We acknowledge the support by the S&#227;o Paulo Research Foundation (FAPESP) through Proc. 2012/02500-8 (RM), 2014/25486-6 (RF) and 2013/07559-3. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The protocol was approved by the local committee of the University of Campinas (protocol number 56602516.2.0000.5404). Written informed consent was obtained from the patient or a legal representative prior to the measurements. We monitored patients that were admitted to the Clinics Hospital at the University of Campinas with a diagnosis of either ischemic stroke or a subarachnoid hemorrhage affecting the anterior circulation. Patients with ischemic strokes affecting the posterior circulation, patients with decompressive ...

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RC Mesquita has one pending patent application and two other patents relevant to this work (United States patents 10,342,488 and 10,064,554). No author currently receives royalties or payments from these patents.
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This paper presented a hybrid optical system that can provide real-time information about cerebral blood flow, cerebral oxygenation, and cerebral oxygen metabolism of neurocritical patients at the beside. The use of diffuse optical techniques had been previously addressed as a potential marker for non-invasive, bedside monitoring in clinical scenarios. A previous study focused on the clinical aspects and the feasibility of optical monitoring during hospitalization in the neuro-ICU through a case report9...

An erratum was issued for:&#160;<a href="https://www.jove.com/t/61608">Real-Time Monitoring of Neurocritical Patients with Diffuse Optical Spectroscopies</a>. The Authors section was updated from:
Rodrigo Menezes Forti1,2 
Marilise Katsurayama2,3 
Lenise Valler2,3 
Andr&#233;s Quiroga1,2 
Luiz Simioni1 
Julien Menko4 
Antonio L. E. Falc&#227;o3 
Li Min Li2,5 
Rickson C. Mesquita1,2 
1Institute of Physics, University of Campinas 
2Brazilian Institute of Neuroscience and Neurotechnology 
3Clinical Hospital, University of Campinas 
4Department of Emergency Medicine, Albert Einstein College of Medicine 
5School of Medical Sciences, University of Campinas
to:
Rodrigo Menezes Forti1,2 
Marilise Katsurayama2,3 
Giovani Grisotti Martins1 
Lenise Valler2,3 
Andr&#233;s Quiroga1,2 
Luiz Simioni1 
Julien Menko4 
Antonio L. E. Falc&#227;o3 
Li Min Li2,5 
Rickson C. Mesquita1,2 
1Institute of Physics, University of Campinas 
2Brazilian Institute of Neuroscience and Neurotechnology 
3Clinical Hospital, University of Campinas 
4Department of Emergency Medicine, Albert Einstein College of Medicine 
5School of Medical Sciences, University of Campinas

An erratum was issued for:&#160;<a href="https://www.jove.com/t/61608">Real-Time Monitoring of Neurocritical Patients with Diffuse Optical Spectroscopies</a>. The Authors section was updated.

Erratum: Real-Time Monitoring of Neurocritical Patients with Diffuse Optical Spectroscopies

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&#160;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 &#181;s 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&#160;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.

