similarly, systems that add NO distal to the ventilator
outlet will increase the VT by about 0.5% (for volume
285

Table 2.
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Comparison of Nitrogen Dioxide and Nitric Oxide Absorption Properties of Different Materials from Published Studies
Absorber Product
(Reference #)
Sofnol B.P.8
Q-Sorb42
Q-Sorb42
Q-Sorb42
Q-Sorb42
Sofnolime45
Sofnolime45
Sofnolime50
Soda lime51
Sofnolime51
Sofnolime51
Intersorb51
Soda Sorb44,52
Soda Sorb44,52
Wako-Lime A44
Wako-Lime A44
Charcoal Filter 63353
Soda lime54
Soda lime54
Soda lime54
Q-Sorb15
Charcoal15
Charcoal 1 Permasorb48
Ca-A zeolite46
Sofnolime46
Sofnolime46
ABEK HgCONO-P347
Charcoal47
DragerSorb47
Concentration (in parts

per million)
Absorption
percentage
NO
NO2
NO
12%
40
20
40
NS
40
40
40
80
47
42
4043
35
10
35
10
80
60
60
60
100
100
120
70
70
70
5570
86
86
12%
0.8
0.5
0.5
35
,1
,1
,1
NS
33.5
3
3.1
4.1
31
6.1
30
10
2.8
2.8
2.8
4.7
4.7
NS
5
5
5
912
17.6
17.6
NS
NS
15
NS
NS
80
4
1
18
100
13
8
12
97
21
90
. 99
. 95
135
135
7
41
100
. 98
. 90
10
99
0
0
FIO2
Indicator
Duration of
Exposure
NS
0.5
1.0
0.5
NS
0.78
0.78
0.78
0.85
0.7
0.7
0.7
0.02
0.02
0.02
0.02
NS
0.8
0.8
0.8
0.9
0.9
0.86
NS
NS
NS
1.0
1.0
1.0
Green-Brown
White-Violet
White-Violet
White-Violet
White-Violet
Green-Brown
Pink-White
White-Violet
White-Violet
Green-Brown
Pink-White
White-Violet
White-Violet
White-Violet
White-Violet
White-Violet
NA
Green-Brown
Pink-White
White-Violet
White-Violet
NA
NA
NA
Green-Brown
Green-Brown
NA
NA
Pink-White
3 min
NS
NS
NS
NS
20 min
20 min
20 min
NS
30 min
30 min
30 min
20 min
20 min
20 min
20 min
NS
NS
NS
NS
72 hrs
72 hrs
12 hrs
24 hrs
1 hr
24 hrs
170 hrs
NS
1015 min
NO2
NS
87.5
100
100
98.6
80
3
0
100
100
84
100
100
100
100
100
. 99
100
. 60
. 60
62
77
100
. 98
. 90
50
95
0
17
FIO2 5 fraction of inspired oxygen; NS 5 not specified; NA 5 not applicable. (Modified from Reference 49, with permission.)
ventilation) at this dose and source gas concentration. At a

dose of 20 ppm with a source gas of 800 ppm, the FIO2 will
be reduced by 2.5%, so the highest possible FIO2 will be
0.975.11 All NO delivery systems will result in a some
reduction in FIO2, but the clinical consequences of these
slight reductions in FIO2 are usually insignificant unless a
very high NO dose is used with a low concentration source
gas cylinder.
From a practical standpoint, when delivering INO
through a mechanical ventilator, the respiratory care practitioner must decide how FIO2 will be set and recorded. If
FIO2 is set to 0.6 and the addition of INO reduces FIO2 to
0.57, the clinician can record the measured FIO2, record the
set FIO2, or increase set FIO2 until measured FIO2 reaches
the ordered value. We believe these changes in inspired
oxygen are insignificant with a good INO delivery device
and low NO dose, but these practical issues need to be
addressed to assure uniform practice.
286
Environmental Contamination with

NO/NO2 and Scavenging
There are concerns regarding contamination of the environment with NO and NO2, and the potential for adverse
effects on health care providers. The OSHA exposure limits for NO (a time-weighted average of 25 ppm for 8 h in
the workplace) is higher than the typical INO dose for
ARDS (# 20 ppm). There are several reports investigating
the presence of NO/NO2 in the ICU.14,16,17,50 55
Krebs et al measured NO and NO2 levels during NO
delivery using the Drager and Siemens delivery systems.14
They positioned a funnel-shaped connector at positions 10
cm, 20 cm, and 50 cm from the ventilator exhalation valve,
as well as 20 cm lateral to the patients head. Monitoring
was accomplished using a chemiluminescence analyzer
for a minimum of 16 hours. They found that mean NO
concentrations were , 50 ppb and peak concentrations

Table 3.
Calculation of Ambient NO Levels
Room volume in cubic feet 3 air exchanges per hour 3 concentration of NO in

tank 3 flow rate 5 ambient NO concentration. Example:
10 ft 3 12 ft 3 8 ft
5 960 ft3
5 5,760 ft3/h
3 NO concentration
800 ppm NO (0.08%)
5 (163,123 L/h)
3 Flow rate
250 L/h
5 Ambient concentration
0.00012%, or about 1 ppm
Room dimensions
3 Air exchanges per hour
Note that the ambient concentration will be very low for the NO doses typically
used clinically (ie, # 20 ppm). NO 5 nitric oxide; ppm 5 parts per million.
(From Reference 11, with permission.)
were , 100 ppb. They noted that when continuous flow of

INO was added to the inspiratory limb, ambient NO levels
were higher than the ventilator systems using phased inspiratory injection.
Mourgeon et al monitored NO and NO2 levels in an ICU
in Paris and compared those values with those measured
near a Paris traffic circle.55 They also observed weather
conditions (eg, cloud cover) and recorded the days during
which NO was and was not used in the ICU. They found
that the ambient NO and NO2 levels in that ICU were
entirely dependent on outdoor concentrations.55
Most modern ICU environments require a certain number of room air exchanges per hour for climate and infection control, as well as patient comfort. If room air exchanges are maintained at . 6 per hour, ambient NO
levels should remain very low. Table 3 provides a method
for estimating NO concentrations in the environment based
on certain known variables. It has been our experience that
ambient NO levels are very low (, 0.25 ppm) during INO
administration, with or without scavenging. Figure 2 depicts room NO and NO2 concentrations one hour following release of 100 ppm of NO into a room at 8 L/min.11
This example represents a worse case scenario, yet both
gases remain at levels , 150 ppb.
If scavenging is used, it is important that it is constructed so that it does not affect expiratory resistance or
the function of the ventilator. It should be recognized that
scavenging gases from the expiratory port of the ventilator
does not completely eliminate ambient contamination, because the ventilator may leak gas (containing NO) internally as part of normal function. Scavenging is typically
accomplished by connecting a volume of aerosol tubing to
the exhalation valve exhaust port and aspirating gases into
the hospital vacuum system. In this situation, the tubing
acts like a reservoir to collect expired gases during phasic
exhalation. We would caution that use of reservoir bags in
the scavenging system can be dangerous. Humidity can
collect in closed systems, increasing expiratory resistance,
or, if suction flow exceeds expiratory flow, negative pressure can be applied to the exhalation valve. In unusual
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situations, when expiratory gases must be scavenged, expired gas can be scrubbed from the gas stream. This is
accomplished by directing gases through a canister of potassium permanganate (Purafil) and charcoal to remove
both NO and NO2.48
Ideal NO Delivery System
Early INO delivery systems were constructed from available equipment and used in a number of investigational
protocols involving patients and experimental animals (Fig.
3). Some of these homemade systems have functioned
well and others may pose hazards due to unstable and
unpredictable NO delivery and NO2 production. Several
problems can complicate NO delivery if not recognized by
the system architects. Mixing of gas in the inspiratory limb
can be incomplete and NO concentrations greater than the
calculated dose can be administered. Streaming of NO in
the inspiratory limb can occur because NOs density and
viscosity are different than the other inspired gases. The
calculated NO concentration may also vary with changes
in mode of ventilation, inspiratory flow pattern, minute
ventilation, or FIO2. Mode of ventilation is particularly a
problem in intermittent mandatory ventilation and pressure support, because VT and flows change dramatically
from breath to breath. Volume control breaths with a constant flow allow for fairly steady concentrations of INO.
However, pressure control breaths or volume control
breaths with a descending flow waveform present a much
more difficult task. The slow-response NO analyzers that
are typically used clinically make it impossible to detect
changes in NO concentration during the ventilatory cycle.
Because investigators have used different delivery systems
and analysis methods, it is difficult to determine the actual
dose administered to the patient in many instances. This
makes interpretation of dose-response studies arduous. To
avoid complications due to inaccurate dosing, NO delivery
systems should provide a precise concentration regardless
of ventilator mode, breath type, or alterations in inspiratory flow.
We believe that the following are important considerations when building a system for delivery of INO.11,56 59
Dependability and safety. INO is used for critically ill
patients. Complex systems will more likely permit errors
that could compromise ventilation, oxygenation, or delivery of the correct NO dose. The function of NO delivery
systems must be thoroughly evaluated in the laboratory
prior to patient use.
Precise and stable NO dose delivery. It is important to
deliver a precise and stable dose to avoid complications
associated with INO. The dose should not vary with changes
in ventilatory pattern or FIO2.
287
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MONITORING
Fig. 2. Ambient NO and NO2 levels for one hour with 100 ppm NO delivered into an ICU room at 8 L/min. Note that concentration readings
are in parts per billion. NO and NO2 measured by chemiluminescence 10 ft from NO flow. Note that ambient NO and NO2 levels remain low
without scavenging other than the usual room ventilation. (From Reference 11, with permission.)
Limit NO2 production. For reasons provided above,

