The beneficial effects of inhaled nitric oxide in patients with severe traumatic brain injury complicated by acute respiratory distress syndrome: a hypothesis.

Abstract

BACKGROUND: The Iraq war has vividly brought the problem of traumatic brain injury to the foreground. The costs of death and morbidity in lost wages, lost taxes, and rehabilitative costs, let alone the emotional costs, are enormous. Military personnel with traumatic brain injury and acute respiratory distress syndrome may represent a substantial problem. Each of these entities, in and of itself, may cause a massive inflammatory response. Both presenting in one patient can precipitate an overwhelming physiological scenario. Inhaled nitric oxide has recently been demonstrated to have anti-inflammatory effects beyond the pulmonary system, in addition to its ability to improve arterial oxygenation. Furthermore, it is virtually without side effects, and can easily be applied to combat casualties or to civilian casualties. PRESENTATION OF HYPOTHESIS: Use of inhaled nitric oxide in patients with severe traumatic brain injury and acute respiratory distress syndrome will show a benefit through improved physiological parameters, a decrease in biochemical markers of inflammation and brain injury, thus leading to better outcomes. TESTING OF HYPOTHESIS: A prospective, randomized, non-blinded clinical trial may be performed in which patients meeting the case definition could be entered into the study. The hypothesis may be confirmed by: (1) demonstrating an improvement in physiologic parameters, intracranial pressure, and brain oxygenation with inhaled nitric oxide use in severely head injured patients, and (2) demonstrating a decrease in biochemical serum markers in such patients; specifically, glial fibrillary acidic protein, inflammatory cytokines, and biomarkers of the hypothalamic-pituitary-adrenal axis, and (3) documentation of outcomes. IMPLICATIONS OF HYPOTHESIS: Inhaled nitric oxide therapy in traumatic brain injury patients with acute respiratory distress syndrome could result in increased numbers of lives saved, decreased patient morbidity, decreased hospital costs, decreased insurance carrier and government rehabilitation costs, increased tax revenue secondary to occupational rehabilitation, and families could still have their loved ones among them.

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BioMed Central
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Journal of Trauma Management &
Outcomes
Open Access
Hypothesis
The beneficial effects of inhaled nitric oxide in patients with severe
traumatic brain injury complicated by acute respiratory distress
syndrome: a hypothesis
Thomas J Papadimos
Address: Department of Anesthesiology, University of Toledo, College of Medicine, 3000 Arlington Avenue, Toledo, Ohio 43614, USA
Email: Thomas J Papadimos - thomas.papadimos@utoledo.edu
Abstract
Background: The Iraq war has vividly brought the problem of traumatic brain injury to the
foreground. The costs of death and morbidity in lost wages, lost taxes, and rehabilitative costs, let
alone the emotional costs, are enormous. Military personnel with traumatic brain injury and acute
respiratory distress syndrome may represent a substantial problem. Each of these entities, in and
of itself, may cause a massive inflammatory response. Both presenting in one patient can precipitate
an overwhelming physiological scenario. Inhaled nitric oxide has recently been demonstrated to
have anti-inflammatory effects beyond the pulmonary system, in addition to its ability to improve
arterial oxygenation. Furthermore, it is virtually without side effects, and can easily be applied to
combat casualties or to civilian casualties.
Presentation of hypothesis: Use of inhaled nitric oxide in patients with severe traumatic brain
injury and acute respiratory distress syndrome will show a benefit through improved physiological
parameters, a decrease in biochemical markers of inflammation and brain injury, thus leading to
better outcomes.
Testing of hypothesis: A prospective, randomized, non-blinded clinical trial may be performed
in which patients meeting the case definition could be entered into the study. The hypothesis may
be confirmed by: (1) demonstrating an improvement in physiologic parameters, intracranial
pressure, and brain oxygenation with inhaled nitric oxide use in severely head injured patients, and
(2) demonstrating a decrease in biochemical serum markers in such patients; specifically, glial
fibrillary acidic protein, inflammatory cytokines, and biomarkers of the hypothalamic-pituitary-
adrenal axis, and (3) documentation of outcomes.
Implications of hypothesis: Inhaled nitric oxide therapy in traumatic brain injury patients with
acute respiratory distress syndrome could result in increased numbers of lives saved, decreased
patient morbidity, decreased hospital costs, decreased insurance carrier and government
rehabilitation costs, increased tax revenue secondary to occupational rehabilitation, and families
could still have their loved ones among them.
Background
Traumatic brain injury (TBI) affects 1.4 million Americans
annually, which includes 1.1 million emergency depart-
ment visits, 235,000 hospitalizations, and 50,000 deaths
Published: 14 January 2008
Journal of Trauma Management & Outcomes 2008, 2:1 doi:10.1186/1752-2897-2-1
Received: 18 October 2007
Accepted: 14 January 2008
This article is available from: http://www.traumamanagement.org/content/2/1/1
© 2008 Papadimos; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[1]. Approximately 5.3 million Americans are disabled
with TBI [2] at a cost of $60 billion annually [3]. The Iraq
war has provided additional cases and cost. At least 28%
of wounded personnel have TBI resulting in $600,000 to
$4,300,000 of care per patient [4-6]. This is based on 2824
wounded personnel as of August 2005 [6].
