Jens K. Rolighed Larsen*, Tina Kobborg, Henrik Zetterberg, Pashtun Shahim, Lars S. Rasmussen
* Aarhus University, Denmark and Centre for Elective Surgery and Neuro Intensive Stepdown Unit, Regionshospitalet Silkeborg, Region Midt, Falkevej 2, DK-8600 Silkeborg, Denmark (t: +45 89 49 55 01; e: firstname.lastname@example.org)
In 1977 , Jöbsis found that transmitted and reflected near-infrared (NIR) signals allowed spectrophotometric analysis and the recording of oxygenation alterations in the forebrain in humans. This was a remarkable observation, considering NIR spectral applications had hitherto been employed in geospatial , pharmaceutical , agricultural  and food  industries. These references speak of a scientific tool that is reliable and consistent, and we could perhaps begin by learning to trust this science.
The problem facing clinicians today is not so much what we see, but whether it should be entrusted to represent something that is deleterious to a person’s health – a ‘clear and present danger’, so to speak. It follows, then, that we must evaluate the risk associated with NIR spectroscopy (NIRS) and, in particular, risk prevention.
Risk of perioperative stroke and the beach chair position
Dr J. Aguirre  has produced an admirable (unpublished) review on the risks of shoulder surgery in the beach chair position (BCP) and the potential benefits of NIRS on stroke prevention in surgery. This highlighted, from a survey among US orthopaedic surgeons, that a low stroke incidence of 0.003% in 200,000 cases (mostly shoulder arthroscopies) was reported. All the reported events (a total of 8) occurred during surgery with patients in the BCP; the risk with the BCP alone ranged between 0.00382% and 0.00461% . Knapp et al.  estimated that the anaesthetic risk of perioperative stroke in men more than 50 years of age is 0.38%. From published studies focusing on non-cardiac, non-neurological surgery, and considering a wide variation in surgical complexity and patient risk factors, an incidence of perioperative stroke ranging from 0.08% to 1.0% has been reported [9, 10]. Most recently, however, Vlisedes and Mashour  reported that, in USA alone, significant increases (14–47%) in the demand for surgical services are expected over the coming years, and it follows that the number of perioperative strokes may increase accordingly. Perioperative stroke in high-risk cardiovascular surgery is well documented, with an incidence ranging from approximately 1.9 to 9.7% . Currently, the incidence of perioperative ischaemic stroke in non-cardiac, non-neurological, and non-major vascular surgery ranges from approximately 0.1% to 1.9%, depending on associated risk factors [10, 13]. Pilot data from the Neurovision study, however, suggest that the incidence of covert stroke in high-risk non-cardiac surgery patients may be as high as 10% . Aguirre’s conclusions, in line with those of some other reviewers [15–17], are clear: shoulder surgery in the upright seated position, and in cardiology procedures , is associated with an elevated risk of adverse neurological events, including those that are covert and delayed (>24 h postoperative). The main issues remain that, because the level of devastation to patients and families is unexpected and substantial , the indemnities and payouts are very high, and the burden on healthcare providers heavy – and that is why we should endeavour to evade the dangers of low cerebral perfusion.
Pitfalls of NIRS methodology
To briefly review our current knowledge about what NIRS can show, we may begin by asking: is it a case of ‘cry wolf’? NIRS is used clinically in cardiac surgery [20–22], paediatric anaesthesia , and conditions of cerebral low-perfusion states in high-risk patients. Some studies show a correlation between NIRS desaturation events and adverse neurological outcome, whilst others do not. A recent BMJ Open systematic review and meta-analysis failed to reveal any benefit from NIRS for cardiopulmonary bypass (CPB) patients, in regard to stroke . However, it underlined that the topic is controversial and the clinical research findings, thus far, have been less than outstanding – results from 80% or more of the clinical trials investigating the topic were excluded from the meta-analysis because of their many flaws (incomplete reporting, insufficient description, blinding, risk of bias etc.). This uncertainty is helping to prevent a clear-cut decision on whether to clinically employ NIRS. In fact, the only randomised controlled trial of the use of cerebral oximetry in non-cardiac surgery that has shown some benefit is the one reported by Casati and colleagues .
Much of the controversy revolves around the methodology, due to the relatively scarce adverse neurological outcomes, such that large numbers of trial participants are required. Attempts to correlate NIRS with some axonal injury biomarkers have found, for example, that biomarkers show a poor correlation with the extent of cognitive deficit – which has been known for decades . This finding could, however, be explained by diffuse cellular damage, whereas neurological injury is often characterised by focal injury . There may be an incidental historical precedence here, as there are similarities with the case of cardiac troponin in myocardial infarction diagnosis .
