Most of the complications that lead to poor outcomes for critically ill neurologic patients are related to secondary injuries caused by cerebral hemodynamic impairments. Therefore, monitoring cerebral physiology of these patients may directly impact morbidity and mortality rates1,2,3,4,5,6,7. Currently, however, there is no established clinical tool for the continuous real-time noninvasive monitoring of cerebral physiology in neurocritical patients at the bedside. Among the potential candidates, diffuse optical techniques have recently been proposed as a promising tool to fill in this gap8,9,10,11. By measuring the slow changes (i.e., on the order of tens to hundreds of ms) of the diffusively scattered near-infrared light (~650-900 nm) from the scalp, diffuse optical spectroscopy (DOS) can measure concentrations of the main chromophores in the brain, such as cerebral oxy- (HbO) and deoxy-hemoglobin (HbR)12,13. Additionally, it is possible to measure cerebral blood flow (CBF) with diffuse correlation spectroscopy (DCS)10,14,15,16,17 by quantifying the rapid fluctuations in light intensity (i.e., from a few µs to a few ms). When combined, DOS and DCS can also provide an estimate of the cerebral metabolic rate of oxygen (CMRO2)18,19,20.
The combination of DOS and DCS has been explored to monitor patients in several pre-clinical and clinical scenarios. For example, diffuse optics has been shown to provide relevant clinical information for critically-ill neonates21,22,23,24, including during cardiac surgeries to treat heart defects23,25,26,27,28. In addition, several authors have explored the use of diffuse optics to assess cerebral hemodynamics during different cerebrovascular interventions, such as carotid endarterectomy29,30,31, thrombolytic treatments for stroke32, head-of-bed manipulations33,34,35, cardiopulmonary resuscitation36, and others37,38,39. When continuous blood pressure monitoring is also available, diffuse optics can be used to monitor cerebral autoregulation, both in healthy and in critically ill subjects11,40,41,42, as well to assess the critical closing pressure of the cerebral circulation43. Several authors have validated CBF measurements with DCS against different gold standard CBF measures18, while CMRO2 measured with diffuse optics has been shown to be a useful parameter for neurocritical monitoring8,18,23,24,28,43,44,45. In addition, previous studies have validated the optically-derived cerebral hemodynamic parameters for long-term monitoring of neurocritical patients8,9,10,11, including for the prediction of hypoxic46,47,48 and ischemic events8.
The reliability of the diffuse optical techniques to provide valuable real-time information during longitudinal measurements as well as during clinical interventions remains largely unaddressed. The use of a standalone DOS system was previously compared to invasive brain tissue oxygen tension monitors, and DOS was deemed to not have a sufficient sensibility to replace the invasive monitors. However, apart from using relatively small populations, the direct comparison of the invasive and non-invasive monitors may be misguided as each technique probe different volumes containing different parts of the cerebral vasculature. Even though these studies ultimately concluded that diffuse optics is not a replacement for the invasive monitors, in both studies DOS achieved a moderate-to-good accuracy, which may be sufficient for cases and/or places wherein invasive monitors are not available.
Relative to other approaches, the key advantage of diffuse optics is its ability to simultaneously measure blood flow and tissue blood oxygenation non-invasively (and continuously) at the bedside using portable instrumentation. Compared to Transcranial Doppler ultrasound (TCD), DCS has an additional advantage: it measures perfusion at the tissue level, whereas TCD measures cerebral blood flow velocity in large arteries at the base of the brain. This distinction may be particularly important when evaluating steno-occlusive diseases in which both proximal large artery flow and leptomeningeal collaterals contribute to perfusion. Optical techniques also have advantages when compared to other traditional imaging modalities, such as Positron-Emission Tomography (PET) and Magnetic Resonance Imaging (MRI). In addition to simultaneously providing direct measures of both CBF and HbO/HbR concentrations, which is not possible with MRI or PET alone, optical monitoring also provides significantly better temporal resolution, allowing, for example, the assessment of dynamic cerebral autoregulation40,41,42 and the assessment dynamically evolving hemodynamical changes. Moreover, diffuse optical instrumentation is inexpensive and portable in comparison to PET and MRI, which is a critical advantage given the high burden of vascular disease in lower- and middle-income countries.
The protocol proposed here is an environment for real-time bedside neuromonitoring of patients at the intensive care unit (ICU). The protocol uses a hybrid optical device together with a clinical-friendly graphical user interface (GUI) and customized optical sensors to probe the patients (Figure 1). The hybrid system employed for showcasing this protocol combines two diffuse optical spectroscopies from independent modules: a commercial frequency-domain (FD-) DOS module and a homemade DCS module (Figure 1A). The FD-DOS module49,50 consists of 4 photomultiplier tubes (PMTs) and 32 laser diodes emitting at four different wavelengths (690, 704, 750 and 850 nm). The DCS module consists of a long-coherence laser emitting at 785 nm, 16 single-photon counters as detectors and a correlator board. The sampling frequency for the FD-DOS module is 10 Hz, and the maximum sampling frequency for the DCS module is 3 Hz. To integrate the FD-DOS and DCS modules, a microcontroller was programmed inside our control software to automatically switch between each module. The microcontroller is responsible for turning the FD-DOS and DCS lasers on and off, as well as the FD-DOS detectors to allow interleaved measurements of each module. In total, the proposed system can collect one combined FD-DOS and DCS sample every 0.5 to 5s, depending on the signal-to-noise ratio (SNR) requirements (longer collection times leads to better SNR). To couple the light to the forehead, we developed a 3D-printed optical probe that can be customized for each patient (Figure 1B), with source-detector separations varying between 0.8 and 4.0 cm. The standard source-detector separations used in the examples presented here are 2.5 cm for DCS and 1.5, 2.0, 2.5 and 3.0 cm for FD-DOS.
The main feature of the protocol presented in this study is the development of a real-time interface that can both control the hardware with a friendly GUI and display the main cerebral physiology parameters in real-time under different temporal windows (Figure 1C). The real-time analysis pipeline developed within the proposed GUI is fast and takes less than 50 ms to compute the optical parameters (see the Supplementary Material for more details). The GUI was inspired by current clinical instruments already available at the neuro-ICU, and it was adapted through extensive feedback by clinical users during the translation of the system to the neuro-ICU. Consequently, the real-time GUI can facilitate the adoption of the optical system by regular hospital staff, such as neurointensivists and nurses. The wide adoption of diffuse optics as a clinical research tool has the potential to enhance its ability to monitor physiologically meaningful data and can ultimately demonstrate that diffuse optics is a good option for non-invasively monitoring neurocritical patients in real-time.