Clinical trial NCT03260569
Conditions: Traumatic Brain Injury
Keywords: Mechanical ventilation Inhaled nitric oxide
Sponsor: University of Cincinnati
Start date: 2018-12-12; Completion date: 2023-12-28
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the changes in respiratory mechanics following traumatic brain injury and determine the effect of inhaled nitric oxide on gas exchange.

Detailed description:
Intubation and mechanical ventilation are common treatments in the care of patients with traumatic brain injury (TBI). Intubation allows for airway control and facilitates removal of respiratory secretions. Mechanical ventilation allows control of arterial carbon dioxide to aid in control of intracranial pressure. Recent evidence suggests that lung protective ventilation (tidal volumes of 6 ml/kg of predicted body weight and moderate positive end expiratory pressure) improves outcomes following brain injury and reduces brain-lung cross talk.

The treatment of respiratory failure in TBI must balance the need to improve lung function with the negative consequences of increased intrathoracic pressure on mean arterial pressure, intracranial pressure and venous return. Traditional treatment of increasing positive end expiratory (PEEP) and mean airway pressure then, represent competing interests. Methods for improving arterial oxygenation while avoiding negative hemodynamic effects are needed.

The impact of head injury on respiratory mechanics has been studied in just a few clinical investigations. (1-3) Of note, the earliest of these noted that the ventilation perfusion (V/Q) matching following TBI was not the result of lung collapse or parenchymal lung disease but secondary to alterations in perfusion. There are three possibilities for this finding:

1. redistribution in regional perfusion, which is partially mediated by the hypothalamus
2. pulmonary microembolism, leading to increased dead space
3. lung surfactant depletion due to excessive sympathetic stimulation and hyperventilation.

The introduction of inhaled pulmonary vasodilators such as inhaled nitric oxide or aerosolized epoprostenol offer an opportunity to improve oxygenation in patients with TBI without increasing airway pressures in the face of V/Q inequalities.

This study will evaluate the changes in respiratory mechanics following TBI and determine the effect of inhaled nitric oxide on gas exchange.

Arms: arm 1: Inhaled nitric oxide at 20 parts per million, administered once during first 36 hours following admission arm 2: Nitrogen only, administered once during first 36 hours following admission
Interventions: intervention 1: Inhaled Nitric Oxide intervention 2: Placebo
Intervention descriptions: intervention 1: Patients randomized to this arm will receive inhaled nitric oxide 20 parts per million. intervention 2: Nitrogen plus oxygen

Protocol documents:
Prot_SAP_003.pdf: 
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Study Title:  Respiratory Mechanics Following Brain Injury: The role of 
inhaled nitric oxide
Principal Investigator: Michael Goodman
Sponsor: USAF 711th Human Performance Wing


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1. Length of time for research
a. 18 months patient enrollment and data collection 
b. 6 months data analysis and preparation of manuscript
2. Research Location(s):  All subjects will be patients in the surgical or neurosurgical 
intensive care unit at the University of Cincinnati Medical Center.  Study records will 
be maintained in the researchers’ office in the MSB.
3. Abstract/Brief Overview:
Intubation and mechanical ventilation are common treatments in the care of 
patients with traumatic brain injury (TBI).  Intubation allows for airway control and 
facilitates removal of respiratory secretions.  Mechanical ventilation allows control 
of arterial carbon dioxide to aid in control of intracranial pressure.  Recent evidence 
suggests that lung protective ventilation (tidal volumes of 6 ml/kg of predicted body 
weight and moderate positive end expiratory pressure) improves outcomes 
following brain injury and reduces brain-lung cross talk. 
The treatment of respiratory failure in TBI must balance the need to improve lung 
function with the negative consequences of increased intrathoracic pressure on 
mean arterial pressure, intracranial pressure and venous return.  Traditional 
treatment of increasing positive end expiratory (PEEP) and mean airway pressure 
then, represent competing interests.  Methods for improving arterial oxygenation 
while avoiding negative hemodynamic effects are needed.
The impact of head injury on respiratory mechanics has been studied in just a few 
clinical investigations. (1-3)  Of note, the earliest of these noted that the ventilation 
perfusion (V/Q) matching following TBI was not the result of lung collapse or 
parenchymal lung disease but secondary to alterations in perfusion. There are 
three possibilities for this finding:
1. redistribution in regional perfusion, which is partially mediated by the 
hypothalamus
2. pulmonary microembolism, leading to increased dead space 
3. lung surfactant depletion due to excessive sympathetic stimulation and 
hyperventilation.
The introduction of inhaled pulmonary vasodilators such as inhaled nitric oxide or 
aerosolized epoprostenol offer an opportunity to improve oxygenation in patients 
with TBI without increasing airway pressures in the face of V/Q inequalities.
This study will evaluate the changes in respiratory mechanics following TBI and 
determine the effect of inhaled nitric oxide on gas exchange.


