The future of non-invasive cerebral oximetry in neurosurgical procedures: A systematic review

Cerebral oximetry

There are several techniques that can measure brain oxygenation, the most common being jugular venous bulb oximetry (SjvO₂) and direct brain tissue oxygenation (PbtO₂) measurement until recently. The former requires placement of a fiberoptic oximeter retrograde into the jugular bulb and measures the arterio-jugular difference of oxygen content (AJDO₂) that is proportional to CBF and inversely proportional to cerebral oxygen consumption, well indicating cerebral perfusion⁸. Previous studies demonstrated its significance in the global measurement of cerebral oxygen saturation and the prognostication of low SjvO₂ in brain injury^8–10. However, continuous SjvO₂ monitoring carries many limitations. First, it is relatively insensitive in detecting focal hypoperfusion that may be at risk for secondary insult¹¹. There are also complications associated with central catheter placement and its invasiveness, and SjvO₂ has limited consistency from one measurement to another^12,13.

In direct PbtO₂ measurement, a small flexible microcatheter is inserted directly into the white matter allowing a focal measurement of cerebral oxygenation. There are two widely used probes: Licox (IntegraNeuroSciences, San Diego, California, USA) and Neurotrend (Codman, Raynham, Massachusetts, USA). The Licox probe uses a polarographic Clark electrode to measure the PbtO₂, whereas the Neurotrend microcatheter uses optical luminescence to measure PbtO₂ as well as PbtCO₂ and pH³. Low PbtO₂ along with prolonged duration and high intensity of the decrease have repeatedly shown to be related to poor clinical outcomes^14–16. PbtO₂ monitoring can also be used in combination with other intra-parenchymal monitors such as ICP monitor¹⁷.

Near infrared spectroscopy (NIRS) is an emerging technique for the same purpose while it offers non-invasive, in vivo and real-time monitoring of cerebral tissue oxygenation. NIRS uses essentially the same approach as pulse oximetry in measuring hemoglobin saturation and is based on the transmission and absorption of near infrared (NIR) ray (ranging between 700 and 850 nm) as it travels through tissue¹⁸. In adults, NIR light cannot pass across the whole head, thus the light source and detecting optode(s) are placed on the same side of the head only a few centimeters apart, which allows the measurement of the superficial cortex (called reflectance spectroscopy)¹⁹.

Oxygenated and deoxygenated hemoglobin have distinct absorption spectra in the NIR and their relative concentrations in tissue can thus be determined by their relative absorption of light in wavelength. Unlike pulse oximeter that measures oxygen saturation of hemoglobin in arterial blood, cerebral oximeter measures oxygen saturation of hemoglobin in the entire tissue bed including brain parenchyma, arterial and venous blood although it is mainly venous blood^18,20.

In the last decade, NIRS has proven its potential as a non-invasive neuromonitoring technique across a spectrum of disorders: carotid endarterectomy²¹, cardiac surgery²², beachchair surgery²³ and neurosurgery^24,25. There has been a rapid expansion of clinical experience using NIRS to monitor cerebral oxygenation, and many evidences showed that NIRS-guided brain protection protocol leads to a reduction in perioperative neurologic complications of surgical procedures²⁵.

Objectives

The purpose of this systematic review was to synthesize prospective and retrospective cohort studies that investigate the benefit of using NIRS in prevention of perioperative and neurointensive care neurologic complications. This systematic review also critically appraises the methodological quality of these studies.

Study eligibility criteria

Studies that were eligible for this systematic review included:

The following studies were excluded:

Eligible studies were limited to those published from January 1, 2005 to December 31, 2016. We truncated eligible studies to this time period because of:

Literature search

Two reviewers (WooJin Kim [WJK] and Benjamin Lo [BL]) independently searched two electronic databases: PubMed and Web of Science. Relevant studies were identified from these databases first without language restrictions. For example, the following search terms were used on PubMed: Cerebral Oximetry AND Neurosurgery.

Study selection and data collection process

Both investigators (WJK and BL) reviewed all titles and abstracts and full reports of all potentially relevant studies. The initial literature search yielded 210 citations (Figure 1). First screening by the limited date of publication (January 1, 2005 – December 31, 2016) and removal of duplicates from the multiple sources yielded 88 citations, which were identified as potentially relevant. These articles were then assessed by screening their titles and abstracts with the following exclusion criteria and, from which, 68 articles were excluded:

Figure 1. Flow diagram of study selection.

The investigators (WJK and BL) then independently applied the inclusion criteria to the full 20 articles. The final selection of seven articles were based on the following exclusion criteria:

Each report was then carefully examined for its methodological quality as outlined in the section Methodological quality assessment, and relevant data were extracted for this study in agreement by both investigators.

