Hybrid diffuse optical appraisal of peripheral and cerebral changes in critically ill patients receiving red blood cell transfusion

Background Red blood cells transfusions (RBCT) are utilized to restore normal values of hemoglobin concentration and hematocrit percentage in anemic patients. As expected, RBCT often leads to local and global alteration of blood flow (BF) and blood/tissue oxygenation which could have local deleterious consequences. This complicates its use and its dosage and there is no consensus on liberal versus restrictive RBCT in critically ill patients. Blood gas sampling is utilized to bring objectivity to RBCT which is a reliable systemic measure. However, it is also hypothesized that the knowledge about the dynamic response of selected organs could improve RBCT outcomes. We carried out a study using non-invasive hybrid diffuse optics (DO) to assess the RBCT effect on the brain and a peripheral muscle by evaluating microvascular BF, oxygen extraction fraction (OEF) and microvascular oxy-, deoxy- and total hemoglobin concentrations ([HbO2], [Hhb], [HbT]) in critically ill patients. We explored the DO’s ability to identify RBCT-induced significant alterations and to provide a quantitative description. Methods Critically ill anemic patients undergoing RBCT were recruited and monitored by hybrid DO. Blood gas samples were extracted to obtain arterial total hemoglobin concentration (Hgb) and hematocrit value. Optical signals, such as BF, OEF, metabolic rate of oxygen extraction (MRO2), [HbO2], [Hhb] and [HbT] were simultaneously measured at the cerebral and the peripheral tissues. The changes in these variables were investigated characterizing the distributions of the cerebral and of the peripheral post-RBCT variables. Results Fourteen out of fifteen recruited subjects were included. After RBCT, Hgb and hematocrit significantly increased (p<0.001). OEF significantly decreased both at peripheral and cerebral level (p<0.001, p<0.001). A significant increase was found in MRO2 (p=0.03, p<0.001), \[HbT\] (p=0.01, p<0.0001) and [HbO2] (p=0.008, p<0.0001) at both levels. BF significantly decreased only at the peripheral level (p<0.001). No change was encountered in \[Hhb\] (p>0.05). No statistical difference was found between cerebral and peripheral signals post-RBCT (p>0.05) apart from MRO2 (p=0.03, higher at peripheral tissue). Conclusions Hybrid DO detected tissue oxygenation improvement after RBCT, enabling a thorough examination. The potential for DO to quantify and alert changes of concern deserves further investigation. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work received funding from the European Union's Horizon 2020 research and innovation program under grant agreements No. 675332 (BitMap), No. 101016087 (VASCOVID) and No. 101017113 (TinyBRAINS). Moreover, the funding was provided by: Fundacio CELLEX Barcelona, Fundacio Mir-Puig, Agencia Estatal de Investigacion (PHOTOMETABO, PID2019-106481RB-C31/10.13039/501100011033), the "Severo Ochoa" Programme for Centres of Excellence in R&D (CEX2019-000910-S); LUX4MED and MEDLUX special programs; Generalitat de Catalunya (CERCA, AGAUR-2017-SGR-1380, RIS3CAT-001-P-001682 CECH, and AGAUR-2021SGR/00810), FEDER EC and LASERLAB-EUROPE V (EC H2020 no. 871124), KidsBrainIT (ERA-NET NEURON), la Fundacio La Marato de TV3 (201724.31, 201709.31 and 202109-30),"PLEC2022-009290, SafeICP" project funded by MCIN/AEI/ 10.13039/501100011033 and by the "European Union NextGenerationEU/PRTR". ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study obtained clearance by the ethical committee of Vall D'Hebron University Hospital (PR(AG)160/2017) and was conducted following the Declaration of Helsinki. Signed informed consent was obtained before the measurements either by the patient or a legal representative. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data will be made available by the corresponding author upon reasonable request taking into account the appropriate norms for personal data privacy. * ICU : Intensive care unit TBI : Traumatic brain injury RBC : Red blood cells RBCT : Red blood cells transfusion COVID-19 : Coronavirus disease 2019 HgbO2 : Arterial oxy-hemoglobin concentration Hgbr : Arterial reduced hemoglobin concentration HCT : Hematocrit TRICC : Transfusion Requirements in critical care DO2 : Oxygen delivery BF : blood flow CBF : Cerebral blood flow PBF : Peripheral blood flow CaO2 : Arterial oxygen content StO2 : Tissue oxygen saturation TCD : Transcranial Doppler ultrasound OEF : Oxygen extraction fraction COEF : Cerebral oxygen extraction fraction POEF : Peripheral oxygen extraction fraction [HbT] : Microvascular total hemoglobin concentration [Hhb] : Microvascular deoxy-hemoglobin concentration [HbO2 ] : Microvascular oxy-hemoglobin concentration MRO2 : Metabolic rate of oxygen CMRO2 : Cerebral metabolic rate of oxygen PMRO2 : Peripheral metabolic rate of oxygen HR : heart rate SpO2 : Oxygen saturation MABP : Mean arterial blood pressure CT : Computer tomography GCS : Glasgow coma scale BTF : Brain trauma foundation Hgb : Arterial total hemoglobin concentration MCHC : Mean corpuscular hemoglobin concentration SaO2 : Arterial oxygen saturation rCBF : Relative cerebral blood flow rBF : Relative blood flow rPBF : Relative peripheral blood flow Δ[HbT] : Change in [HbT] Δ[HbO2 ] : Change in [HbO2 ] Δ[Hhb] : Change in [Hhb] PaCO2 : Arterial pressure of carbon dioxide PbrO2 : Partial pressure of tissue oxygenation SD : Standard deviation p : p-value SNR : Signal-to-noise ratio IQR : Interquartile range ICP : Intracranial pressure NIRS : Near-infrared spectroscopy TRS : Time-resolved spectroscopy DCS : Diffuse correlation spectroscopy DO : Diffuse optics rOEF: Relative oxygen extraction fraction rCOEF : Relative cerebral oxygen extraction fraction rPOEF : Relative peripheral oxygen extraction fraction rMRO2 : Relative metabolic rate of oxygen rCMRO2 : Relative cerebral metabolic rate of oxygen rPMRO2 : Relative peripheral metabolic rate of oxygen PaO2 : Partial pressure of oxygen SaO2 : Arterial oxygen saturation MRI : magnetic resonance imaging PET : positron emission tomography SAH : subarachnoid hemorrhage CBV : cerebral blood volume NA : not available