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4. Purpose of Study: 
To determine the changes in respiratory mechanics in patients with traumatic brain 
injury (within 36 hours of admission and day 3 following admission.
To evaluate the effect of inhaled nitric oxide on gas exchange in patients with 
traumatic brain injury within 36 hours of admission. 
Hypothesis: Inhaled nitric oxide improves oxygenation and reduces deadspace to 
tidal volume ratio following TBI.
5. Background:
Intubation and mechanical ventilation are common treatments in the care of 
patients with traumatic brain injury (TBI).  Intubation allows for airway control and 
facilitates removal of respiratory secretions.  Mechanical ventilation allows control 
of arterial carbon dioxide to aid in control of intracranial pressure.  Recent evidence 
suggests that lung protective ventilation (tidal volumes of 6 ml/kg of predicted body 
weight and moderate positive end expiratory pressure) improves outcomes 
following brain injury and reduces brain-lung cross talk. Figure 1.
Respiratory failure following traumatic brain injury is a common complication 
resulting in hypoxemia and is associated with release of inflammatory mediators 
which may damage distal organs including the brain.  The etiology of respiratory 


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failure following brain injury is multifactorial.  Isolated head trauma is associated 
with neurogenic pulmonary edema and changes in ventilation perfusion matching.  
Concomitant trauma to the chest and pulmonary contusion may further worsen 
lung injury.  It has been suggested that brain injury primes the lung to be a greater 
risk to a second hit (pneumonia, ventilator induced lung injury, lung contusion). 
Loss of consciousness can lead to aspiration of oral or gastric contents leading to 
pneumonia. Importantly, respiratory failure following TBI is implicated in 50% of 
deaths and prolonged ICU and hospital stay. (4,5)
The treatment of respiratory failure in TBI must balance the need to improve lung 
function with the negative consequences of increased intrathoracic pressure on 
mean arterial pressure, intracranial pressure and venous return.  Traditional 
treatment of increasing PEEP and mean airway pressure then, represent 
competing interests.  Methods for improving arterial oxygenation while avoiding 
negative hemodynamic effects are needed.
The impact of head injury on respiratory mechanics has been studied in just a few 
clinical investigations. (1-3)  Of note, the earliest of these noted that the ventilation 
perfusion (V/Q) matching following TBI was not the result of lung collapse or 
parenchymal lung disease but secondary to alterations in perfusion. There are 
three possibilities for this finding:
1. redistribution in regional perfusion, which is partially mediated by the 
hypothalamus
2. pulmonary microembolism, leading to increased dead space 
3. lung surfactant depletion due to excessive sympathetic stimulation and 
hyperventilation.
The introduction of inhaled pulmonary vasodilators such as inhaled nitric oxide or 
aerosolized epoprostenol offer an opportunity to improve oxygenation in patients 
with TBI without increasing airway pressures in the face of V/Q inequalities.
In 1983, Cooper and Boswell demonstrated that hypoxemia in a series of 21 
patients with head injury was related to a decrease in functional residual capacity 
and increased shunt. (2) In this study the addition of 10 cm H2O PEEP reversed 
the fall in FRC and improved oxygenation. However, these patients were all 
paralyzed and nursed in the supine position.  Paralysis and the supine position are 
known to decrease FRC even in normal subjects under anesthesia.  
More recently, Koutsoukou et al evaluated 21 subjects with brain injury (intracranial 
hemorrhage and TBI) and no evidence of acute lung injury and found that PEEP 
of 10 cm H2O prevented a deterioration in respiratory mechanics at five days.  On 
day 1, PaO2/FIO2 was > 400 (FIO2= 0.46) but both lung elastance and airways 
resistance were slightly elevated in both groups. These findings are not 