our clinical goal is to maintain NO2 as low as possible.
NO and NO2 monitoring. It is important to directly
monitor INO. It is also necessary to monitor NO2 because
of its potentially injurious effects.
Permit scavenging of NO. Although current investigations suggest that NO scavenging is unnecessary, these
systems can be adapted easily and cheaply if required.
Maintain proper ventilator function. Care must be taken
to assure that adapting the ventilator to deliver NO does
not affect adversely the ventilators operation. In particular, the alarm systems should not be affected. The addition
of NO will lower the FIO2, and for that reason O2 concentration should be monitored downstream from the point of
NO titration into the system (note that it is impossible to
deliver 100% O2 during INO therapy). Though there has
been concern regarding the effect of NO on the internal
components of ventilators, blenders, and flow meters that
are exposed to NO, after thousands of hours of INO delivery we have not detected any damage to or malfunction
of equipment related to NO exposure.
On November 22, 1996, the FDA proposed that NO
administration devices, NO analyzers, and NO2 analyzers
be classified as Class II devices for purposes of regulation.
At that time, risks and special controls for NO administration apparatus were proposed (Table 4). The American
Society for Testing and Materials has also recently begun
a project to develop standards for NO delivery devices.
288
Delivery Systems for Adult Mechanical Ventilators

Continuous Injection into the Inspiratory Limb (ci)
A simple method of INO delivery is continuous administration into the inspiratory limb of the ventilator circuit.24,60 77 The mean NO concentration delivered to the
patient is estimated from the NO flow and the minute
ventilation71,75,77,78:
E
desired [NO] 5 (NO flow 3 [NO]source)/V
This type of NO delivery system is adequate for pediatric continuous flow ventilators, but is not recommend for
use with adult ventilators. The phasic flow during adult
mechanical ventilation and use of either no flow during
expiration or low level continuous flow for triggering causesci systems to produce varying, unpredictable NO concen-trations. One problem with ci is that the inspiratory
limb of the ventilator circuit can fill with NO during the
expiratory phase. If the inspiratory limb fills with NO, the
subsequent inspiration will deliver a large bolus of NO
during the initial portion of each breath (Fig. 4).78 The
degree of underestimation of the calculated dose with the
ci delivery system is a function of the expiratory time.
When expiratory time is short, the delivered NO concentration is lower because there is less time for the inspiratory limb to fill with NO. This method results in an in-

spired NO concentration that may be more than double the
intended dose.71,75 81
NO delivery using continuous injection is also affected
by the inspiratory flow waveform, minute ventilation, and
by the site at which NO is titrated into the circuit. Continuous injection will not deliver a stable dose with ventilatory modes such as pressure support ventilation or synchronized intermittent mandatory ventilation in which VT
and inspiratory time (TI) vary from breath to breath (Fig.
5).71,75,77,78,82 Injection of additional gas into the circuit
also augments VT during either volume or pressure control
ventilation.83 Ventilator triggering can also be adversely
affected by continuous injection. This is particularly true
of flow-triggering systems.84 To deliver a more stable NO
concentration with continuous injection into the inspiratory limb, mixing chambers can be used.71,76,77 However,
a mixing chamber in the inspiratory limb will affect compressible volume (reducing delivered VT) and may act as
a site of NO2 production.
Westfelt et al recommend that the mixing chamber have
a volume greater than the VT, in order to stabilize delivered NO concentrations.75 At a respiratory rate of 10
breaths/min they found an increases in NO2 of 502150%
(typically from ' 0.5 ppm to ' 1.2 ppm) when using an
inspiratory mixing chamber. Sydow et al71 found an NO2
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MONITORING
increase of approximately 30% in both volume control and

pressure control ventilation with the addition of a mixing
chamber. These authors did not evaluate performance with
pressure support or intermittent mandatory ventilation.
Systems that inject a continuous flow of NO into the
inspiratory circuit are of particular concern during clinical
use because the inspiratory circuit can fill with O2-deficient gas during the expiratory phase. Tibballs et al79 determined that under certain conditions this may cause the
patient to receive a hypoxic gas mixture during the subsequent breath. For example, using an 800 ppm NO source
and an NO flow of 300 mL/min (to produce an average
E of 12 L/min), the total NO flow
[NO] of 20 ppm with a V
during a 5-second period (respiratory rate 12 breaths per
min) is 25 mL. At a VT of 300 mL, this results in an 8%
reduction in FIO2. If the expiratory time is 30 seconds (near
apnea) and the subsequent VT is 300 mL, then the FIO2 is
reduced by 50%.11
Inspiratory Phase Injection into the
Inspiratory Limb (ii)
NO may be injected into the ventilator circuit at a constant flow, but only during the inspiratory phase.85 89 The
delivered NO concentration is calculated from the source
Fig. 3. Schematic representation of a ventilator system illustrating the various points at which NO can be introduced.78 The premixing
system (pre) introduces NO into the high pressure air inlet of the ventilator. NO can also be introduced into the inspiratory limb of the
ventilator circuit (I) or at the Y-Piece (y). This injection can occur either throughout the ventilatory cycle or electronically coupled to the
ventilator so that flow occurs only during the inspiratory phase. Wall suction is used to scavenge expired NO, which may be unnecessary
if low NO doses are used. (From Reference 78, with permission.)
289

Table 4.
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Risks and Special Controls for NO Delivery Systems, as

Proposed by the Food and Drug Administration on
November 22, 1996
Risks:
Loss of NO therapy and incorrect NO

concentration
Adverse effects on ventilator function
Excessive NO2 administration
Catastrophic release of NO
Alteration of the NO or respiratory gas
Electrical hazard
Adverse effect on other electronic devices via
electromagnetic emission
Special Controls:
Reserve (backup) NO delivery system

NO and NO2 gas analysis device with alarms
Cylinder pressure gauge
Battery backup power
Specification and testing for accuracy and stability
of NO delivery
Specification and testing for NO concentration
profile within a breath
Gas-specific connectors with integral check valve
Standards: software and hardware documentation,
electromagnetic compatibility documentation,
resistance to environmental effects on the device
Identification of compatible ventilators and other
respiratory gas systems
Oxygen gas analyzer
Specifications and testing for NO2 production
Design and testing for NO2 concentration profile
within a breath
Testing and instruction for flushing the device
Limiting the total quantity of NO subject to
catastrophic release
Testing for adulterations from use of the device
Electrical safety (leakage current testing)
Electromagnetic compatibility documentation
Fig. 4. NO delivery patterns with five systems.78 The peaks represent inspirations. The target NO concentration is 20 ppm in all
cases. Note that only the premixing system (pre) delivers a constant NO dose regardless of the ventilatory pattern. Also note the
very high spikes of NO with some delivery systems. pre 5 premixing; ii 5 inspiratory injection into the inspiratory circuit; iy 5
inspiratory injection at the Y-piece; ci 5 continuous injection into
the inspiratory circuit; cy 5 continuous injection into the Y-piece.
NO 5 nitric oxide; NO2 5 nitrogen dioxide. (From Reference 11, with

permission.)
gas concentration and inspiratory flow using the following

formula60,78,90:
[NO] calculated 5 ([NO] source 3 NO flow 3 %TI)/
E
V
(a)
where %TI is the percent of the ventilatory cycle that
E is the minute venthe ventilator is in inspiration, and V
tilation. This is mathematically equivalent to:
[NO] calculated 5 ([NO] source 3 NO flow)/(ventilator inspiratory flow 1 NO flow)
(b)
Formula (a) can be used for variable inspiratory flows
(eg, pressure control ventilation), whereas Formula (b) can
be used for constant inspiratory flows (eg, volume control
ventilation). This method has been accomplished by using
a nebulizer drive mechanism that operates during inspira-
290
tion. The gas supply to the nebulizer contains the NO