Assessment

For this systematic review, the following items were reviewed in order to clarify the effectiveness of using non-invasive NIRS in neurosurgical and neurocritical settings:

Methodological quality assessment

For this systematic review, we sampled the QUADAS-2 tool (Quality Assessment of Diagnostic Accuracy Studies Tool– Revised Version)²⁶. The following nine areas were used in methodological quality assessment, as they would apply to effectiveness of non-invasive NIRS in neurosurgical and neurocritical settings:

We also followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement 2009 and flow diagram to ensure adequate reporting items²⁷.

Study selection

Seven studies were included in this systematic review after careful selection from 88 citations and articles (Figure 1).

A meta-analysis was not feasible in this review to statistically pool outcomes obtained from the included studies. Marked between-study differences was noted with:

In addition, there is no standardization of diagnostic tests and no reference value of these tests between investigating centres.

Study result and synthesis of results

This systematic review identified four prospective and two retrospective cohort studies. Of the seven methodologically rigorous studies identified in this systematic review, the following neurosurgical and neurocritical conditions were presented:

Assessment of the studies

Article 1: Detection of cerebral ischemia in neurovascular surgery using quantitative frequency-domain near-infrared spectroscopy. In this prospective cohort study, Calderon-Arnulphi et al. directly assessed the use of NIRS (Oxiplex TS, ISS) in monitoring cerebral ischemia during open neurovascular procedures²⁸. The authors monitored 25 neurovascular procedures including aneurysm clipping, AVM resection, CEA, STA-MCA bypass, ECA-MCA bypass, EDMS and BOT performed between May 2004 and February 2006 at the University of Illinois at Chicago for cerebral oxygenation. Diagnostic testing using quantitative NIRS (Q-NIRS) measured tissue oxyhemoglobin, deoxyhemoglobin, and total hemoglobin, and brain tissue oxygen saturation as evidence of intraoperative cerebral ischemia. Reference standard testing was absent in this study although the authors compared the measurements to the unaffected contralateral hemisphere for comparison. In addition due to the quantitative nature of Q-NIRS measurements, recordings could only be compared over time as well as with recordings obtained in other patients. In five cases that exhibited clinical evidence of ischemic events during the procedure, Q-NIRS monitoring showed a decrease in oxyhemoglobin, total hemoglobin and PbtO₂, and an increase in deoxyhemoglobin in the affected region, validating NIRS as a continuous and non-invasive intraoperative cerebral oxygenation monitoring technique²⁸.

Article 2: Evaluation of cerebral ischemia using near-infrared spectroscopy with oxygen inhalation. In this prospective cohort study, Ebihara et al. employed 30 normal volunteers without a history or risk factors of cerebral disease to evaluate cerebral hemodynamics in comparison with 33 patients with cerebral ischemia by NIRS (TEG-4000, Hitachi Medical Cooperation) upon oxygen inhalation at Jichi Medical University, Tokyo²⁹. The patients with ischemia were determined by the prediagnosed conditions of stenosis or occlusion of the ICA or MCA visualized by MR angiography. In these patients, change in CBF in the are of the MCA was evaluated with N-isopropyl-p-[¹²³I] Iodoamphetamine single-photon-emission computed tomography (¹²³I-IMP SPECT) as reference standard testing with NIRS as diagnostic testing. In all patients with ischemia, NIRS found lower tissue oxygenation in ischemic regions than in normal regions, 85% of which (28 of 33 cases) agreed with those measured by SPECT confirming its efficacy in replacing some of the conventional methods to evaluate cerebral oxygenation²⁹.

Article 3: The application of near-infrared oximetry to cerebral monitoring during aneurysm embolization: a comparison with intraprocedural angiography. In this prospective cohort study, Bhatia et al. also compared the values of NIRS (INVOS-4100, Somanetics Corp) acquired during coil embolization with incidence of vasospasm as detected from angiography²⁴. Thirty-two SAH patients who underwent embolization at the Kings College Hospital, London, UK between February and November 2005 were included. While bilateral NIRS were placed on the forehead at constant anatomic positions, ipsilateral angiography was performed every 10 to 15 minutes. An independent neuroradiologist classified any vasospasm in the parent vessel as mild (25% baseline), moderate (50%), severe (75%) or total (100%). There also was no significant association between the side of aneurysm and baseline regional cerebral oxygenation signal measured by NIRS (p = 0.243). However, the authors found a significant association between vasospasm (and its degree) and reduction in ipsilateral NIRS data on regional cerebral oxygen saturation (p < 0.001)²⁴.

Article 4: Correlation between cerebral blood flow and oxygen saturation in patients with subarachnoid hemorrhage and traumatic brain injury. In this prospective cohort study, Shafer et al. evaluated NIRS (INVOS-5100, Somanetics Corp) in relation with portable xenon enhanced CT (Xe/CT), which is considered to be gold standard for assessing cerebral perfusion in patients in the neurointensive care unit (ICU) of numerous established medical centres³⁰. The authors performed cross sectional analysis of imaging studies conducted in 22 patients with SAH and TBI at the University of New Mexico Hospital from June 2008 to December 2009. No statistically significant relationship was found between two diagnostic testing methods as evaluated by using the Spearman correlation coefficients: 0.05 and -0.05, right and left side respectively. The authors, however, report few limitations of this study such as the small sample size, the different etiology and location of brain injury, and the different patient specific physiologic factors.