<table>
	<tbody>
		<tr>
			<td>3D Printer</td>
			<td>Sethi3D</td>
			<td>S2</td>
			<td>3D-printer used to print the customizable probes</td>
		</tr>
		<tr>
			<td>Arduino UNO</td>
			<td>Arduino</td>
			<td>UNO REV3</td>
			<td>Microcontroller responsible to interleave the DCS and FD-DOS measurements</td>
		</tr>
		<tr>
			<td>DCS Correlator</td>
			<td>Correlator.com</td>
			<td>Flex11-16ch</td>
			<td>Component of the DCS module</td>
		</tr>
		<tr>
			<td>DCS Dectectors IO Boards</td>
			<td>Excelitas Technology</td>
			<td>SPCM-AQ4C-IO</td>
			<td>Component of the DCS module</td>
		</tr>
		<tr>
			<td>DCS Detectors</td>
			<td>Excelitas Technology</td>
			<td>SPCM-AQ4C</td>
			<td>Component of the DCS module</td>
		</tr>
		<tr>
			<td>DCS Laser</td>
			<td>CrystaLaser</td>
			<td>DL785-120-SO</td>
			<td>Component of the DCS module</td>
		</tr>
		<tr>
			<td>DCS Power supply</td>
			<td>Artesyn</td>
			<td>UMP10T-S2A-S2A-S2A-S2A-IES-00-A</td>
			<td>Component of the DCS module (power supply for the DCS detecto; 2, 5 and 30V)</td>
		</tr>
		<tr>
			<td>FD-DOS fibers</td>
			<td>ISS</td>
			<td>Imagent supplies</td>
			<td>The fibers used for FD-DOS detection and illumination are provived by ISS</td>
		</tr>
		<tr>
			<td>Flexible 3D printer material</td>
			<td>Sethi3D</td>
			<td>NinjaFlex</td>
			<td>Material used to print the flexible customizable probes</td>
		</tr>
		<tr>
			<td>Imagent</td>
			<td>ISS</td>
			<td>Imagent</td>
			<td>FD-DOS module</td>
		</tr>
		<tr>
			<td>Laser safety googles</td>
			<td>Thorlabs</td>
			<td>LG9</td>
			<td></td>
		</tr>
		<tr>
			<td>Multi-mode fiber</td>
			<td>Thorlabs</td>
			<td>FT400EMT</td>
			<td>Multi-mode fiber used for DCS illumination</td>
		</tr>
		<tr>
			<td>Neutral density filter 1.0 OD</td>
			<td>Edmund Optics</td>
			<td>53-705</td>
			<td>Neutral density filter for the short source detector separations</td>
		</tr>
		<tr>
			<td>Single-mode optical fiber</td>
			<td>Thorlabs</td>
			<td>780HP</td>
			<td>Single-mode optical fiber used for the DCS detectors</td>
		</tr>
		<tr>
			<td>System battery</td>
			<td>SMS</td>
			<td>NET4</td>
			<td>System battery used for transportation</td>
		</tr>
	</tbody>
</table>

real-time monitoring of neurocritical patients with diffuse optical spectroscopies

Neurophysiological monitoring is an important goal in the treatment of neurocritical patients, as it may prevent secondary damage and directly impact morbidity and mortality rates. However, there is currently a lack of suitable non-invasive, real-time technologies for continuous monitoring of cerebral physiology at the bedside. Diffuse optical techniques have been proposed as a potential tool for bedside measurements of cerebral blood flow and cerebral oxygenation in case of neurocritical patients. Diffuse optical spectroscopies have been previously explored to monitor patients in several clinical scenarios ranging from neonatal monitoring to cerebrovascular interventions in adults. However, the feasibility of the technique to aid clinicians by providing real-time information at the bedside remains largely unaddressed. Here, we report the translation of a diffuse optical system for continuous real-time monitoring of cerebral blood flow, cerebral oxygenation, and cerebral oxygen metabolism during intensive care. The real-time feature of the instrument could enable treatment strategies based on patient-specific cerebral physiology rather than relying on surrogate metrics, such as arterial blood pressure. By providing real-time information on the cerebral circulation at different time scales with relatively cheap and portable instrumentation, this approach may be especially useful in low-budget hospitals, in remote areas and for&#160;monitoring in open fields (e.g., defense and sports).

Ideally, the normalized autocorrelation curves obtained with the DCS module should be approximately 1.5 at the zero delay-time extrapolation (when using single-mode fibers14), and the curves should decay to 1 at longer delay times. The curve should be smooth, and it should have a faster decay for the longer source-detector separations. An example of a good autocorrelation is shown in Figure 2A. Figure 2B shows an example of a bad auto-cor...

Watch this Scientific Journal Video about Real-Time Monitoring of Neurocritical Patients with Diffuse Optical Spectroscopies at JoVE.com

Real-Time Monitoring of Neurocritical Patients with Diffuse Optical Spectroscopies

Presented here is a protocol for non-invasively monitoring cerebral hemodynamics of neurocritical patients in real-time and at the bedside using diffuse optics. Specifically, the proposed protocol uses a hybrid diffuse optical systems to detect and display real-time information on cerebral oxygenation, cerebral blood flow and cerebral metabolism.

Neurophysiological monitoring is an important goal in the treatment of neurocritical patients, as it may prevent secondary damage and directly impact ...