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unexpected in the presence of an endotracheal tube in a sedated subject lying in 
bed head up. These changes in respiratory mechanics worsened after day 5 and 
only elastance was spared in the group receiving 10 of PEEP. (3)
Mechanical ventilation following TBI is provided with the normal goals, reduce the 
work of breathing, provide adequate oxygenation, maintain normo- or hypocapnia 
and avoid lung injury.  However, in an effort to improve brain tissue PaO2 (TbO2) 
mechanical ventilation in TBI may include increases in mean airway pressure and 
FIO2 unrelated to the degree of lung dysfunction.  Ventilatory support is always a 
balance of competing interests.  Increases in airway pressure by increasing tidal 
volume, prolonging inspiratory time or increasing PEEP must be balanced against 
the risk of lung injury and hemodynamic interference.  In TBI these must be 
furthered balanced against the impact on mean arterial pressure, cerebral 
perfusion pressure and venous return. (6)
Inhaled nitric oxide (INO) is a selective pulmonary vasodilator that at low doses (5-
20 ppm) improves V/Q matching and at higher doses (80 ppm) reduces pulmonary 
artery pressures.  Nitric oxide plays a role in a number of biologic processes and 
pathways that have been associated with improvements in brain function. (7,8) 
INO has been used in patients with TBI with successful increases in oxygenation 
in small case series. (10-11). These reports are not systematic applications of INO 
but rather rescue therapy in the face of ARDS.
The use of INO in ARDS has not proven to impact outcomes. (12-13) Several 
studies have shown improved gas exchange but no changes in morbidity or 
mortality.  Despite these findings, INO is often used in ARDS to help improve gas 
exchange without increasing the risk of lung injury by increasing lung volumes or 
pressures.
This study will determine the etiology of lung dysfunction following TBI and 
describe the effect of INO on cardiorespiratory variables. 
Inhaled nitric oxide (INOmax) is FDA approved and delivered via the INOmax DSIR 
and FDA cleared delivery and monitoring device.  The use of inhaled nitric oxide 
is limited to a maximum of 80 ppm.  We will deliver 20 ppm, a dose that is widely 
prescribed. 
6. Study design:
This study will determine the impact of inhaled nitric oxide on gas exchange and 
hemodynamics in a series of up to 43 patients with TBI over an 18 month period. 
The delivery of INO will be blinded.  The study will also describe the changes in 
respiratory mechanics over a 3 day period.


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All subjects ≥ 18 years of age, admitted to the University of Cincinnati Medical 
Center with traumatic head injury requiring mechanical ventilation within 24 hours 
of admission will be screened for enrollment. 
Following informed consent, patients will have assessments of respiratory function 
accomplished using the existing monitors within the mechanical ventilator.  The 
NM3 respiratory monitor and airway sensor will be placed for continuous recording 
of data.  Within 36 hours of admission, the following measurements will be made 
by the study staff:
1.
Static and dynamic lung compliance using tidal volume and airway pressures 
(CLstatic = Pplat  -PEEP/VT) CLdynamic= Pplat - PEEP/VT).  These 
measurements are made non-invasively using the integral monitoring of the 
mechanical ventilator.
2.
Airway resistance using airway pressures and flow (Raw = Pplat - PEEP/Mid 
Expiratory flow).  These measurements are made non-invasively using the 
integral monitoring of the mechanical ventilator.
3.
Dead space to tidal volume ratio (Vd/Vt) will be calculated using the Enghoff 
modification of the Bohr equation:  Vd/Vt = PaCO2 - PeCO2/PaCO2, where Vd 
is the dead space volume and Vt is the tidal volume; PaCO2 is the partial 
pressure of carbon dioxide in the arterial blood, and PeCO2 is the mixed expired 
partial pressure of carbon dioxide in the expired (exhaled) air. In the absence 
of arterial blood gases we will calculate PaCO2 from determination of alveolar 
concentrations (PACO2) in expired gas.
4.
Functional residual capacity (FRC) will be measured by the automated system 
within the GE Carestation ventilator, which uses a step change in FIO2 to 
measure FRC through nitrogen washout while monitoring oxygen consumption 
and carbon dioxide production. These measurements are made non-invasively 
using the integral monitoring of the mechanical ventilator.
5.
Positive end expiratory pressure (PEEP) will be titrated from baseline PEEP as 
set at time of enrollment to-15 cm H20 (in 5-cm H2O increments) while 
measuring all the variables listed in #1-4 above.  This method will determine 
the best PEEP and determine recruitability of the lung. FRC will be measured 
at three levels of PEEP from baseline to a maximum of 15 cm H2O. This is an 
automated measurement requiring approaximately 15 minutes to complete. If 
the patient develops hypotension (systolic pressure < 90 mm Hg or mean 
arterial pressure < 60 mm Hg) participation in the PEEP trial will be terminated.
6.
Following these initial measurements, patients will be randomized to receive 
either a placebo (nitrogen and oxygen) or inhaled NO at 20 ppm for 2 hours ± 
30 minutes.  After receiving the placebo or inhaled NO, the measurements in 
#1-4 will be reassessed (no change in PEEP will be made during this time 
unless required for clinical purposes).    
7.
If the patient remains on the ventilator at day 3 (72 hours after admission),  1-
6 above will be repeated.