required to achieve the desired patient dose after mixing
with gas delivered from the ventilator. Because the gas
flow from the nebulizer is constant during inspiration, this
method will only deliver a constant NO dose with constant
flow ventilation.78 However, individual ventilator nebulizer systems function differently and a given ventilator
will deliver a varying flow with changes in flow pattern.
Injection during the inspiratory phase with a constant flow
does not deliver a constant NO dose during pressure control (see Fig. 4). This system also augments VT delivery
from the ventilator and decreases the FIO2.
The major benefit of the inspiratory injection method is
minimizing NO2 production (because the residence time
of NO with O2 is minimized). However, this method does
not allow precise control of the inspired NO concentration,
and is only available with a few ventilator systems. For
this method to be acceptable, flow from the ventilator must
be continuously and precisely measured, and the injected
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MONITORING
Instead, the NO bleeds out the expiratory limb of the ventilator during expiration. Perhaps more importantly, continuous injection at the Y-piece prevents the accurate measurement of inspired NO concentration and the dose can
only be approximated by mathematical calculation. This
system suffers many of the same limitations of NO titration into the inspiratory circuit, specifically, augmentation
of VT, reduction in FIO2, decreased ability to trigger the
ventilator, and changes in delivered NO dose with changes
in inspiratory flow and minute ventilation (see Figs. 4 and
5). Using this INO delivery technique, errors of up to
322% in delivered INO have been identified at an inspiration-expiration ratio of 1:4.95
Inspiratory Phase Injection into the Y-Piece (iy)
Fig. 5. NO delivery with five systems during synchronized intermittent mandatory ventilation (SIMV) and pressure support ventilation (PSV).78 The peaks represent inspirations. The first and third
breaths during synchronized intermittent mandatory ventilation represent mandatory breaths. Note that only the premixing system
provides a constant NO dose with changes in ventilatory pattern.
pre 5 premixing; ii 5 inspiratory injection into the inspiratory circuit; iy 5 inspiratory injection at the Y-piece; ci 5 continuous
injection into the inspiratory circuit; cy 5 continuous injection into
the Y-piece. (From Reference 78, with permission.)
dose of NO must be precisely titrated so that the delivered

NO and inspiratory flow waveform are not affected.91
A case of severe methemoglobinemia (67% metHb) has
been reported using this delivery system.92 This methemoglobinemia was attributed to very high delivered NO concentrations resulting from a fixed NO injection flow, while
the ventilator TI and VT were variable (the patient was in
the pressure support mode). Due to the relatively slow
response time of the NO analyzer, these variable high
doses were not detected.
Continuous Injection into the Y-Piece (cy)
In an effort to reduce NO2 formation, several authors
have suggested introducing NO at the Y-piece of the ventilator circuit.90,9295 This reduces NO/O2 residence time.
If NO is continuously added at the Y-piece, the inspiratory
circuit will not fill with NO during the expiratory phase.
Inspiratory phase injection delivers NO at a constant

flow into the Y-piece during the inspiratory phase.96 99
This system functions well when inspiratory flow and
minute ventilation are constant. However, when inspiratory flow is not constant (eg, pressure control ventilation)
or minute ventilation varies (eg, synchronized intermittent
mandatory ventilation or pressure control ventilation), the
delivered NO concentration is variable and unpredictable
(see Figs. 4 and 5).71,78 Like the system that injects NO
into the inspiratory circuit, FIO2 and VT are augmented by
the NO gas flow.
Tracheal Injection
Another method for administration of a constant flow of
INO is by way of an endotracheal tube into the trachea.100,101
Problems associated with this method are similar to titration at the Y-piece. In addition, we believe that this method
is dangerous. During apnea, O2-free NO gas would continue
to flow into the trachea, and quickly produce hypoxia.
Premixing System (pre)
Many papers have described systems to administer INO
to adult mechanically ventilated patients by premixing the
NO with N2 (or air) and introducing the mixture proximal
to the gas inlet of the ventilator.23,42,70,79,82,96,102110 These
systems typically add the O2/N2/NO gas mixture to the low
flow inlet of the Siemens Servo 900C ventilator or the high
pressure air or O2 inlet of a ventilator such as the Puritan
Bennett 7200 ventilator. We have also successfully delivered
NO in this manner via a Drager Evita 4. A multicenter, double blind, placebo-controlled study of the use of INO for the
treatment of ARDS used a low pressure premixing
system.111The premixing NO system maintains a constant
and predictable INO concentration regardless of changes in
ventilatory pattern (see Figs. 4 and 5).78
291
Fig. 6. NO delivery system used for mechanically ventilated adult

patients at the Massachusetts General Hospital. NO (800 ppm) is
mixed with N2 (or air) and introduced into the air inlet of the ventilator (Puritan-Bennett 7200). The external blender setting and
ventilator FIO2 setting determine the delivered NO. NO, NO2, and
O2 are measured at the ventilator outlet. (From Reference 11, with
permission.)
Hess and colleagues have designed a pre-mixing system

using the Puritan-Bennett 7200 ventilator to deliver INO
to nearly 200 patients (Fig. 6).22,56,58,78 Using an air/O2
blender, NO (eg, 800 ppm) is added to the O2 inlet of the
blender and N2 or air is added to the air inlet of the blender.
The choice of air or N2 as the diluent is determined by the
extent of NO2 production. NO must be mixed with N2
when high NO doses (. 20 ppm), high FIO2 (eg, . 0.90),
or low minute ventilation are required.22 The gas mixture
leaving the blender is delivered to the high pressure air
inlet of the ventilator. The final NO delivered to the patient
is determined by the FIO2 setting on the external blender
and the FIO2 setting of the ventilator. Tables 5 and 6 show
nomograms to assist in determining initial set points for
the blender and flow meter settings to achieve the desired
INO concentration. The actual dose should be confirmed
by direct measurement. FIO2 should also be measured to
determine the effect of NO/N2 dilution on delivered FIO2.
It has been our experience, and that of other researchers,
that air/O2 blenders do not always deliver a precise NO
concentration.112 This is particularly problematic when 2
or more blenders are used in series, which can result in
flow from one of the blenders that is less than that required
for accurate gas mixing. Additionally, the precision of a
blender is best at an indicated FIO2 of 0.60, and worst at
extremes of the spectrum (FIO2 ranges between 0.22 0.30
and 0.90 0.99) Although multiple blenders in series can
be used to deliver the desired dose, we have found such
systems to be unnecessarily complex. Blenders require a
minimum flow output of 15 L/min to be accurate. To
achieve this, the blender may bleed gas into the room,
contributing to ambient contamination with NO. By their
design, it is not possible to completely stop flow from
either gas in the blender. In other words, a small amount
292
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MONITORING
(as much as 2 ppm in our experience) of NO is delivered

with the blender set at an FIO2 of 0.21. This creates the
illusion that NO therapy has been discontinued, which can
result in rebound hypoxemia and pulmonary hypertension
when the NO delivery system is disconnected from the
ventilator. It should also be recognized that most of the
NO2 in the delivery system is produced in the high pressure hoses, which may be problematic when multiple blenders are used in series. Regardless of their configuration,
the high pressure hoses in the NO delivery system should
be kept as short as possible to limit NO2 production.
Premixing before the ventilator has the advantage of
delivering a constant NO dose throughout inspiration, that
is not affected by changes in minute ventilation or inspiratory flow pattern. One disadvantage of this system is the
potential for greater NO2 production with ventilators that
have large internal volumes.22 Although with this system
there is a potential for damage to the blender and ventilator
due to the NO, we have not detected any damage, even
after thousands of hours of INO therapy. Another potential
disadvantage of this system is that the INO dose will change
when the ventilator FIO2 setting is changed. However, it is
easy to compensate for this by adjusting the setting on the
external blender. Clinicians should be aware of the effects
(on both NO dose and FIO2) of changing the FIO2 setting.
Another potential issue with this system is the effect of
nebulized medications. Depending on how this is accomplished, the nebulizer may affect the delivered INO dose
(even for systems that power the nebulizer from the ventilator). The Puritan Bennett 7200 is a good example. If
FIO2 is , 0.60 the nebulizer is powered by air. If FIO2 is .
0.60, the nebulizer is powered by oxygen. When using a
premixing system at an FIO2 , 0.60, operation of the nebulizer will result in a bolus of NO from the air source of
the ventilator (which contains NO at a much higher concentration than is supposed to be delivered to the patient).
The nebulizer function should not be used in this situation.
Delivery Systems for Pediatric
Mechanical Ventilation
For continuous flow ventilators such as those used in pediatrics (including high frequency oscillators), NO can be
titrated into the inspiratory limb of the ventilator circuit using
the continuous injection method (Fig. 7).58,70,72,85,101,113124
Ideally NO should be titrated into the system near the ventilator outlet to ensure adequate mixing, and FIO2 should be
measured downstream of the point that NO is injected into
the system. By introducing NO prior to the humidifier, mixing is enhanced. Monitoring lines should be near the Y-piece,
though not in a position to be contaminated by expiratory
gases. NO2 production is relatively low because the residence
time in the system is short. The expected NO can be calculated as:

