Non-Invasive Monitoring of Microvascular Oxygenation and Reactive Hyperemia using Hybrid, Near-Infrared Diffuse Optical Spectroscopy for Critical Care

Critically ill patients, particularly those with sepsis and other similar conditions, often exhibit impaired reactive hyperemia and microvascular oxygenation^1,2,3. During the first waves of COVID-19 pandemic, an unforeseen number of patients required intensive care management, during which the impact of the virus on the endothelium became evident but without a clear strategy to assess and manage^4,5,6. As a result, there has been a growing recognition of the importance of detecting endothelial dysfunction, which can be indirectly evaluated by reactive hyperemia, in critical care, i.e., the intensive care unit (ICU) populations⁷. A practical, robust, and widely available assessment of oxygen delivery and consumption to the tissues is expected to be of utmost importance in optimizing resuscitation strategies and directly addressing microcirculatory issues. Studies have consistently demonstrated that persistent microcirculatory alterations and lack of coherence between macrocirculation and microcirculation are, to some extent, predictive of organ failure and unfavorable outcomes in patients affected by septic shock or hemorrhagic shock, among other critical conditions, even when systemic parameters are considered to be normal^8,9,10. It has become evident that relying solely on macrocirculatory parameters is inadequate, as microcirculation plays a critical role in tissue oxygenation and organ function^11,12,13. This paper describes a protocol that uses a new multi-modal device based on near-infrared diffuse optical technologies that has been developed within an international consortium that focuses on ICU patients. The project, VASCOVID (https://vascovid.eu), was motivated by the COVID-19 pandemic to evaluate microvascular health in peripheral muscles in intensive care. We have designed a protocol using the developed VASCOVID device that aims to enhance our understanding of these parameters and how these parameters can be useful in managing critically ill patients with a much broader scope than COVID-19 patients.

Near infrared spectroscopy (NIRS) has been utilized to assess microcirculation non-invasively for decades in a broad range of clinical applications including, the ICU patients^14,15,16,17. It is important to note that the simplest application of NIRS, i.e., continuous wave NIRS (CW-NIRS), is implemented in widely used and clinically approved devices^17,18, used for measuring the absolute concentrations of oxy- (HbO) and deoxy-hemoglobin (HbR) to calculate the blood/tissue oxygen saturation (StO₂) of the microvasculature. While these devices have found niche uses in clinical management, such as during cardiac surgery, they have clear limitations due to the physics of photon propagation in tissues. This means that their accuracy, precision, and repeatability are questionable, hence, they are often utilized as trend monitors^19,20. Furthermore, their results are heavily influenced by superficial tissues such as the overlaying adipose and skin layers.

Time-resolved NIRS (TRS) employs short laser pulses in the picosecond range at multiple wavelengths to assess their delay and broadening after traversing through a tissue²¹. This allows TRS to separate the effects of absorption from scattering to obtain robust, accurate, and precise estimates, also allowing it to calculate the total hemoglobin concentration (HbT). Since TRS also resolves pathlengths, it can be utilized to better separate superficial signals from the deep signals of interest^18,21. This comes at the cost of complexity, price, and bulkiness. However, in recent years, TRS systems have come down in complexity and cost, resulting in more accessible and easier-to-use devices. This manuscript describes a device that uses a compact original equipment manufacturer (OEM) commercial TRS module^22,23.

Diffuse correlation spectroscopy (DCS) is another near-infrared technology that utilizes the temporal statistics of diffuse speckles to quantify the movement of light-scattering particles, which are dominated by red blood cells in tissues^16,24. This, in turn, is well known to be an indicator of microvascular blood flow, which we refer to as the blood flow index (BFI)²⁵. The simultaneous use of TRS and DCS in a hybrid optical device offers insights into oxygen metabolism by utilizing common models to derive the local oxygen extraction fraction and multiplying by the blood flow^15,26,27.