Monitoring brain physiology noninvasive in real-time during neurocritical patient treatment may reduce mobility and mortality rates, which is particularly critical in remote areas and open fields. With the rise in portable and relatively cheap instrumentation, diffuse optics can be used to measure blood flow and oxygenation simultaneously, with a high temporal resolution and without critical care interference. The real-time feature has the potential to guide treatment strategies for brain injuries in the neuro ICU basis of patient-specific cerebral physiology, rather than universally applied standard protocols or surrogate metrics.Before moving the system into the ICU, connect all the fibers to the relevant lasers and detectors and make sure they are properly attached to the optical probe. Then, obtain consent from either the patient or a legal representative and bring the cart to the patient's room. Upon arrival, turn off the DCS laser.And in the File menu, click Load Settings File to load the appropriate probe settings file. Place the probe on the curved side of the calibration phantom, ensuring good contact with the surface, and click Optimize All Detectors to optimize the PMT bias voltage. In the Calibrate menu, click Calculate Waveform Calibration Values For Optical Props and Multiple Distances to run the calibration for multiple source detector separations.In the Text-Mon menu, open the user-defined option to check that the measured optical properties match the pre-specified values and that the fitting of R-squared is close to one. Then, probe the phantom again to measure the optical properties of the phantom marked as check to ensure that the calibration was adequate. The measured optical properties should be within 10%of the values specified in the phantoms.To prepare the patient for the analysis, first use sanitizing wipes to clean both the probe and the patient's forehead. Place double-sided tape on the probe, taking care that the tape is not in direct contact with the optical fiber tips, and place laser safety goggles onto the patient. Place the probes over the region of interest and wrap the elastic straps around the patient's head.Then, turn on the DCS laser. Before beginning the data acquisition, enter the DCS source detector separations in the Settings tab of the graphic user interface. To begin the acquisition, press Start in the system software.Click Optimize All Detectors to optimize the PMT bias voltage for the patient, and check the optical properties and R-squared of the DOS fitting as demonstrated. Turn on the DCS detectors and check that each DCS detector is measuring an adequate light intensity. Typically, more than 10 kilohertz are required.If the measured intensity exceeds 800 kilohertz, use a neutral density filter to reduce the photon counts to avoid damaging the detectors. Check the auto-correlation curves in the Correlation Curves tab of the graphic user interface to ensure a good skin coupling, and reposition the optical probe, if necessary. When a good contact between the probe and the skin is achieved, click Stop to stop the data collection and set the experiment and patient identifiers in the Folder text box and the region of interest name in the File name text box.Then, press Start to start the data acquisition. After starting the measurement, enter the relevant patient information in the Experiment Info tab and click Mark to ensure that any relevant event that occurs during the monitoring period is marked. After each mark, enter the event description in the Experiment Info tab.At the end of the assessment, press Stop in the graphic user interface to stop the data collection. Turn off the DCS detector switch and turn the DCS laser key to the off position. Click all detectors off to turn off the PMTs and remove the probe from the patient's head and the double-sided tape from the probe.Then, clean the probe and the system and accessories with sanitizing wipes. Normalized auto-correlation curves obtained with the DCS module should be approximately 1.5 at the zero delay time extrapolation and should decay to one at longer delay times. In this example of a bad auto-correlation curve, it is not possible to distinguish the curves for the different source detector separations.While in this example, the curve's tail did not match the model used. Here, the time series from a monitoring session for a sedated stroke patient during which the patient's bronchial and oral secretions were suctioned can be observed. The patient motion induced by the intervention clearly disturbed the optical signal, leading to unphysiological spikes in the optical parameters.Soon after the intervention, the hemodynamic parameters returned to approximately the same values as before the intervention, as expected for a stable patient. During this monitoring session, 13 days after hospitalization for ischemic stroke, the cerebral blood flow and cerebral metabolic rate of oxygen in the ipsilesional forehead were considerably lower than their contralesional parameters in the symmetric region, while a high oxygen extraction fraction was observed in both hemispheres. Careful analysis of this representative laterality index data of a different patient revealed one significant period of impairment between the first and the third days after hospitalization and a second period starting after the third day of hospitalization.Using continuous arterial blood pressure monitors, our protocol can be slightly modified to also assess cerebral regulation in neurocritical patients, providing clinical relevant data. The potential to assess each patient's neurophysiology at the bedside can help us to better understand the progress of different injuries and impact of different courses of care.

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2.0K 조회수.  University of Campinas. Monitoring brain physiology noninvasive in real-time during neurocritical patient treatment may reduce mobility and mortality rates, which is particularly critical in remote areas and open fields. With the rise in portable and relatively cheap instrumentation, diffuse optics can be used to measure blood flow and oxygenation simultaneously, with a high temporal resolution and without critical care interference. The real-time feature has the potential to guide treatment strategies for brain inj...