Table 5.
FIO2
Setting
0.90
0.80
0.70
0.60
0.50
0.40
0.30
0.21
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MONITORING
Nomogram to Determine External Blender Setting to Achieve Approximate Delivered INO Concentration
External Blender Setting (800 ppm Source Gas)
100
90
80
70
60
50
40
30
29
28
27
26
25
24
23
22
101
88
76
63
50
100
37
74
24
49
73
97
12
23
35
46
58
69
81
91
10
21
31
41
51
62
72
81
9
18
27
36
45
54
63
71
8
15
23
31
38
46
54
61
6
13
19
26
32
38
45
51
5
10
15
21
26
31
36
41
4
8
12
15
19
23
27
30
3
5
8
10
13
15
18
20
1
3
4
5
6
8
9
10
Notes: 800 parts per million (ppm) nitric oxide (NO) added to O2 inlet of external blender and N2 (or air) added to air inlet of external blender. Outlet of external blender leads to air inlet of
ventilator. The actual delivered dose must always be confirmed by analysis. The numbers in the body of the table represent approximate delivered NO concentration. This nomogram has been used
successfully at Massachusetts General Hospital since 1993 in conjunction with a Puritan Bennett 7200 Ventilator and Bird Blender. For NO source gas concentrations other than 800 ppm, appropriate
mathematical adjustments can be easily made to the target doses in the body of the Table. For example, if a 400 ppm source gas cylinder is used, the target doses in the body of this table should be
divided in half. FIO2 5 fraction of inspired oxygen. (From Reference 11, with permission.)
Table 6.
Flow
Rate
(L/min)
16.0
15.0
14.0
13.0
12.0
11.0
10.0
9.0
8.0
7.5
7.0
6.5
Nomogram to Determine Flowmeter Setting to Achieve Approximate Delivered INO Concentration

NO Flow (800 ppm Source Gas)
1.75
1.50
1.25
1.00
0.90
0.80
0.70
0.60
0.50
0.40
0.30
0.20
0.18
0.15
0.13
0.10
0.08
0.05
0.03
79
69
73
77
58
62
66
70
75
82
47
50
53
57
62
67
73
80
43
45
48
52
56
61
66
73
81
38
41
43
46
50
54
59
65
73
77
82
34
36
38
41
44
48
52
58
64
68
73
78
29
31
33
35
38
41
45
50
56
59
63
68
24
26
28
30
32
35
38
42
47
50
53
57
20
21
22
24
26
28
31
34
38
41
43
46
15
16
17
18
20
21
23
26
29
31
33
35
10
11
11
12
13
14
16
17
20
21
22
24
9
9
10
11
11
13
14
15
17
18
20
21
7
8
8
9
10
11
12
13
15
16
17
18
6
7
7
8
8
9
10
11
12
13
14
15
5
5
6
6
7
7
8
9
10
11
11
12
4
4
4
5
5
5
6
7
7
8
8
9
2
3
3
3
3
4
4
4
5
5
6
6
1
1
1
2
2
2
2
2
2
3
3
3
Notes: 800 parts per million (ppm) nitric oxide (NO) added to O2 inlet of external blender and N2 (or air) added to air inlet of external blender. Outlet of external blender leads to air inlet of
ventilator. The actual delivered dose must always be confirmed by analysis. The numbers in the body of the table represent approximate delivered NO concentration. This nomogram has been used
successfully at Massachusetts General Hospital since 1993 in conjunction with a Puritan Bennett 7200 Ventilator and a Bird Blender. For NO source gas concentrations other than 800 ppm,
appropriate mathematical adjustments can be easily made to the target doses in the body of the Table. For example, if a 400 ppm source gas cylinder is used, the target doses in the body of this table
should be divided in half. (From Reference 11, with permission.)
[NO] 5 (NO flow 3 source ppm) 4 (NO flow

1 ventilator flow)
However, this should be considered an approximation,
and the actual delivered NO should be measured. Once the
delivered NO is established, the dose should remain constant provided that the total flow through the system does
not change.
Skimming et al73,74 have illustrated that gas streaming
can occur when NO is infused into a continuous flow of
gas. Due to this effect, the highest NO concentration is
closest to the tubing wall nearest to the infusion port, and
the lowest concentration is between the tubing axis and the
tubing further wall. Gas mixing is greater with corrugated
tubing than smooth tubing. However, Skimming et al73,74

also found that gas mixing was virtually complete 12 inches
(30 cm) from the point of NO infusion. Thus, to avoid
dosing errors, it is prudent to infuse NO at least 12 inches
(30 cm) from the point of monitoring.
We have successfully used INO with high frequency
oscillation by titration into the continuous gas stream proximal to the humidifier (injection upstream from the humidifier is important for optimal mixing). However, NO
delivery by high frequency jet ventilation is unreliable and
should be avoided. Jet ventilators are often used in tandem
with a conventional ventilator or use a second gas source
for entrainment and spontaneous breathing. During jet ven-
293
Fig. 7. NO delivery system used for mechanically ventilated neonatal patients at Massachusetts General Hospital. NO (800 ppm) is
introduced into the inspiratory circuit of the ventilator with continuous flow. The NO flow and circuit flow determine the delivered
NO. NO, NO2, and O2 are sampled near the Y-piece. (From Reference 11, with permission.)
tilation, entrainment is affected by respiratory impedance

and position of the catheter in the airway. If NO is present
in the entrainment gas, delivered NO dose will be unpredictable. The same is true for NO delivered via the jet
ventilator, but not the entrainment gas. The production of
NO2 in such a system might also be a problem and has not
yet been studied. In our opinion, NO should not be delivered by jet ventilation until reliable methods are designed.125
This is likely to be problematic due to the difficulty of
measuring NO distal to the point of gas injection into the
airway (ie, the trachea).
Delivery Systems for Manual Ventilators
For manual ventilation, NO can be diluted with O2 and
introduced into the gas inlet port of the manual ventilator
(Fig. 8).56,113,114,126,127 We have used this system with selfinflating resuscitators as well as flow-inflating resuscitators. The expected [NO] (see Table 5) can be calculated as:
[NO] 5 (NO flow 3 source ppm)/(NO flow 1 O2 flow)
Before using this system to ventilate the patient, the
delivered INO concentration should be analyzed to assure
the correct delivered dose. It must be recognized that INO
delivery may change with changes in minute ventilation if
the flow into the manual ventilator is less than the minute
ventilation. We have used this system for bedside manual
ventilation and during patient transport for diagnostic procedures. Because this system is only used intermittently,
care must be taken to avoid NO2 generation between uses,
which could result in a large NO2 delivery if the resuscitator is unused for a prolonged period. The clinician should
flush the resuscitator with O2 before and after each use (ie,
squeeze the bag 35 times). Although some have described
the use of potassium permanganate air filtration medium
to scavenge exhaled NO and NO2 during the use of manual
294
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MONITORING
Fig. 8. NO delivery system used for manual ventilation. The manual

ventilator should be squeezed 35 times to clear any residual NO2
before attaching the ventilator to the patient. (From Reference 11,
with permission.)
ventilators,115 we have generally found this to be unnecessary with the low INO doses used in ARDS. We have
also found that many patients can be disconnected briefly
(ie, less than one hour) from INO during transport for
diagnostic tests or operations if FIO2 is increased to support
the patients oxygenation.
NO Delivery with Anesthesia Ventilators
The architecture of the anesthesia ventilator poses significant obstacles to the delivery of a stable dose of INO.
Anesthesia ventilators are configured to recirculate expired gas so as to conserve anesthetic and prevent release
of anesthetic into the room air. Systems that introduce a
continuous flow of NO into the inspiratory limb95 could
administer an unintended high NO dose because the recirculated expired gas may already contain a significant
NO concentration.
Anesthesia ventilators provide a continuous flow of oxygen, to which air and/or anesthetic gases can be added.
This continuous flow (termed fresh gas flow) is supplied
at a rate that can be varied (0.3 to . 12 L/min) depending
on the style of ventilation and ventilatory requirements. If
this were the only gas source available during inspiration,
NO delivery could be accomplished in the same fashion as
a continuous flow ventilator (ie, by introducing a continuous flow of NO into the fresh gas flow). The patients
expired gas passes into a bellows (or bag if employing
manual ventilation) for storage until needed for the next
inspiration. During the expiratory phase, the continuous
fresh gas flow is also diverted from the inspiratory limb
into the bellows (Fig. 9), mixing with the patients expired
gas. If the bellows capacity is exceeded, excess gas is
released through a pressure relief valve into the ventilators scavenging system. On inspiration, a combination of
Fig. 9. A typical anesthesia ventilator system. It is difficult to safely