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Subjects will receive placebo or drug for no more than 5 hours total.
If the patient responds to NO with a brisk increase in SpO2 or PaO2 – sudden 
withdrawal of NO can result in a fall in oxygenation (rebound pulmonary hypertension).  
This is uncommon in the absence of pulmonary hypertension.  Prevention of rebound 
pulmonary hypertension is accomplished by increasing FIO2 by 10-20% prior to 
discontinuation of NO, followed by a return to baseline FIO2 over 30 mins.
If ICP goes up by >20% NO will be discontinued.
7. Research data collection/study procedures: 
The patient baseline demographics including injury mechanism, severity and 
distribution, Glasgow coma scale score, age, gender, any witnessed aspiration, 
and lung mechanics measurements listed above will be collected to data sheets 
and then entered into a RedCap database.  We will also record ventilator settings, 
lung compliance, airways resistance, dead space to tidal volume ratio, functional 
residual capacity, blood gases and duration of total mechanical ventilation, days in 
the ICU, hospital days and survival will be collected from the medical record and 
also entered into the RedCap database.   See sequence of events for study 
measures.
8. Specimen collection: 
The following blood samples will be taken:
At baseline up to 3.5 ml will be taken. 1.5 ml for arterial blood gas testing  (tests 
include: arterial pH, PaCO2, PaO2, SaO2 and HCO3) ) and 2 ml for measurement 
of inflammatory mediators specific to the lung.
After 90 to 120 minutes of nitric oxide/placebo delivery, less than 1.5 ml will be 
taken for arterial blood gas testing.
At the end of the study, up to 3.5 ml will be taken. 1.5 ml for arterial blood gas and 
2 ml for measurement of inflammatory mediators specific to the lung.
The blood will be taken from indwelling lines when possible.  If we are unable to 
obtain any of the blood samples, the subject will remain in the study and all other 
data will continue to be collected 


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9. Potential Benefits: 
The detailed measurement of respiratory mechanics will be provided to the clinical 
team.  This information which is not routinely measured can be used to optimize 
ventilator support beyond traditional monitoring.  The determination of FRC and 
recruitability of the lung may assist the clinical team in identifying the best PEEP 
for each individual patient.
If the patient has a significant increase in PaO2 associated with INO/placebo 
delivery, the clinical team can use that information to implement INO therapy as 
part of clinical care. It is unlikely that placebo will increase oxygenation 
appreciably.  We will not unblind the study, the clinical team will have to make this 
decision based on a supposition of INO delivery.
Understanding the changes in respiratory function following TBI and the response 
to INO may improve treatment regimens for future patients.
10.Potential Risks, Discomforts, and inconveniences: 
Level of risk: Greater than minimal risk.
The measurements to be made utilize non-invasive measures of lung volumes, 
flows, and pressures to determine mechanics.
Arterial puncture/venipuncture may cause pain/discomfort, bruising, fainting, and 
infection from phlebotomy sites.
Hypotension in severe pulmonary hypertension and left ventricular failure (very 
uncommon).
Methemoglobinemia has only been reported at 80ppm.  
The stepwise increase in PEEP to determine changes in FRC will be limited to a 
maximum of 15 cm H2O. PEEP can decrease venous return and cause transient 
hypotension. The risk of hemodynamic compromise at these low pressures is 
small.  All subjects will have blood pressure and heart rate continuously monitored 
(as is standard of care) throughout the measurements.
Research personnel will remain at the bedside throughout the measurements of 
respiratory mechanics which will require approximately 30 minutes to complete.
11.Data Safety monitoring plan and/or DSMB: 
Dr. Jason Schrager will act as medical monitor for the study. He will review 
subjects’ research data and adverse events to ensure patient safety.  The medical 


