This review has focused on the role of NO and its metabolites in a few disease processes commonly encountered in the acute care setting (sumarized in Fig.
). We have argued that NO and its metabolites nitrate and nitrite can be potential biomarkers that need to be developed further from a diagnostic and prognostic perspective and that is likely to improve management in the acute care setting. Measured exhaled NO (feNO) concentration is immediately available and may be a reliable tool for assessment of airway inflammation in an acute asthma exacerbation. Concentration of NOx in multiple biological samples (plasma, urine, nasal secretion, CSF) measured via HPLC can also be reliably obtained in a rapid manner since the HPLC run per sample takes an average of 8 minutes [8
]. Samples can be batched and run on the HPLC. Hence, both NO and NOx have the potential of being rapidly determined biomarkers for multiple disease processes encountered in the acute care setting (summarized in Fig.
There are limitations to using NO and it’s metabolites as biomarkers. Although NOx can give a fairly reliable idea of systemic NO bioavailability, its concentration in urine and plasma being heavily dependent on renal activity, it cannot be an entirely accurate measure of NOS functionality. Additionally, the presence of nitrite and nitrate in everyday diet adds another restriction towards using NOx in plasma and urine as absolutely indicative of disease process [8
]. Single feNO or NOx determinations simply may not be enough. Thus, sequential measurements of the biomarkers may be needed to get a better handle on the evolution of the disease process, initially as the patient presents in the acute phase and then during the course of critical care. Further, sampling from multiple compartments may be more informative of the disease process. For instance, for AKI, plasma and urinary NOx measurements simultaneously would enable us to determine the fractional excretion of urinary NO metabolites, potentially a more informative parameter for the disease entity than urinary NOx alone.
Given the non-specific nature of NO and its metabolites, they will be unlikely to entirely replace pre-existing tests. Hence, this type of analysis should be in addition to the standard diagnostics and biomarkers. Having a more comprehensive picture will only improve diagnosis, prognosis and effectiveness of treatment and reveal how NO is or may be playing a role in the acute disease process. NO-based analyses might not be able to differentiate between primary pulmonary versus cardiac disease. However, in the setting of a relevant clinical presentation and work up, analyzing NO and metabolites might be a valuable assessment for a NO component, and as such, an adjunct.
General state of health and co-morbid disease states might influence results, and hence have significant limitations on the use of NO or NO metabolites as biomarkers. Dietary NOx, as alluded to above, is a potentially significant limitation due to the fact that in the ED and critical care settings we cannot always predict or select patients based on fasted states or dietary patterns.
There is obvious value in obtaining a non-invasive specimen for determining levels of biomarkers for disease states. This will require the development, validation and then clinical usage of relatively simple, rapid and cost-effective techniques that may sample multiple body fluids collected non-invasively, such as nasal washes, saliva and urine [86
]. Future studies will improve our understanding of NO pathophysiology and thus enable us to rationally devise pharmacological treatment for manipulating NO in acute disease states. While many of these therapeutic approaches remain speculative, better understanding of the underlying mechanisms that regulate NO function will ultimately improve our ability to implement such therapies. Adaptation to and validation of a point-of-care test with the assistance of an industry partner will enable inexpensive screening capacity on a dipstick, point-of-care type of a platform, to aid treatment decisions [87
]. This has obvious global health implications that go far beyond any specific clinical setting [87
Overall, what is most importantly highlighted, for acute care and non-acute care physicians alike, is the ongoing research need to determine the physiological roles of NOx, and if it can be used unequivocally both as diagnostic biomarker of disease and for treatment regimens, in a variety of clinical settings.