and precisely deliver NO with this system. (From Reference 11,
with permission.)
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MONITORING
limitations of the standard anesthesia ventilator, it may not

be practical to set the fresh gas flow greater than the minute
ventilation. We prefer to use a critical care ventilator rather
than an anesthesia ventilator for NO delivery during anesthesia. The I-NOvent Delivery System (see below) can
be used to add NO to the inspiratory limb of an anesthesia
circuit if fresh gas flow equals (or exceeds) the minute
ventilation. This application of the I-NOvent poses several
problems. The flow readings by the I-NOvent will be inaccurate because of the presence of anesthetic gases. This,
coupled with the recirculation of NO that is able to pass
through the absorber at high concentrations, requires that
delivered NO be monitored carefully. The effects of anesthetic gases on NO monitors is not fully understood and
requires further investigation.
Commercial Systems for Mechanical Ventilation
fresh gas flow and bellows gas is delivered to the patient

to achieve the desired VT.
During anesthesia ventilation, the actual delivered INO
dose will be difficult to predict for several reasons. The
NO uptake and expired NO concentration can vary significantly from patient to patient. As the fresh gas flow enters
the bellows during the expiratory phase, the NO concentration in the bellows is diluted and some NO may be lost
through the pressure relief valve. During inspiration, as the
gas from the bellows is delivered through the CO2 absorber to the inspiratory limb, some NO may be scavenged
by the absorber.42 47 It is difficult to determine the contribution the bellows makes to the delivered VT and NO
concentration.
Adding a continuous flow of NO into the inspiratory
limb of the breathing circuit downstream from the CO2
absorber will result in the loading of some portion of the
inspiratory limb with pure source NO because there is no
flow in the inspiratory limb downstream from the CO2
absorber during expiration (fresh gas flow is directed into
the bellows). Thus, the beginning of the following inspiration would contain a high NO concentration.
Nitric oxide can be added to the fresh gas flow by
connecting the source NO cylinder to the nitrous oxide
(N2O) inlet of the anesthesia ventilator and regulating the
amount of NO by adjusting the N2O flow meter. However,
the difference in density of NO and N2O will result in an
erroneous flow reading on the N2O flow meter, which in
turn affects the accuracy of predicting the NO concentration. Using the N2O flow meter to introduce the NO into
the anesthesia ventilator ensures a consistent, stable NO
concentration if the fresh gas flow is greater than the minute
ventilation. If the fresh gas flow is less than minute ventilation, then recirculation of gases will occur and result in
higher-than-intended NO concentrations and a greater reduction in the oxygen concentration. Given the design
Several manufacturers are developing systems for delivery of INO, and these are at various stages of development. At the time of this writing, most have not been
approved for use by the FDA, and none can be used by
institutions that do not have a valid FDA Investigational
New Drug Number for the use of INO.
I-NOvent Delivery System
The I-NOvent Delivery System (INO Therapeutics) is a
universal NO delivery system designed for use with most
conventional critical care ventilators. It can be used with
either phasic flow ventilators (eg, adults) or continuous
flow ventilators (eg, neonates). In its typical configuration,
the delivery system is mounted on a transport cart that
holds two 800 ppm NO gas cylinders (Fig. 10). The system is factory-configured for the specific cylinder concentration required in the intended country of use. NO concentrations of 0 80 ppm can be delivered using the 800
ppm source gas cylinder, 0 40 ppm can be delivered using a 400 or 450 ppm cylinder, and 0 20 ppm can be
delivered using a 300 ppm cylinder. The system is delivered with 800 ppm tanks containing 1963 L and pressurized to 2000 psig. An integral battery allows 30 minutes of
operation in the absence of an external power source. At
the time of this writing, I-NOvent Delivery System is the
only commercial NO delivery system that has received
FDA approval for purchase by hospitals who have a valid
Investigational New Drug Number for administration
of INO.
The principle of operation of the I-NOvent Delivery
System is shown in Figure 11. An injection module is
inserted into the inspiratory circuit between the ventilator
output and the humidifier. The injection module includes
a hot film flow sensor and a gas injection tube. Flow in the
ventilator circuit is precisely measured and NO is injected
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MONITORING
Fig. 11. Schematic representation of the Ohmeda I-NOvent Delivery System in a mechanical ventilator circuit. Flow is measured at
the ventilator outlet and NO is injected proportional to that flow to
achieve the desired NO dose. Gas is sampled from the inspiratory
circuit, near the Y-piece, and analyzed for NO, NO2, and O2.
Fig. 10. The Ohmeda I-NOvent Delivery System. Top: User interface and monitoring panel. Middle: Flow sensor inspiratory limb of
ventilator circuit. Bottom: The I-NOvent Delivery System interfaced
with a mechanical ventilator system.
proportional to that flow to provide the desired NO dose.

This design allows a precise and constant NO concentration in the inspired gas for any ventilatory pattern. NO
flows through either a high flow or a low flow controller.
The high and low flow controllers assure that the delivered
296
NO concentration is accurate over a wide range of ventilator flows and desired NO concentrations. By delivering
NO proportional to the ventilator flow, residence time is
reduced and NO2 production is minimized.
The I-NOvent Delivery System includes monitoring of
O2, NO, and NO2. Gas is sampled downstream from the
point of injection, near the Y-piece in the inspiratory circuit. Gas concentrations are measured using electrochemical cells that can be calibrated at regular intervals by the
user. Alarms can be set by the user for high NO, low NO,
high NO2, high O2, and low O2. Additional alarms include
loss of source gas pressure, weak or failed electrochemical
cells, calibration required, delivery system failures, and
monitoring failures.
The I-NOvent Delivery System uses a dual-channel design: one channel controls INO delivery and the other
controls monitoring. This design permits INO delivery independent of monitoring, which is an important safety
feature, and allows that the monitoring system can be calibrated without interruption of INO delivery.
A manual INO delivery system is also available with the
I-NOvent Delivery System. With an oxygen flow to the
manual ventilator set at 15 L/min, the I-NOvent injects gas
to provide an INO concentration of 20 ppm. As with any
manual ventilator system for INO, it is important to squeeze
the bag 35 times to clear residual NO2 before attaching it
to the patient.
Two independent evaluations of the I-NOvent Delivery
System have been published. Kirmse et al128 evaluated the
I-NOvent connected to the Puritan Bennett 7200 and Siemens Servo 900C at inspired NO concentrations of 2 ppm,
5 ppm, and 20 ppm, and a variety of ventilator modes.

They found the error between the target and delivered dose
to be 1.3% with the Puritan Bennett 7200, and 3.9% with
the Siemens Servo 900C.128 They also found that the INOvent reduced NO2 production from a mean of 5.8 ppm
(pre-mixing with compressed air) to 0.5 ppm when using
the I-NOvent. Pre-mixing with nitrogen instead of air reduced NO2 levels to 0.3 ppm. They concluded that, the
I-NOvent provides a constant NO concentration independent of ventilatory pattern, and NO2 formation is minimal.128
Young et al evaluated the I-NOvent at 10 ppm NO and
40 ppm NO using VT of 500 mL, 700 mL, and 900 mL,
respiratory rates of 10 breaths per minute, 15 breaths per
minute, and 20 breath per minute with constant, sine, and
decelerating flow patterns at 30 L/min, 40 L/min, and 50
L/min.129 They found delivered INO to be 10.210.7 ppm
with a setting of 10 ppm and 40.5 42 ppm with a setting
of 40 ppm.
One limitation of the I-NOvent is that the maximum NO
flow is 6.34 L/min. At very high constant flow rates (. 90
L/min) and high NO settings (. 40 ppm), the I-NOvent
will be unable to deliver the set NO unless the cylinder
concentration is changed or ventilator settings adjusted.
NOdomo
The NOdomo (Nitric Oxide Dosing and Monitoring Unit,
Dragerwerk, Germany) system is designed to interface with
the Drager family of mechanical ventilators (Fig. 12). Currently, the system will operate with the Drager Evita 1,
Evita 2, Evita 4, and Babylog 8000 ventilators.
The NOdomo delivery system is a mass flow controller,
adding a proportion of NO from a cylinder into the breathing circuit. The system is typically operated with a cylinder of NO/N2 with an INO concentration of 100 ppm or
1000 ppm. If a cylinder of 100 ppm is used, the set value
is 0.0 ppm. If a 1000 ppm cylinder is used, the set value is
00.0 ppm. A 100 ppm NO cylinder allows an INO delivery
concentration of 0.1 to 9.9 ppm, and a cylinder of 1000
ppm NO allows a dose range of 1 to 99 ppm. If a cylinder
with a different NO concentration is used, the delivered
NO can be calculated by the formula:
[NO] 5 [NO]cylinder/selector switch setting
(100 or 1000 ppm) 3 set concentration (ppm)
The manufacturer recommends using the specified 100
ppm or 1000 ppm NO cylinders. If a different concentration is used, the selector switch should be set at a level
greater than the tank concentration. Table 7 shows the
range of delivered NO using specified and unspecified
cylinder concentrations.
The delivery of INO is controlled by the electronic flow
controller, based on the input signal from the value set on
the unit and the flow signal from the ventilator. The
Table 7.
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MONITORING
Range of Delivered Inhaled Nitric Oxide Using Specified

