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

Department of Anesthesiology, University of Toledo, College of Medicine, 3000 Arlington Avenue, Toledo, Ohio 43614, USA. .
Journal of Trauma Management & Outcomes 02/2008; 2(1):1. DOI: 10.1186/1752-2897-2-1
Source: PubMed


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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Available from: Thomas John Papadimos, Oct 17, 2014
    • "Terpolilli et al.,[89] observed the protective effect of INO as it selectively dilates cerebral resistant vessels in hypoperfused areas, and thus, improved collateral blood circulation in the brain. It was hypothesized by Papadimos[10] that INO could improve metabolic function and prevent death of the ischemic penumbra under conditions of transient reduction of CBF. Furthermore, regional vascular protective effects were nicely described by Cannon et al.[11] "
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    ABSTRACT: Patients with traumatic brain injury complicated by acute respiratory distress syndrome (ARDS) are not uncommon in intensive care unit (ICU). The ventilatory management of patients combined with both of these catastrophic conditions is not straightforward. Evidence-based permissive hypercapnia strategy for ARDS could be fatal in patients with intracranial hypertension. Adjunctive use of inhaled nitric oxide (INO) is well-defined as a rescue therapy in severe ARDS, but its specific role in intracranial hypertension is somewhat uncertain. We report a case, which following traumatic brain injury developed both intracranial hypertension and ARDS. INO was given for ARDS, but coincidentally it also improved the raised intracranial pressure (ICP) and patient's neurological outcome. The case report will be followed by literature review on the role of INO in raised ICP.
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    ABSTRACT: The ventilation of patients with acute brain injuries can present significant challenges. Frequently, guidelines recommending management strategies for patients with traumatic brain injuries come into conflict with what is now considered best ventilatory practice. In this review, we will explore many of these areas of conflict. The use of ventilatory strategies to control partial pressure of carbon dioxide in patients with traumatic brain injury is associated with the development of acute lung injury. Analysis of the International Mission for Prognosis And Clinical Trial (IMPACT) database has confirmed the association between hypoxia and poor neurological outcome. Although a recent meta-analysis has suggested a survival benefit for steroids in acute lung injury, the use of steroids has been associated with a worsening of outcome in patients with traumatic brain injuries and their effects on the brain have not been fully elucidated. There are unlikely to be randomized controlled trials advising how best to ventilate patients with acute brain injuries because of the heterogeneous nature of such injuries. Hypoxia should be avoided. The more widespread use of multimodal brain monitoring, including brain tissue oxygen and cerebral blood flow monitoring, may allow clinicians to tolerate a higher arterial partial pressure of carbon dioxide than has been traditional, allowing a less injurious ventilatory strategy. Modest positive end-expiratory pressure can be used. In severe respiratory failure, most 'rescue' strategies have been attempted in patients with acute brain injuries. Choice of rescue therapy at present is best decided on a case-by-case basis in conjunction with local expertise.
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    ABSTRACT: Although the mechanisms underlying mild traumatic brain injury (mTBI) are becoming well understood, treatment options are still limited. In the present study, mTBI was induced by a weight drop model to produce a closed head injury to mice and the effect of inhaled nitric oxide (INO) was evaluated by a short term memory task (object recognition task) and immunohistochemical staining of glial fibrillary acidic protein (GFAP) and CD45 for the detection of reactive astrocytes and microglia. Results showed that mTBI model did not produce brain edema, skull fracture or sensorimotor coordination dysfunctions. Mice did however exhibit a significant deficit in short term memory (STM) and strong inflammatory reaction in the ipsilateral cortex and hippocampus compared to sham-injured controls 24hrs after mTBI. Additional groups of untreated mice tested 3 and 7 days later, demonstrated that recognition memory had recovered to normal levels by Day 3. Mice treated with 10ppm INO for 4 or 8hrs, beginning immediately after TBI demonstrated significantly improved STM at 24hrs when compared with room air controls (p<0.05). Whereas mice treated with 10ppm INO for 24hrs showed no improvement in STM. Mice treated with INO 10ppm for 8hrs exhibited significantly reduced microglia and astrocyte activation compared with room air controls. These data demonstrate that mTBI produces a disruption of STM which is evident 24hrs after injury and persists for 2-3 days. Treatment with low concentration or short durations of INO prevents this memory loss and also attenuates the inflammatory response. These findings may have relevance for the treatment of patients diagnosed with concussion.
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