Complications occur frequently in TBI, and respiratory
dysfunction represents a primary non-neurological sys-
tem failure [7]. These patients are confronted with a mas-
sive inflammatory response with the release of cytokines
[8] and neuropeptides [9] that are deleterious to the brain.
Furthermore, this inflammatory response renders the
lungs less tolerant of stressors causing ischemia-reper-
fusion and subsequent mechanical insults [10], i.e., mas-
sive brain injury may incite ventilator induced lung injury.
This occurs through neurogenic pulmonary edema [7],
ventilator associated pneumonia [11], and/or acute lung
injury (ALI)/adult respiratory distress syndrome (ARDS)
[12] that may be secondary to inflammatory ultrastruc-
tural changes in pneumatocyte type II cells [13] through
the initiation/migration of activated neutrophils into the
lungs [14]. In the face of severe pulmonary insufficiency,
such as occurs in neurogenic pulmonary edema, pneumo-
nia, and ALI/ARDS, oxygen delivery to the brain may be
compromised. INO delivered at 10–80 parts per million is
an effective pulmonary vasodilator that rapidly degrades
in vivo [15] and improves arterial oxygenation [16-20].
However, clinical trials have not shown improved out-
comes with its use in ARDS [21-23], including a large
phase III study in the United States [24]. Nonetheless,
inhaled nitric oxide (INO) has been successfully used
twice in TBI patients with ALI/ARDS [25,26].
In severe TBI (Glasgow coma scale {GCS} ≥ 8) it has been
recommended that the partial pressure of oxygen in arte-
rial blood be maintained at a minimum of 100 mm Hg
[27], cerebral perfusion pressure maintained between 60–
70 mm Hg [28], and the partial pressure of carbon dioxide
in arterial blood maintained at 32–35 mm Hg [29].
Increased intracranial pressure (ICP) may then be pre-
vented from occurring. Effective oxygen delivery and
decreased inflammation will assist in meeting these
parameters.
Very recent basic science and clinical research has brought
into question the results of the above-mentioned ARDS
trials, especially as they may relate to TBI. Mathru et al
have demonstrated that INO attenuates ischemia-reper-
fusion injury in the lower extremities of humans [30], and
Gazoni et al have demonstrated such attenuation in ani-
mal lungs [31]. Hu et al concluded that INO decreased
oxidative damage and inflammation along with reduced
alveolar leakage in mature adult rat lungs [32]. Most
importantly, Aaltoren et al have shown that pigs with
meconium aspiration have hippocampal neuronal injury
[33], however when INO is administered to pigs with
meconium aspiration, hippocampal neuronal injury is
inhibited [34]. This occurs through diminished DNA oxi-
dation in the hippocampus and is accompanied by
decreased levels of glutathione, a biomarker of oxidative
stress [34]. Finally, Da et al demonstrated that INO, with
concurrent administration of steroids, will decrease the
inflammatory response in porcine sepsis through up-reg-
ulation of the glucocorticoid receptor (GR) [35].
Thus, use of INO in patients with severe TBI and ARDS
will show a benefit through improved physiological
parameters and a decrease in biochemical markers of
inflammation and brain injury, leading to better out-
comes.
Presentation of the hypothesis
While INO is a potent pulmonary vasodilator, and has
been thought to remain only in the pulmonary system,
recent work has demonstrated that INO may go down-
stream to improve other organs [35] in the following
manner. The view that red blood cells (RBC) consume NO
has been altered to one in which the RBC is a deliverer of
NO [36]. NO reacts, not only with heme iron, but also
with cysteine (Cys)-93 on the hemoglobin β-unit [37].
NO reactions with heme iron cause NO's inactivation, but
S-nitrosylation of Cys-93 makes hemoglobin a carrier of
NO bioactivity [38]. Also, an increase in S-nitrosothiol
proteins occurs in sepsis (including RBC S-nitrosothio-
hemoglobin and hemoglobin [Fe]NO) [39,40]. This accu-
mulation of hemoglobin [Fe]NO as a 5-coordinate α-
heme NO does not allow NO release to the Cys-β93 resi-
due. However, dissociation of oxygen from the 5-coordi-
nate α-heme-NO occurs so that delivery of oxygen occurs
without an extensive vasodilation [41]. Thus, according to
Goldfarb and Cinel, NO excess that interacts with hemo-
globin will lead to products that prevent NO toxicity [42].
Goldfarb and Cinel also point out that S-nitrosylated
albumin can transport NO bioactivity downstream, i.e., to
other organs [42] and that NO stabilized through hemo-
globin or other proteins by reversible S-nitrosylation may
be the way NO extrapulmonary effects get downstream
[42].