and Unspecified Cylinder Concentrations for the NOdomo
System
Cylinder Concentration
100 ppm
1000 ppm
50 ppm
200 ppm
Setting range
0.1 to 9.9 ppm
1 to 99 ppm
0.1 to 9.9 ppm
1 to 99 ppm
Delivered concentration
0.1 to 9.9 ppm
1 to 99 ppm
0.05 to 4.95 ppm
0.2 to 18.9 ppm
NOdomo unit does not measure flow, but instead receives

the value for flow output measured by the ventilator partner (Fig. 12). This allows the NOdomo device to accurately deliver NO in any mode of ventilatory support. A
disadvantage is that it is only compatible with the Drager
ventilators. The maximum NO flow is 13 L/min and the
minimum flow is 25 mL/min. As with any proportional
system, as the desired NO concentration increases the FIO2
decreases. A maximum of 10% of total delivered flow is
available from the delivery unit. Gas from the delivery
system is directed into an elbow in the breathing circuit.
The manufacturer claims that delivery of gas into the elbow increases turbulence, enhances mixing, and eliminates
streaming of gases that causes inaccurate monitoring.
In addition to the flow control component, the NOdomo
system has NO and NO2 analyzers, a pump for sampling
gas from the ventilator circuit, water trap, and alarm unit.
The analyzers are electrochemical sensors. Both analyzers
have an adjustable high concentration alarm, but neither is
equipped with a low gas concentration alarm.
Sydow et al have evaluated the NOdomo delivery
system at 10 ppm and 30 ppm during ventilation of a
lung model using volume control and pressure control
breaths, as well as airway pressure release ventilation.130
They found that the NOdomo delivery device tended to
provide NO concentrations 4% greater than set. At an
NO concentration of 10 ppm, NO2 was # 0.2 ppm. At
an NO concentration of 30 ppm, NO2 was # 1.9 ppm.
Sydow et al concluded that although inspiratory NO
concentration fluctuates depending on the inspiratory
flow, this delivery device allows stable NO administration without requiring adjustments when ventilator settings are changed.130
Servo 300
Because current generation ventilators use microprocessor technology to set the delivered FIO2, it seems reasonable to use similar technology to set the delivery of other
gases such as NO. Microprocessor technology coupled
with precision solenoids could be used to mix air, O2, and
NO to achieve the desired FIO2 and NO.
297
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MONITORING
Fig. 13. NO delivery system for spontaneous breathing using a

high flow gas delivery system. NO, air, and O2 are blended to
achieve the desired FIO2 and NO dose. (From Reference 11, with
permission.)
and injects NO to achieve the desired dose. It operates at

a ventilator flow range of 20 60 L/min and delivers INO
in the range of 225 ppm. The system has an integral
chemiluminescence analyzer. The Pulmonox mini is of
similar design, except electrochemical monitoring cells are
used instead of chemiluminescence, which reduces the size
and cost. The Pulmonox is available only in Europe.
Delivery Systems for Spontaneous Breathing
Fig. 12. Top: Front panel of Drager NOdomo. Bottom: Internal
design of Drager NOdomo. (From Reference 11, with permission.)
A system developed in Sweden by Servotek AB (Arlov,

Sweden), and available in Europe, integrates NO delivery
into the Servo 300 ventilator.87,131135 A stock gas mixture
of NO/N2 is mixed with air and O2 within the ventilator,
and a target FIO2 and NO dose is delivered to the patient.
This system has been evaluated in detail using a test lung133
and an animal model.135 In the in-vitro evaluation, it was
determined that this system delivered an accurate and precise NO concentration independent of ventilator settings.
This was confirmed in an animal model. However, results
of the animal model also suggested that the expiratory NO
monitoring featured by this delivery system may limit its
utility because of NO uptake.63
Pulmonox
The Pulmonox (Messer Griesheim, Austria) is a universal system that measures flow from the inspiratory circuit
298
INO can be delivered to spontaneously breathing patients. Although ARDS patients requiring INO are usually
mechanically ventilated, other patients with primary pulmonary hypertension might not be intubated. Several systems have been described to deliver INO to spontaneously
breathing patients. A high-flow system ($ 60 L/min) with
a tight-fitting face mask can be used (Fig. 13).11,70 The
expected [NO] can be calculated as described previously:
[NO] 5 (NO flow 3 source ppm)/(total flow)
Exhaled gas can be scavenged by the hospital vacuum
system. Inspiratory reservoir bags should be avoided with
these systems because of the likelihood of NO2 generation
within the bag.
INO can also be administered to spontaneously breathing patients using a transtracheal O2 catheter100 or a nasal
cannula.69,136 There are several limitations of these systems. It is not possible to analyze the delivered dose, and
the dose varies with the ventilatory pattern of the patient.57
NO/N2 can be delivered directly to the cannula from a
source cylinder, provided that this NO concentration is

Table 8.
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MONITORING
Calculation of NO for Delivery by Nasal Cannula
[NO] in cannula 5 (desired NO dose 3 mean inspiratory

flow)/(cannula flow)
NO flow 5 (cannula flow 3 [NO] in cannula)/(source NO cylinder
concentration)
Assume: tidal volume 5 400 mL
inspiratory time 5 1 second
source NO cylinder concentration 5 800 ppm
nasal cannula flow 5 2 L/min
desired NO dose 5 5 ppm
mean inspiratory flow 5 400 mL/1 second 5 24 L/min
[NO] in cannula 5 (5 ppm 3 24 L/min)/2 L/min 5 60 ppm
NO flow 5 (2 L/min 3 60 ppm)/800 ppm 5 0.15 L/min
Therefore, 0.15 L/min of 800 ppm NO should be mixed with 1.85
L/min of air to produce 60 ppm NO in the cannula at 2 L/min. This
will provide an NO dose of 5 ppm for the above ventilatory pattern.
Note that the NO dose will vary with the ventilatory pattern. Similar
calculations can be performed for any combination of tidal volume,
inspiratory time, source NO cylinder concentration, nasal cannula
flow, and desired NO dose.
Because most of the inspiratory flow consists of NO-free ambient air,
changing the O2 flow will have a negligible effect on the delivered
NO dose. Although changing the NO flow will change the NO
concentration in the cannula, the inspiratory dose of NO remains
relatively unchanged if the NO flow and ventilatory pattern do not
change.
NO 5 nitric oxide. (From Reference 11, with permission.)
relatively low (eg, # 80 ppm). Alternatively, the NO flow

can be titrated into the main gas flow to the cannula. The
main gas flow (carrier gas) can be O2 or air, depending on
the O2 requirements of the patient. Nitrogen is not recommended as a carrier gas because of the potential for hypoxia. Some investigators have used a split cannula design
(eg, CO2 sampling cannula), with O2 administration via
one of the cannula prongs and NO administration via the
other prong. The delivered dose is calculated based on assumptions about the patients ventilatory pattern (Table 8).
It is difficult to scavenge NO with a nasal cannula administration system, although scavenging is probably unnecessary with the low doses that are typically used. A
pulse-dose delivery system136 can minimize ambient contamination, minimize waste of source gas (a particular
advantage for home use), and perhaps improve patient
comfort because flow occurs only during inspiration. However, pulse-dose systems are more expensive and complex.
With a pulse-dose delivery system, mixing of NO with O2 is
discouraged because of the potential for NO2 production.
Monitoring NO and NO2
Two types of analyzers are available for monitoring NO
and NO2 in breathing systems, electrochemical and chemiluminescent; each has a role in monitoring NO and NO2.
Fig. 14. Schematic diagram of an electrochemical analyzer. (A)