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monitor will have the power to temporarily or permanently halt enrollment if it is 
deemed that patient safety is compromised.
12.Data Analysis: 
Descriptive statistics will be employed to summarize relevant patient demographic 
factors as well as on baseline measurement of clinical variables.  As a check on 
the success of randomization, these variables will be compared between groups 
using t-tests or chi-square tests, as appropriate.
The primary endpoint for this study is a change in PaO2:FiO2 ratio of 20 percent 
or greater between baseline and Day 3.  The proportions of patients achieving 
success according to this criterion will be compared between groups using a two-
sided z-test with pooled variance
Group sample sizes of 19 in group one and 19 in group two achieve 82% power to 
detect a difference between the group proportions of 0.40. The proportion in group 
one (the treatment group) is assumed to be 0.10 under the null hypothesis and 
0.50 under the alternative hypothesis. The proportion in group two (the control 
group) is 0.10. The test statistic used is the two-sided Z test with pooled variance. 
The significance level of the test was targeted at 0.05. The significance level 
actually achieved by this design is 0.0361.
Respiratory mechanics will be presented as descriptive (Mean, SD, range).
Up to 43 subjects may be enrolled, in order to obtain the required 38 evaluable 
subjects.  Patients will be removed from the study and its analysis if extubated by 
the clinical treatment team during the 72 hour NO protocol.
13.Data storage and confidentiality (include sample storage if applicable) 
We will ensure that paper forms are stored securely under lock and key when not 
in the direct custody of an investigator.  Forms may have direct identifiers for the 
purposes of linking data from different medical records. Electronic data will not be 
entered with direct identifiers. A subject number will be used to link back to the 
identifier. The key linking identifier to subject number will not be stored with the 
electronic data. Electronic data will be stored in a password protected Redcap 
database.  Analytical datasets will be stored on secure servers that also limit 
access to the investigator team. Should results of the study be published or 
reported, individual names or other identifying information will not be used.  One 
year after the study and publication are complete the data will be destroyed.


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14.Study Population 
All subjects ≥ 18 and ≤ 75 years of age, admitted to the University of Cincinnati 
Medical Center with traumatic head injury requiring mechanical ventilation within 
24 hours of admission will be screened for enrollment.  Inclusion criteria will 
include:
1.
TBI with head CT findings of injury by penetrating or blunt mechanism
2.
Requiring mechanical ventilation within 24 hours of admission
3.
Negative pregnancy test
Exclusion criteria will include:
1. Brain death
2. Expected survival < 48 hours
3. Pneumothorax causing chest tube to be placed
4. Elevated inspired oxygen concentration (FiO2 > 0.65) on assessment
5. Hemodynamic instability (systolic BP < 100 mmHg, cardiac arrhythmias)
6. Uncontrolled ICP (>20 mmHg) necessitating bolus hypertonic saline therapy
7. Unilateral or bilateral pupil dilation and no reactive pupil
8. Spinal cord injury with hypotension
9. Severe ARDS (PaO2/FIO2 < 100)
10. Flail sternum or unilateral flail chest wall segment (2 places on ≥ 3 ribs)
11. Pulmonary contusion or lobar infiltrate visible on admission chest xray
12. Chronic lung disease with PCO2 > 60mmHg and HCO3- > 32mmol/L
13. ICP >20mmHg longer than 30 minutes despite hypertonic saline or mannitol 
therapy
14. Known heart failure (heart failure defined as EF<20%)
15. CVP > 20 mm Hg with associated systolic blood pressure < 100mmHg
15. Consenting process and plan 
Study personnel will screen patients for inclusion and exclusion. 
Due to the study population, all patients will be cognitively impaired due to their 
injuries, therefore surrogate consent will be obtained. Prior to approaching the 
patient’s LAR/nok we will contact the patient’s admitting physician and the ICU 
attending to assure their assent for patient enrollment. 
The LAR/next of kin is identified using the social worker’s note and contact 
information at the patient’s bedside maintained by the nursing staff.  Once the 