INO and glucocorticoid regulation may be important, not
only in sepsis, but also in TBI. Da et al have demonstrated
that glucocorticoid receptor (GR) up-regulation decreased
the inflammatory response in a porcine model of sepsis
using INO in combination with glucocorticoids (neither
intervention worked well alone) [35]. In contrast to Da's
work, though, up-regulation of GR in the central nervous
system has been considered detrimental in some animal
models of TBI [43-46], but these studies did not involve
INO. In humans high levels of total serum cortisol

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(CORT), adrenocorticotropic hormone (ACTH), and cate-
cholamines are present early in TBI [47,48]. However, a
low plasma ACTH concentration early in TBI is associated
with better intensive care unit survival [49,50]. This may
be part of an adaptive down-regulation as demonstrated
by Lee et al in which cortical GR expression was down reg-
ulated after 6 hours of injury in the ischemic cortex of rats
[51]. Thus indicating an organism's attempt at neuropro-
tection. It may be that INO reaching the central nervous
system allows brain GR to be down regulated.
In view of new findings on its downstream effects and lack
of side effects [52], INO may be delivered to the brain and
cause GR expression in the brain/hippocampus to be
muted. Thus enhancing a neuroprotective effect while at
the same time allowing the rest of the body to up-regulate
GR in response to steroids and INO administration, and
assisting the body in its anti-inflammatory efforts.
Testing the hypothesis
The hypothesis may be confirmed by achieving the fol-
lowing aims: (1) demonstrating an improvement in phys-
iologic parameters, ICP, and brain oxygenation with INO
use in patients with severe TBI, and (2) demonstrating a
decrease in biochemical serum markers of TBI with INO
use. Specifically, glial fibrillary acidic protein (GFAP,
which is specific for TBI [53,54]), inflammatory cytokines
(TGF-β, TNF-α, IL-2, IL-6, IL-1β), CORT, ACTH, and corti-
sol-binding globulin will be evaluated.
A prospective, randomized, non-blinded clinical trial may
be performed in which patients meeting the following
case definition could be entered into the study: a subject
whose GCS is ≥ 8, who has clinically qualified for intrac-
ranial pressure monitoring, whose trachea is intubated,
whose oxygenation and ventilation is being supported by
a ventilator, and in whom the ratio of partial pressure of
oxygen in arterial blood to inspired oxygen is less than
200 with radiographic evidence of lung injury. The sub-
jects should be randomized into two groups, those that
will receive treatment without INO, and those who will
receive INO. Invasive monitoring of CNS, renal, and car-
diopulmonary parameters will be necessary. Follow-up at
28 days and 6 months can be through hospital records, an
information-gathering tool, and the social security death
index.
Biochemical markers will be evaluated by enzyme-linked
immunosorbent assays (ELISA). Physiologic monitors
shall include: pulmonary artery catheter for cardio-pul-
monary-vascular indices (cardiac output (CO), cardiac
index (CI), mixed venous oxygenation (SVO2), central
venous pressure (CVP), systemic vascular resistance index
(SVRI), pulmonary vascular resistance index (PVRI),
stroke volume index (SVI), right ventricular ejection frac-
tion (RVEF), right ventricular end diastolic volume
(RVEDV), left ventricular stroke work index (LVSWI),
right ventricular stroke work index (RVSWI), oxygen deliv-
ery (DO2), oxygen uptake (VO2), and oxygen extraction
ratio (O2ER)), arterial line for blood pressure, foley cath-
eter with abdominal pressure monitor, LICOX® Brain Oxy-
gen tissue monitor (records brain partial pressure of
oxygen, intracranial pressure, and brain temperature), cer-
ebral oximetry, pulse oximetry, and transcranial doppler
monitor for middle cerebral artery velocities. Also arterial
blood gases, cerebral perfusion pressure, lactate, and
methemoglobin will be monitored.
The subjects' entire physiologic/biochemical/hematologic
profiles will be available for analysis, such as hemoglobin,
hematocrit, electrolytes, etc., as will the injury severity
score (ISS) and Apache II score.
Implications of hypothesis
Inhaled nitric oxide in humans with TBI and ARDS has
been used successfully on two occasions to improve out-
comes. It has also been shown to be effective in hippoc-
ampal preservation in animals. Positive results could
immediately affect treatment of military and civilian TBI
patients worldwide. A decreased inflammatory response
and increased arterial oxygen tension in TBI patients with
ARDS, through the use of INO, could potentially lead to
decreased ICP and better brain oxygenation. This would
result in increased numbers of lives saved, decreased
patient morbidity, decreased hospital costs, decreased
insurance carrier and government rehabilitation costs,
increased tax revenue secondary to occupational rehabili-
tation, and families could stay intact.
Competing interests
The author(s) declare that they have no competing inter-
ests.
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