Structure of the polytetrafluoroethylene (PTFE)-bonded membrane
sensing electrode. (B) Schematic of an electrochemical sensor. A
semipermeable diffusion membrane covers the capillary disk. Position of the three electrodes is also shown. (From Reference 1,
with permission.)
The principles of operation for each analyzer will be reviewed and recommendations for use will be provided.
Electrochemical Analyzers
Electrochemical analyzers have some similarity to other
fuel cell technologies used in respiratory care. When NO
diffuses into a reactive electrolyte solution, electrons are
released or absorbed.1 The current generated between electrodes, caused by this release or absorption, is proportional
to the concentration of NO or NO2 in the gas sample.
Electrochemical cells for NO and NO2 monitoring utilize
a semi-permeable diffusion membrane, acid or alkaline
electrolyte, and a series of 3 electrodes. The electrodes
include an anode (sensing electrode), cathode (counter electrode), and reference electrode (Fig. 14).
Gas contacts the diffusion barrier and a small amount of
NO or NO2 passes into the electrolyte. The sensing electrode is positioned nearest the membrane, and the counter
electrode and reference electrode are positioned deeper in
the electrolyte. The reference electrode provides a bias
voltage so that the sensing electrode is kept at a pre-determined operating voltage. The current flow through the
circuit is proportional to NO or NO2 concentration, and is
measured as voltage across a resistance.1
The electrons generated during the oxidation reaction at
the sensing electrode are consumed at the counter elec-
299
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MONITORING
Fig. 15. Diagram of a single reaction chamber chemiluminescence analyzer. In this device, sample flow is controlled by the capillary tube.
In the NO2 mode, the chemical or catalytic converter is used to convert NO2 to NO. Ozone is produced from ambient air by an ozonator.
In the sample chamber excited NO2 is created and the photomultiplier measures the emitted photons. (From Reference 1, with permission).
trode via reduction of oxygen. The reaction at each electrode is:

4NO 1 2H2O 1 3O2 3 4HNO3
NO2 monitors use similar principles of operation but
different electrochemistry. With an NO2 analyzer, NO2 is
reduced to NO at the cathode:
NO2 1 2H1 1 2e 3 NO 1 H2O
cuit.1 Humidity affects the sensor by adding a layer of

water vapor over the membrane, which reduces diffusion.
Pressure increases result in a rise in partial pressure, which
causes inaccurately high NO or NO2 readings. Temperature affects diffusion and can adversely impact auto-oxidation of the electrolyte solution.75 This effect is negligible in the clinical range of 20 40 C. The accuracy of
current electrochemical sensors is clinically acceptable in
the range of 0 80 ppm.
Water is then oxidized at the cathode:

2H2O 3 4H1 1 4e 1 O2
Chemiluminescence Analyzers
The sum of these two equations yields
Chemiluminescence analyzers determine gas concentrations by measuring stimulated photoemission. The NO

chemiluminescence analyzer causes NO to react with ozone
(O3) to produce NO2 with an electron in an excited state.1
When the electron decays to its original energy level a
photon is released, with energies in the wavelength range
of 600 3000 nm. The photon emissions are measured by
a photomultiplier that converts luminescent intensity into
an electrical signal. In order to assure that NO2 production
is unrelated to the availability of ozone, ozone is pumped
into the reaction chamber at a constant rate that is several
orders of magnitude greater than the NO concentration to
be measured.
Nitrogen dioxide is measured in a chemiluminescence
analyzer by converting NO2 to NO and performing the
2NO2 3 2NO 1 O2
Electrochemical analyzers are small, portable, relatively
inexpensive, easy to calibrate, and use a small sample
volume. The response time of electrochemical sensors is
very slow, with a typical response time of 30 to 40 seconds. They can be sidestream or mainstream sensors. The
sidestream sensors can have an active withdraw system
such as a vacuum pump, or can utilize the pressure in the
ventilator circuit to deliver gas to the analyzer. The latter
system has considerably slower response time and is ineffective in systems at ambient pressures.
Electrochemical sensors can be adversely affected by
humidity, temperature, and pressure in the ventilator cir-
300

Table 9.
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MONITORING
Comparison of Electrochemical and Chemiluminescence Analyzers

Electrochemical
Accuracy
Range of measurement
Sources of error
Clinically acceptable
NO 3100 ppm
NO2 0.510 ppm
Humidity, pressure
Response time
Configuration/sample flow
Size
Consumables
1030 seconds
Sidestream, Mainstream
Small, light weight
Fuel cells
Ozone production
Suitable for expired gas measurement
Ease of use/calibration
Oxygen percent correction required
No
No
Simple/quick calibration
No
Chemiluminescence
High (ppm, ppb, ppt)
NO 1023 2100 ppm
NO2 1023 2100 ppm
Quenching (oxygen)
Viscosity (humidity, oxygen)
0.1520 seconds
Sidestream
Large, heavy
Chemical converters, sample lines, capillaries, ozone
generator, scrubber contents
Yes
Yes
Difficult/prolonged calibration
Yes
NO 5 nitric oxide; NO2 5 nitrogen dioxide.
same measurement described above. This requires a high

temperature (600 800 C) stainless steel catalytic converter or a chemical converter constructed of molybdenum.1 The latter operates at lower temperatures, but has
the disadvantage of requiring replenishment of the converter material (which is consumed during the reaction).
Figures 15 and 16 show 2 chemiluminescence analyzers.
The accuracy of chemiluminescence analyzers is in the
parts per billion (ppb) or even parts per trillion (ppt) range.
Accuracy can be affected by quenching, viscosity, and
contaminant gases being recognized as NO.1 Quenching
refers to the collision of other gas molecules with the
excited NO2 and formation of NO2 at its base energy level.
Quenching causes inaccurately low NO2 readings and can
cause the NO2 display to read , 0 ppm. Oxygen, CO2, and
water vapor are the most common sources of quenching in
the ventilator circuit. Saturated gas at 20 C will reduce the
NO2 signal by 12%. CO2 at 40 mm Hg will reduce the
signal by only 0.5%. Oxygen has a small effect, but at high
inspired concentrations is the most likely source of NO2
inaccuracies. At 100% oxygen, the NO signal is diminished by 7% to 15%.137
The presence of other nitrogen oxides will also adversely
impact accuracy of the measurement. Viscosity refers to
changes in the gas sample rate caused by humidity or the
presence of oxygen. Because the accuracy of the analyzer
depends on consistent gas flow, any increase in viscosity
will result in fewer NO molecules entering the chamber.
Humidity and oxygen both cause inaccurately low NO and
NO2 readings.
The advantages of chemiluminescence analyzers include
high accuracy, ability to measure concentrations in the ppb
range, faster response time, and greater specificity. Disadvantages include cost, size, the need for sample drying,
and the requirement of a scrubber to eliminate ozone contamination from the work area. Table 9 compares the features
of electrochemical and chemiluminescence analyzers.
Several authors have evaluated commercially available
electrochemical and chemiluminescence analyzers.138 146
Fig. 16. A dual reaction chamber chemiluminescence analyzer. It

differs from the single chamber device in that the sample gas is
split; one portion is used to measure NO directly, the other to
measure NO2 indirectly. (From Reference 1, with permission.)
301

These studies found that most electrochemical analyzers
are suitable for clinical use, although some devices perform better than others.144 146 Studies of chemiluminescence analyzers report substantial differences in response
times, sample chamber volumes, and accuracy. Nishimura
et found wide variations in response time and suggested
that all measurement systems should report response time
and transport delay of monitoring equipment.142
Summary
From a practical standpoint, technical issues related to
NO delivery are as important as therapeutic issues. The
therapeutic benefits will be consistently obtained only with
a reliable delivery system, and hazards and toxicity may be
more problematic with an unreliable delivery system. It is
incumbent upon clinicians to ensure that their INO delivery system is safe and reliable.
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Discussion
Stewart: One of my concerns is that
were starting to use INO with high
frequency oscillation ventilation, and
we deliver INO in the inspiratory limb
and measure it just prior to the Ypiece. Im concerned with dynamic hyperinflation, or gas trapping, about
whats actually going on at the alveolar level, and how much NO2 is being produced. Do you have any comments on the use of INO in techniques
prone to gas trapping, such as inverse
ratio or high frequency oscillation or
high frequency jet ventilation?
Branson: I think those are 3 very
different things. In high frequency oscillation, the delivery of INO is actually fairly easy because its a constant
flow. Now, what effects happen in the
lung with air trapping and especially
delivery of INO to alveolar units that
eventually have airways collapse in
front of them, thats a good question.
What happens to that INO? With high
frequency jet ventilation it is virtually
impossible to deliver an accurate INO
concentration unless youre going to
deliver INO through the jet ventilator
and INO through the entrainment gas
at a constant rate. If you try to rely on
entraining INO and the patients compliance changes, the position of the
catheter changes, the endotracheal
tube changes, all bets are off, and you
dont know what INO youre delivering. The same thing goes if you just
deliver it through the jet catheter because you dont know what happens
to the gas that youre entraining. Inverse ratio ventilation, again, isnt
unique unto itself in terms of INO delivery, but in the systems that you have
air trapping, especially behind closed
airways, like in the patient with chronic
obstructive pulmonary disease, the fate
of that INO Im unsure about.
306
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MONITORING
146. Strauss JM, Krohn S, Sumpelmann R, Schroder D, Barnert R. Evaluation of two electrochemical monitors for measurement of inhaled
nitric oxide. Anaesthesia 1996;51(2):151154.
Hess: I think you bring up a very