In order to assess the microcirculation at the ICU, NIRS is often utilized with a vascular occlusion test (VOT), which is an ischemic challenge that is performed by blocking the blood supply to the probed peripheral muscle for a certain duration (a few minutes)^{28,29,30,31,32}. Most commonly, it is executed by inflating a tourniquet wrapped around the upper arm above the systolic pressure³³. During the VOT, the clinicians assess the response of the microvascular blood oxygenation to changes in blood flow to derive oxygen metabolism at rest and reactive hyperemia³⁴. The assumption is that during the VOT, with the cuff inflated well above the limb occlusion pressure, there is no inflow or outflow of blood. Therefore, the start of VOT shows a downward slope of StO₂, i.e., deoxygenation (DeO₂), as oxygen is consumed by the tissue, which allows an estimate of the metabolic rate of oxygen consumption. When the VOT ends and the cuff is deflated, blood rushes in to compensate for its depletion, leading to a hyperemic response. This rush generates a sharp upward slope in StO_2, i.e., a reoxygenation (ReO₂). The hyperemic response, which is an increase beyond the initial baseline with a slow recovery back to the baseline, estimates the reactive hyperemia. The combination of NIRS with a VOT has gained increasing interest in intensive care due to its ease of use and potential for predicting adverse outcomes and even mortality in critical conditions such as sepsis^35,36,37.

During the COVID-19 pandemic, our groups have initiated a worldwide consortium and recently completed the so-called HEMOCOVID-19 trial, showing an association between peripheral microcirculatory alterations and severity of acute respiratory distress syndrome in COVID-19 patients⁶. This was supported by other works as well^7,38. All these studies were done with the above-mentioned CW-NIRS systems, hence suffering from their shortcomings. Furthermore, the execution of VOT was not standardized across different studies and is affected by various parameters like occlusion duration, tourniquet pressure, and operator-based variations^29,39,40. A literature review clearly shows that for VOT and NIRS to gain traction in the clinics, it is important to measure blood flow, have standardized protocols, and have a robust NIRS system¹¹. Therefore, we have proposed that by utilizing a more advanced form of NIRS (TRS), measuring blood flow, and standardizing the cuff control during VOT, a better discrimination of pathological conditions from healthy ones could be achieved. To that end, we have developed this hybrid diffuse optical device that integrates multiple modules encompassing two near-infrared diffuse optical modules of TRS and DCS, pulse oximetry, and an automated tourniquet. The pulse oximetry module provides the heart rate (HR), perfusion index, and percentage of arterial oxygen saturation (SpO₂). A fast tourniquet is used in the device, which is critical for performing VOT. The device comes with an optional accessory box that allows us to acquire additional information during the use for extended and continuous quality control, such as routine and practical measurement of the instrument response function (IRF) for TRS and the measurement on a tissue-mimicking phantom for evaluating longitudinal stability. The device is shown as being utilized in the ICU in Figure 1.

Figure 1: Bedside arrangement of the portable device in the ICU with the probes and cuff attached to the patient. Please click here to view a larger version of this figure.

The multimodal smart probe incorporates source and detector optical fibers for both TRS and DCS with optical filters inside the device that prevent interference between DCS and TRS. The source-detector separation used in this system is 25 mm. Additionally, the probe incorporates a capacitive touch sensor, providing a valuable safety feature to prevent laser hazards according to the laser safety standard (IEC 60601-2-22:2019)⁴¹. The laser safety system within the device ensures that the laser emission occurs only when the probe is in contact with the tissue. If detachment of the probe is detected, the lasers are immediately switched off, ensuring the safety of both patients and operators. Moreover, the probe is integrated with an accelerometer, load sensor, and light sensor for additional functionality and data collection purposes.

This paper describes the automated protocol where we probe the brachioradialis muscle simultaneously with a VOT using the developed device. The protocol timeline is shown in Figure 2. The protocol is completely automated, and no operator interventions are needed throughout its execution. By leveraging the capabilities of this novel device, we aim to gain valuable insights that let the physicians understand the physiopathology of peripheral oxygen consumption better and also assess the ratio of oxygen consumption and delivery thereby helping them to improve patient care comprehensively and efficiently.

Figure 2: Protocol timeline. The patient is at rest throughout the timeline with 0 mmHg pressure at initial baseline and recovery period. The VOT is performed with a tourniquet inflated to a pressure of 50 mmHg higher than the patient's systolic blood pressure. Please click here to view a larger version of this figure.