Neuroprotection via optimizing cerebral blood flow after cardiac arrest (neuro-intact) study – A phase II proof-of-concept study protocol

Fig. 1. Conceptual figure. Conceptual figure comparing standard-of-care versus proposed strategy. The varying impairment in cerebral autoregulation and phasic variations in cerebral blood flow after return of spontaneous circulation suggest a potential neuroprotective benefit of actively tailoring systemic blood pressure targets to maintain optimal cerebral blood flow. This is guided by bedside transcranial Doppler ultrasound and near-infrared spectroscopy, by correlating changes in surrogates of cerebral blood flow with changes in mean arterial pressure. A tailored blood pressure strategy may also benefit extra-cerebral organ perfusion (heart and kidneys), the autoregulatory mechanisms of which are similarly impaired following successful resuscitation. Abbreviations: OHCA, out-of-hospital cardiac arrest; BP, blood pressure; TCD, transcranial Doppler ultrasound; NIRS, near-infrared spectroscopy; NSE, neuron-specific enolase; hsTNT, highly-sensitive Troponin T; NT-proBNP, N-terminal pro-brain natriuretic peptide; penKID, proenkephalin; bio-ADM, bioactive adrenomedullin; TIMP2, tissue Inhibitor of metalloproteinase 2; IGFBP7, insulin-like growth factor-binding protein 7.

Fig. 2. Schematic representation of the NEURO-INTACT study design. Comatose OHCA survivors undergo serial cerebral autoregulation assessment using combined TCD and NIRS at three timepoints over 48 h, with MAP titrated to the individualized MAPopt for 72 h. Biomarker sampling and clinical outcome assessments are performed at specified intervals through one year. *Severity of illness on admission will be assessed using the Pittsburgh Cardiac Arrest Category and complemented by serum levels of lactate and neuron-specific enolase at baseline. These will be accounted for in the post-hoc adjustment. Abbreviations: CCU, Coronary Care Unit; OHCA, out-of-hospital cardiac arrest; MAP, mean arterial pressure; H, hour; CPC, Cerebral Performance Category; HRQoL, health-related quality of life; IV, intravenous; CVP, central venous pressure; TCD, transcranial Doppler ultrasound; NIRS, near-infrared spectroscopy; BP, blood pressure; MAP, mean arterial pressure; PaCO2, arterial partial pressure of carbon dioxide; FiO2, fraction of inspired oxygen; COx, cerebral oxygenation index; Mxa, mean velocity index.

Fig. 3. (i) Conceptual illustration of the cerebral oximetry index (COx) plotted against MAP, demonstrating derivation of MAPopt from the curve nadir. When autoregulation mechanism is intact, the COx–MAP curve is U-shaped; MAPopt represents the pressure at which autoregulation is most effective. (ii) A flat curve at uniformly low Mxa and/or COx across the full measured MAP range: autoregulation is fully preserved throughout — all assessed pressures are equally safe and the current MAP is maintained without adjustment. (iii) A monotonically decreasing Mxa and/or COx with increasing MAP (across the measured range) with no visible nadir: most commonly indicating that the measured MAP range falls below the patient's lower limit of autoregulation (LLA) – a trial of higher MAP is undertaken to seek the nadir before applying the default target. (iv) A flat curve at uniformly high Mxa and/or COx (>0.3): total vasoparalysis, representing complete loss of myogenic tone with fully pressure-passive CBF — the protocol reverts to the default MAP ≥75 mmHg with rSO2 ≥50%. Abbreviations: COx, cerebral oximetry index; MAP, mean arterial pressure; NIRS, near-infrared spectroscopy; MAPopt, optimal mean…