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LAR/next of kin is identified, the investigator and/or the study coordinator arranges 
to meet the LAR/next of kin in a private waiting room.  The study staff allows the 
LAR/next of kin to decide if additional family members, friends, or advisors will be 
present.  We frequently speak to the LAR/next of kin with a clergy member present 
or a family friend who has a medical background. 
The informed consent, including the Health Insurance Portability and 
Accountability Act (HIPAA) authorization language approved by the University of 
Cincinnati and University of Cincinnati Medical Center’s legal teams, is presented 
and reviewed to the LAR/nok and any questions are answered.  
The study is time sensitive but LAR/nok will be allowed to review the consent 
document for 12 hours. A phone number is provided for the LAR/nok to call with 
additional questions. Subjects who cannot be enrolled during the first 36 hours 
after admission to UCMC will be considered screen failures.
Once subjects are deemed to be able to provide informed consent, the researchers 
will take them through the consenting process.
16.Compensation: 
None.  
17.Subject costs: 
None.
18.Literature cited 
1. Schumacker PT, Rhodes GR, Newell JC, Dutton RE, Shah DM, Scovill WA, Powers 
SR. Ventilation-perfusion imbalance after head trauma. Am Rev Respir Dis. 1979 
Jan;119(1):33-43.
2. Cooper KR, Boswell. PA.  Reduced FRC and abnormal oxygenation in patients with 
severe head injury. Chest 1983;84:29-35.
3. Koutsoukou A, Perraki H, Raftopoulou A, Koulouris N, Sotiropoulou C, Kotanidou A, 
Orfanos S, Roussos C. Respiratory mechanics in brain-damaged patients. Intensive 
Care Med. 2006 Dec;32(12):1947-54. 
4. Gruber A, Reinprecht A, Illievich UM, et al. Extracerebral organ dysfunction and 
neurologic outcome after aneurysmal subarachnoid hemorrhage. Crit Care Med 1999; 
27:505–514.
5. Holland MC, Mackersie RC, Morabito D, et al. The development of acute lung injury 
is associated with worse neurologic outcome in patients with severe traumatic brain 
injury. J Trauma 2003; 55:106–111.
6. Pelosi P, Severgnini P, Chiraranda M.  An integrated approach to prevent and treat 
respiratory failure in brain injured patients. Curr Opin Crit Care 2005;11:37-42.


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7. Garry PS, Ezra M, Rowland MJ, Westbrook J, Pattinson KT. The role of the nitric oxide 
pathway in brain injury and its treatment--from bench to bedside. Exp Neurol. 2015 
Jan;263:235-43. 
8. Terpolilli NA, Kim SW, Thal SC, Kuebler WM, Plesnila N. Inhaled nitric oxide reduces 
secondary brain damage after traumatic brain injury in mice. J Cereb Blood Flow 
Metab. 2013 Feb;33(2):311-8. 
9. Papadimos TJ, Medhkour A, Yermal S. Successful use of inhaled nitric oxide to 
decrease intracranial pressure in a patient with severe traumatic brain injury 
complicated by acute respiratory distress syndrome: a role for an anti-inflammatory 
mechanism? Scand J Trauma Resusc Emerg Med. 2009 Feb 17;17:5.
10.Papadimos TJ. The beneficial effects of inhaled nitric oxide in patients with  severe 
traumatic brain injury complicated by acute respiratory distress syndrome: a 
hypothesis. J Trauma Manag Outcomes. 2008 Jan 14;2(1)
11.Vavilala MS, Roberts JS, Moore AE, Newell DW, Lam AM. The influence of inhaled 
nitric oxide on cerebral blood flow and metabolism in a child with traumatic brain injury. 
Anesth Analg. 2001 Aug;93(2):351-357.
12. Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis 
K, Hyers TM, Papadakos P. Effects of inhaled nitric oxide in patients with acute 
respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric 
Oxide in ARDS Study Group. Crit Care Med. 1998;26:15–23. doi: 10.1097/00003246-
199801000-00011.
13.Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in 
acute lung injury: results of a European mulitcentre study. Intensive Care 
Med. 1999;25:911–919