There is evidence to suggest that the technology has yet to reach maturity. Some technical matters remain to be resolved; for example, when is adverse truly adverse? Other factors to be resolved are scalp fixation of probes, sweating, hair, artefacts resulting from skin perfusion (which can be countered), depth and areas. Recently, it was shown that an improved NIRS signal-to-noise ratio resulted after correcting for artefacts arising from skin perfusion [29–31].
Signal response and interpretation are also important. Cerebral autoregulation (CA) is currently a subtopic of special interest, and it has been suggested that it is more relevant to monitor the normal limits of CA – and keep the patient within its lower and upper limits . The term cerebral oximetry (COx) has been well explained in a recent review , as has the rationale for using it, and how it is derived from NIRS. COx is perhaps key to further NIRS development in signal improvement and interpretation, according to Addison .
It is beyond doubt that NIRS technology is reliable but needs further clinical validation: no matter how good the data and the signal response are, its utility will be decided by clinical predictive power. A future strategy to this end must be drafted. Do we conduct one (or more) sufficiently powered, international, multicentre, randomised controlled trials, with the aim of preventing adverse neurological outcomes – i.e. ‘Plan A’? This would involve much effort and expenditure. A major disadvantage of this approach is that unsolicited product manufacturers could take advantage of any windfall of a successful outcome, without risking the investment. Alternatively, ‘Plan B’ would be to further investigate the outcome parameters to which NIRS desaturation could be correlated, preferably in high-risk patients in high-risk surgery. Patients positioned in the BCP for shoulder surgery are relevant for this purpose [19, 34]. In this clinical setting, hydrostatic force reduces cerebral perfusion pressure, and general anaesthetics compromise cerebral autoregulation. Worse still, localised blood vessel lesions may further compromise localised flow. This is particularly true, for example, of arteriosclerotic lesions within the Circle of Wills . Whilst adverse neurological outcomes are relatively rare in BCP patients, they are still reported to be in the range 0.003–1.0% . In regard to the scale of the EU population, this still represents a vast number of patients at risk. However, since the estimated incidence of neuraxis sequelae is low, a very large number of trial subjects would be required.
Biomarkers of neuronal injury
Hypothetically, sensitive biomarkers may reveal if or when cerebral tissue desaturation becomes deleterious – a surrogate for axonal injury. A threshold probably exists for cells subjected to hypoxia beyond which cell injury becomes irreversible, as occurs in other organ systems . If used to investigate perioperative subclinical neuronal injury alongside NIRS, this could provide substantial new insights into ‘silent’ cerebral ischaemia under low-perfusion states. Furthermore, it could reveal the existence of a threshold of irreversible cell injury, both in terms of oxygen level and duration of deoxygenation.
During irreversible injury cells undergo necrosis or apoptosis, and sensitive biomarkers – tau, neurofilament light (NFL) and calpain-cleaved αII-spectrin N-terminal fragment (SNTF) – are released into the bloodstream. These have recently received much attention , as they were found to be well correlated to concussion symptoms, in ice-hockey players . Kalm and colleagues reported that serum NFL was correlated with cerebrospinal fluid (CSF) NFL, and is independent of blood–brain barrier permeability, but is representative of the degree of acute cell injury sustained from radiation . Furthermore, higher serum levels of phosphorylated neurofilament heavy chain (pNFH) predicted delirium in hospitalised patients with acute cognitive dysfunction .
To this end, our group recently conducted a small pilot study, with the goal of detecting biomarker release (tau, SNTF and NFL) into the blood during BCP shoulder surgery in patients, and if this could be associated with NIRS desaturation (Larsen JR et al., unpublished data) and postoperative cognitive dysfunction (POCD). In this non-randomised (uncontrolled), non-interventional study, undertaken in 2015–2016 at our centre, 28 patients underwent shoulder surgery with NIRS monitoring (INVOS™, Medtronic), after a POCD test battery. Biomarker samples collected at baseline (preoperative) were compared with samples at 2 h and 3–5 days postoperatively. The results showed that, following surgery, NFL had increased from baseline by Day 3 (p=0.0249: Figure 1) and s-tau had decreased (from 2 h to 3 days: p=0.0189, Figure 2), indicative of an effect occurring from baseline to 2 h. NIRS desaturation below an absolute value of 55% was correlated (weakly) with change in tau (p=0.05) postoperatively (Figure 3, unpublished data).
Serum SNTF was below detection level in all patients, and there was no change in POCD scores. Despite obvious methodological problems (such as the absence of a control group), which prevent further extrapolation of these results, we infer that: (1) there was a detectable neuromarker release in BCP patients under general anaesthesia; (2) NIRS desaturation corresponded with biomarker change (p=0.05); and (3) POCD was unchanged. These findings warrant further investigation using NIRS in adult patients undergoing cardiac surgery, Slater and colleagues  suggested that the threshold of neurocognitive decline is correlated with a calculated NIRS desaturation score (rSO2). The rSO2 score generated is an area-under-the-curve measurement, which accounts for both depth and duration of desaturation below the 50% (absolute) saturation threshold, and lasting >3000% seconds. Our data indicate the possibility of a threshold time (and depth) of desaturation before injury can be anticipated (Figure 3).