Article 5: Usefulness and limits of near infrared spectroscopy monitoring during endovascular neuroradiologic procedures. In this retrospective cohort study, Mazzeo et al. well demonstrated the continuous measurement of regional cerebral oxygenation using NIRS (INVOS-5100, Somanetics Corp) in 25 patients undergoing elective endovascular procedures following cerebral aneurysm, AVM, dural AVF and meningioma over a period of 12 months starting January 2007³¹ at the University of Messina, Italy. Regional cerebral oxygenation was significantly affected by the different phases of the neuroendovascular procedure: induction of anesthesia, interventional procedure, and recovery from anesthesia, with the interventional procedure having the most reduction of cerebral oxygenation (p < 0.001). An effect of the different underlying pathology on cerebral oxygenation was also evident during the interventional procedure, the more invasive the procedure the greater the impact on cerebral oxygenation. Overall, this study showed an effect of the underlying cerebral pathology and also in relation to the advancing stages of the interventional procedure on regional cerebral oxygenation. NIRS monitoring was also able to early detect intraoperative harmful events resulting in cerebral hypoxic episodes. However, this study also lacks comparison to other reference standard monitoring modalities. The author also reports the possible artifacts related to contrast agent used³¹.

Article 6: Validation of frontal near-infrared spectroscopy as noninvasive bedside monitoring for regional cerebral blood flow in brain-injured patients. In this retrospective study, Taussky et al., similarly to the study by Shafer et al., assessed the statistical correlation of NIRS (CASMED FORE-SIGHT, Branford) and CT perfusion with respect to regional CBF measurements in their retrospective study over a period of 3 years from February 2008 to June 2011³². This study involved 8 patients (6 suffered SAH, 1 ischemic stroke and 1 ICH) who were admitted to the neurointensive care unit at the Mayo Clinic in Jacksonville, Florida. Regions of interest was obtained 2.5 cm below the NIRS bifrontal scalp probe on CT perfusion with an average volume between 2 and 4 ml to accurately compare the physiologically identical location. The authors found a statistically significant linear correlation between frontal NIRS cerebral oxygenation measurement with regional CBF on CT perfusion imaging³². The authors also describe different methods of CBF measurements such as Kety-Schmidt model, Xe/CT, PET, and MRI with perfusion-weighted imaging in this article^33,34.

Article 7: Near-infrared spectroscopy in carotid artery stenting predicts cerebral hyperperfusion syndrome. In this final retrospective study, Matsumoto et al. conducted an evaluation study in 64 patients with internal carotid artery stenosis who underwent carotid artery stenting at the Kokura Memorial Hospital, Fukuoka, between June 2006 and June 2007, where NIRS (INVOS-5100, Somanetics Corp) was used as a perioperative monitor for regional cerebral oxygen saturation³⁵. Split-dose [¹²³I] iodoamphetamine single photon emission computed tomography (SPECT) and Technetium-99m hexamethylpropyleneamine oxime SPECT were performed before and after the procedure, respectively, as reference modalities to evaluate cerebral perfusion. In the patients who had neurological deterioration post-procedure and the subsequent diagnose of CHS by SPECT had the recorded increase of post-perfusion regional cerebral oxygen saturation (>24% vs. <10%) using NIRS perioperatively³⁵. This study shows that NIRS can be an excellent non-invasive predictor of CHS after carotid artery stenting.

Methodological quality of included studies

In summary, all seven studies have strong methodological quality (Table 1). They had representative patient populations, clear selection criteria and clear study design. Clear study protocols for reducibility with ethics board approval were included. Clinical results were described in sufficient detail and were applicable to appropriate clinical practice. The main methodological weakness in few studies included small sample size and lack of appropriate reference standard testing modality, which were stated by the authors.

The results gained from these studies are clinically useful and shed light on how the use of non-invasive and inexpensive continuous measurement of cerebral oxygenation by NIRS is effective in neurosurgical and neurocritical settings.

Limitation and neurosurgical considerations

One major limitation of NIRS in neuromonitoring is the lack of a universal standard threshold for normal cerebral oxygenation, unlike pulse oximetry. Each patient had different baseline values and the thresholds, which correlate with symptomatic cerebral ischemia is variable. It is therefore more useful in elective neurosurgical and endovascular procedures (such as carotid artery stenting or angioplasty for vasospasm) where patients can be monitored before intervention to establish a reliable baseline.

The NIRS value would depend on the absorption of infrared signal between the sensor and the brain, i.e. the scalp, the skull bone, the dura, and any interposed tissue or implant. This physical limitation renders the application in common neurosurgical condition problematic. For example, in head injury patients with scalp swelling or skull fracture, and those with recent craniotomy or cranioplasty. Finally, the NIRS sensor detects a relatively small area of brain parenchyma and may not reflect loco-regional ischemia that is distant from the sensor.