Inhaled Nitric Oxide in Brain Injury

NCT ID: NCT03260569

Last Updated: 2025-04-30

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

13 participants

Study Classification

INTERVENTIONAL

Study Start Date

2018-12-12

Study Completion Date

2023-12-28

Brief Summary

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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

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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.

Conditions

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Traumatic Brain Injury

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Following initial non-invasive measurements, patients will be randomized to either an active treatment (inhaled nitric oxide at 30 parts per million) or placebo (nitrogen only). After two hours, measurements will be reassessed. If the patient remains on the mechanical ventilator at 72 hours post-admission, a third set of non-invasive measurements will be taken.
Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Investigators
Both nitric oxide and placebo nitrogen will be made available in unmarked cylinders.

Study Groups

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Inhaled Nitric Oxide

Inhaled nitric oxide at 20 parts per million, administered once during first 36 hours following admission

Group Type ACTIVE_COMPARATOR

Inhaled Nitric Oxide

Intervention Type DRUG

Patients randomized to this arm will receive inhaled nitric oxide 20 parts per million.

Placebo

Nitrogen only, administered once during first 36 hours following admission

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Nitrogen plus oxygen

Interventions

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Inhaled Nitric Oxide

Patients randomized to this arm will receive inhaled nitric oxide 20 parts per million.

Intervention Type DRUG

Placebo

Nitrogen plus oxygen

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

* Hospital admission with traumatic brain injury (penetrating or blunt)
* Requirement for mechanical ventilation
* Glasgow Coma Score \> 3

Exclusion Criteria

* Brain death
* Expected survival \< 48 hours
* Air leak (bronchopleural fistula, tracheal injury)
* Current inspired oxygen concentration (FiO2) \> 0.65
* Hemodynamic instability (systolic blood pressure \< 100 mm Hg, cardiac arrhythmia)
* Uncontrolled intracranial pressure (\> 20 mm Hg)
* Spinal cord injury with hypotension
* Severe acute respiratory distress syndrome (ARDS) (PaO2/FiO2 \< 100)
* Chest abbreviated injury score (AIS) \> 3
* First rib fracture
* Flail chest
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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University of Cincinnati

OTHER

Sponsor Role lead

Responsible Party

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Michael Goodman

Instructor

Responsibility Role PRINCIPAL_INVESTIGATOR

Locations

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University of Cincinnati

Cincinnati, Ohio, United States

Site Status

Countries

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United States

References

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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. doi: 10.1164/arrd.1979.119.1.33.

Reference Type BACKGROUND
PMID: 420436 (View on PubMed)

Cooper KR, Boswell PA. Accurate measurement of functional residual capacity and oxygen consumption of patients on mechanical ventilation. Anaesth Intensive Care. 1983 May;11(2):151-7. doi: 10.1177/0310057X8301100212.

Reference Type BACKGROUND
PMID: 6346942 (View on PubMed)

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. doi: 10.1007/s00134-006-0406-0. Epub 2006 Oct 20.

Reference Type BACKGROUND
PMID: 17053881 (View on PubMed)

Gruber A, Reinprecht A, Illievich UM, Fitzgerald R, Dietrich W, Czech T, Richling B. Extracerebral organ dysfunction and neurologic outcome after aneurysmal subarachnoid hemorrhage. Crit Care Med. 1999 Mar;27(3):505-14. doi: 10.1097/00003246-199903000-00026.

Reference Type BACKGROUND
PMID: 10199529 (View on PubMed)

Holland MC, Mackersie RC, Morabito D, Campbell AR, Kivett VA, Patel R, Erickson VR, Pittet JF. The development of acute lung injury is associated with worse neurologic outcome in patients with severe traumatic brain injury. J Trauma. 2003 Jul;55(1):106-11. doi: 10.1097/01.TA.0000071620.27375.BE.

Reference Type BACKGROUND
PMID: 12855888 (View on PubMed)

Pelosi P, Severgnini P, Chiaranda M. An integrated approach to prevent and treat respiratory failure in brain-injured patients. Curr Opin Crit Care. 2005 Feb;11(1):37-42. doi: 10.1097/00075198-200502000-00006.

Reference Type BACKGROUND
PMID: 15659943 (View on PubMed)

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. doi: 10.1016/j.expneurol.2014.10.017. Epub 2014 Oct 29.

Reference Type BACKGROUND
PMID: 25447937 (View on PubMed)

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. doi: 10.1038/jcbfm.2012.176. Epub 2012 Nov 28.

Reference Type BACKGROUND
PMID: 23188422 (View on PubMed)

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. doi: 10.1186/1757-7241-17-5.

Reference Type BACKGROUND
PMID: 19222848 (View on PubMed)

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):1. doi: 10.1186/1752-2897-2-1.

Reference Type BACKGROUND
PMID: 18272001 (View on PubMed)

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):351-3 , 3rd contents page. doi: 10.1097/00000539-200108000-00023.

Reference Type BACKGROUND
PMID: 11473859 (View on PubMed)

Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis K Jr, 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 Jan;26(1):15-23. doi: 10.1097/00003246-199801000-00011.

Reference Type BACKGROUND
PMID: 9428538 (View on PubMed)

Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. The European Study Group of Inhaled Nitric Oxide. Intensive Care Med. 1999 Sep;25(9):911-9. doi: 10.1007/s001340050982.

Reference Type BACKGROUND
PMID: 10501745 (View on PubMed)

Provided Documents

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Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

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2017 Goodman

Identifier Type: -

Identifier Source: org_study_id

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