Ballard and colleagues  showed that POCD declined significantly up to one year postoperatively, compared with non-surgical controls, and that a pragmatic regime consisting of bispectral and NIRS monitoring to conservative (standard) values significantly reduced the risk of POCD in an elderly, non-cardiac surgery cohort.
The future of NIRS applications
Functional NIRS (fNIRS) permits monitoring in both awake and unconscious subjects. Clinically, brain oxygen supply is considered sufficient when patients are awake and have normal function. However, if cerebral oxygen saturation fails and gives rise to unconsciousness, or if patients are sedated or rendered unconscious by injury or disease, neurological assessment is difficult, and often impossible. Consequently, bedside monitoring of adequate tissue oxygenation is essential, so NIRS is perfectly suited to monitor traumatic brain injury (TBI) or anoxic brain injury (ABI) [42, 43].
In the advanced neurorehabilitation unit at the Neuro-Intensive Stepdown Unit (NISA) in Silkeborg, Denmark , two categories of patients are frequently encountered: (1) patients with signs of paroxysmal sympathetic hyperactivity (PSH)  – an insufficiently understood and often poorly managed serious complication, post-trauma or post-haemorrhage, and (2) patients with ABI, following cardiac arrest. In Europe, every year, an estimated 375,000 people experience sudden cardiac arrest . These two categories of patients vary widely with respect to symptoms and recovery, and assessment of their progress and recovery – other than by bedside neurological assessment – is difficult. Both categories are ideally suited for extra scrutiny, and fNIRS, coupled with sensitive biomarkers, could ideally monitor progress, intervention and pharmaceutical treatment effects.
fNIRS was successfully used to monitor distinct types of brain activities during motor and cognitive tasks . fNIRS uses specific wavelengths of light correlated with the functional magnetic resonance imaging (fMRI) BOLD signal . Unlike fMRI, fNIRS has no operating sound, provides higher temporal resolution (faster sampling frequency), and participants are not restricted to a confined space nor required to stay in a motionless, supine position. Hence, fNIRS is an ideal technique for monitoring changes relating to cortical activity, not only in laboratory settings but also in more everyday working and field conditions. fNIRS has been extensively used in infants , and can be coupled with electroencephalography . It has not previously been used in advanced neurorehabilitation in cognitive impaired patients, although it possesses ground-breaking research potential, particularly in combination with biomarker analysis. Such technologies could be ‘game-changing’ in this emerging field . fNIRS offers objective criteria, which are often difficult to obtain in rehabilitation. A further advantage of fNIRS is that the equipment is battery operated and portable, and is deployable later in successful recovery. fNIRS with multichannel resolution could become commercially available, allowing parts of the brain other than the prefrontal cortex to be visualised. NIRS has been recently successfully used to monitor the systemic circulation , total body water content , and even to evaluate lipids in atheromatous coronary lesions via endovascular access [53, 54]. Finally, fNIRS may extend to the outer margins of medicine . This is as much a testimony to the creativity of investigators as to the versatility of the technology.
For those with specialised requirements who wish to build their own system, an open forum for the NIRS technical network (known as OpenNIRS), already exists, through which collaborative resources are made available on a shared basis . As with other shared internet resources, this is likely to have a significant impact on the speed of dissemination of the technology. One must bear in mind, though, that the associated cost of such technological developments (e.g. signal analysis and software development) are typically high.
To summarise, the strengths of NIRS in clinical monitoring and assessment are that it is affordable, continuous, direct, sustainable, portable and cost-efficient, with virtually zero running costs, compared with radiography. It also appears to be an objective method, although this has not been fully explored or validated. In this respect, NIRS fills a technology gap, but more clinical validation is needed. As to the interpretation of desaturation events, an assimilation between neurological biomarkers and NIRS area under the curve would be a significant development. fNIRS may aid in the documentation of ongoing rehabilitation, spontaneous recovery, physiotherapy and ergotherapy, and also advanced neuropharmaceuticals, where it could prove to be mandatory in the evaluation, monitoring and diagnostics involved in these areas.
A disadvantage, in regard to NIRS, is that the many clinical randomised controlled trials that have demonstrated reduced neurological deficit outcomes have not yet been published; however, this may be some time in the making, since the risk a priori is low. There is still an opportunity to optimise the interpretation of artefacts from scalp sweating, hair, etc. As scientists, we delight in creating solutions for the future – for tackling big problems – but we must also ensure these potential solutions are validated.
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