important question, Tom, and I know
Bill (Hurford) and I have had discussions about this back home already.
What happens to the production of
NO2 in the lung if you are delivering
INO and a high concentration of oxygen to a slow space of the lung that
is dead space where the INO really
isnt being taken up? Could you be
making NO2 in those regions? And
could that contribute to some toxicity
in those lung regions? I dont know
the answer, and I dont know if anyone here has any input on that. One of
the problems is you really cant, I dont
think, measure the NO2 in the expired
gas, because the NO2 that is being generated in those lung regions is probably being taken up, so there could be
toxicity that would not be reflected by
the level of NO2 in the expired gas.
Actually, I just gave part of my talk
for tomorrow, so maybe you can sleep
through that part of it.
Gerlach: Just one comment to the
Drager NOdomo device. Its not a
technical problem: its just a problem
of approval. Nowadays, you can connect this device with nearly all commercially available ventilators. So its
definitely connectable to the PuritanBennett ventilator, to the Siemens ventilators, and, of course, to the Drager
ventilators. It was just a problem of
approval that they were not allowed
to connect the interfaces.
Branson: I think thats true. However, the device thats sold in the
United States, to people who have investigational new drug numbers, still
remains the only device that connects
to the Drager. But yes, theres no reason why it wouldnt work if they had
the proper interface.
Hess: How well does it work with
changes in tidal volume, breath-to-
breath, and changes in flow within the

breath, such as with pressure support
ventilation? Can it keep up with those
kinds of changes in flow and maintain
a relatively constant INO concentration?
Gerlach: I dont have the exact numbers, but we tested and compared the
Siemens 300, the Drager NOdomo device, and the so-called Pulmonox device. The NOdomo and Siemens are
more or less comparable. The Siemens
is a little bit better in constant delivery. The Pulmonox is very bad. It has
variations of about 300% up and down
during the delivery of INO. You cant
buy this device any more. The classic
Pulmonox device is out. Now they
have a smaller one, called Mini-Pulmonox that is a little better in terms of
constant delivery, but as you already
mentioned, its supplied only with
electrochemical monitoring. Both the
NOdomo and Siemens are very constant even at low volumes, for instance,
in pediatric patients when high concentrations are used. With an artificial
lung model, changing resistance and
compliance with extreme variations,
the constant signal of NO in both devices is very good.
Branson: I think Sydows paper1 in
Chest evaluates the NOdomo. Its very
accurate with pressure support. It tends
to over-deliver, I think, by about
510%, but I dont know whether
thats an issue. The Pulmonox device
is sold by SensorMedics here, the mini
device, here in the United States. But
they only use it for neonates and pediatrics. Its not sold for adults.
REFERENCE
1. Sydow M, Bristow F, Zinserling J, Allen
SJ. Flow-proportional administration of nitric oxide with a new delivery system: inspiratory nitric oxide concentration fluctuation during different flow conditions.
Chest 1997;112(2):496504.
Channick: What about transport

ventilators and INO delivery? Whats
the state of the art, or is there any?
Branson: I dont know that there is

any. The ventilator is not so important
as the INO delivery device. If the INO
delivery device is capable of monitoring the flow rates within the range of
what that ventilator produces, then you
ought to be able to deliver nitric oxide
with it. Weve only used it in one case,
where a patient went to angiography
for bleeding from pelvic trauma to get
bead embolization to prevent bleeding, and the patient was down in the
CT area for probably 9 hours. We had
him on an Impact 750 ventilator measuring the flow and delivering INO
just like we would with any other ventilator, and didnt appear to have any
problem.
Gerlach: The system we are using
is the Siemens 300, which doesnt need
any additional device except the bottle with the primary NO gas. For instance, for high doses, say, 100 ppm,
AND
we often hear the question of whether

this is just due to an FIO2 reduction.
However, we worked with and are still
working with 10,000 ppm primary
gases for dose-response curves. This
is a bottle of, I think, two liters. All
you have to do is if you carry the
patient on a rolling bed, then you just
have to put the small bottle beside
them. Otherwise, its the same device
as for normal ventilation.
Hess: An issue I think Rich (Branson) brought up in his presentation was
that the commercial Siemens device
measures NO in the expiratory limb
of the circuit. Is that true? Because I
think thats problematic. The NO
should be measured in the inspiratory
limb of the circuit, because the NO uptake varies depending on the disease.
Gerlach: The commercially available system has a monitoring system
with an electrochemical cell that can
be connected to the outflow valve, and
you can also connect it everywhere
you have tubing connectors: you can
put it at the PEEP valve and in the
MONITORING
inspiratory limb. But this is, of course,

not very useful, and the system we
used was an additional external chemiluminescence analyzer.
Branson: In the device from Siemens, is the monitor a mainstream sensor? Does it vacuum off the gas, or is
it directly in line?
Gerlach: Its a mainstream electrochemical sensor, connected with a twoliter reservoir, and you can put this
between the valve and the outflow, or
anywhere between the tubing and the
ventilator. Its like a CO2 mainstream
sensor.
Branson: I think the issue is that
its a mainstream monitor, so if you
try to put it in the inspiratory limb,
downstream from the humidifier, its
never going to work because its always going to be wet, which is why I
think they put it on the expiratory side.
You could put it on top of the humidifier, but you would not be accurately
measuring any NO2 formation that occurred downstream of that site.
307

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Inhaled Nitric Oxide: Delivery Systems and Monitoring

RESPIRATORY CARE MARCH 1999 VOL 44 NO 3

by the difficulties in safe and accurate INO delivery. Early

INHALED NITRIC OXIDE: DELIVERY SYSTEMS

Cylinders for NO are constructed of an aluminum alloy.

RESPIRATORY CARE MARCH 1999 VOL 44 NO 3

INHALED NITRIC OXIDE: DELIVERY SYSTEMS

Characteristics of a Storage Room for Nitric Oxide

Well ventilated to prevent accumulation of NO . 25 parts per

Compressed Gas Association (CGA) 626 valve outlet has

RESPIRATORY CARE MARCH 1999 VOL 44 NO 3

higher than the amount permitted for drinking water.14

INHALED NITRIC OXIDE: DELIVERY SYSTEMS

RESPIRATORY CARE MARCH 1999 VOL 44 NO 3

INHALED NITRIC OXIDE: DELIVERY SYSTEMS

equimolecular reductions in NO, but only in the presence

RESPIRATORY CARE MARCH 1999 VOL 44 NO 3

connection sites), increased circuit compressible volume,

INHALED NITRIC OXIDE: DELIVERY SYSTEMS

Concentration (in parts

ventilation) at this dose and source gas concentration. At a

Environmental Contamination with

RESPIRATORY CARE MARCH 1999 VOL 44 NO 3

INHALED NITRIC OXIDE: DELIVERY SYSTEMS

Calculation of Ambient NO Levels

Room volume in cubic feet 3 air exchanges per hour 3 concentration of NO in

800 ppm NO (0.08%)

0.00012%, or about 1 ppm

were , 100 ppb. They noted that when continuous flow of

RESPIRATORY CARE MARCH 1999 VOL 44 NO 3

INHALED NITRIC OXIDE: DELIVERY SYSTEMS

Limit NO2 production. For reasons provided above,

Delivery Systems for Adult Mechanical Ventilators

RESPIRATORY CARE MARCH 1999 VOL 44 NO 3

INHALED NITRIC OXIDE: DELIVERY SYSTEMS

increase of approximately 30% in both volume control and

RESPIRATORY CARE MARCH 1999 VOL 44 NO 3

INHALED NITRIC OXIDE: DELIVERY SYSTEMS

Risks and Special Controls for NO Delivery Systems, as

Loss of NO therapy and incorrect NO

Reserve (backup) NO delivery system

NO 5 nitric oxide; NO2 5 nitrogen dioxide. (From Reference 11, with

gas concentration and inspiratory flow using the following

tion. The gas supply to the nebulizer contains the NO

RESPIRATORY CARE MARCH 1999 VOL 44 NO 3

INHALED NITRIC OXIDE: DELIVERY SYSTEMS

dose of NO must be precisely titrated so that the delivered

RESPIRATORY CARE MARCH 1999 VOL 44 NO 3

Inspiratory phase injection delivers NO at a constant

INHALED NITRIC OXIDE: DELIVERY SYSTEMS

Fig. 6. NO delivery system used for mechanically ventilated adult

Hess and colleagues have designed a pre-mixing system

(as much as 2 ppm in our experience) of NO is delivered

RESPIRATORY CARE MARCH 1999 VOL 44 NO 3

INHALED NITRIC OXIDE: DELIVERY SYSTEMS

Nomogram to Determine Flowmeter Setting to Achieve Approximate Delivered INO Concentration

[NO] 5 (NO flow 3 source ppm) 4 (NO flow