Advancing Understanding of Cerebrovascular Hemodynamic Perturbations in Pediatric Cerebral Malaria Using a Modified Critical Closing Pressure Evaluation- A Prospective, Observational Study

Background: Cerebral malaria (CM) results in significant mortality globally. Abnormal cerebral blood flow (CBF) has been described in CM and may contribute to poor outcomes. Changes to vascular tone may be contributing to flow aberrations but measuring it in the clinical setting is difficult. Critical closing pressure (CrCP) is calculated as CrCP = intracranial pressure (ICP) + vascular tone + venous pressure. If CrCPs other components are determined, vascular tone can be inferred. CrCP can also be used to determine the diastolic closing margin (DCM = diastolic blood pressure (DBP)-CrCP) which represents the lower safety limit of cerebral perfusion pressure. Methods: Children 6 months-12 years with CM and age-matched healthy controls were enrolled. Using concurrent transcranial doppler ultrasound (TCD) CBF velocities and systemic blood pressure measurements, CrCP was determined, and DCM calculated. Non-invasive estimates of ICP were assessed and venous flow was measured. Vascular tone was deduced. Differences in CrCP between controls and CM patients were determined. DCM and its association with outcome was assessed. Results: We enrolled 220 children with CM and 400 controls. In CM patients, there were significantly more children with CrCP > 1SD below (n = 37, 17%) and > 1 SD above (n = 42, 19%) the mean normal value of the control group (n = 15, 5% > 1SD below and n = 20, 5% > 1 SD above, p < 0.001 for both). Opening pressure, an estimate of ICP, was not different between patients and controls. Venous flows were higher in children with CM than controls, but no difference was seen in CM patients with CrCP less than, within, or greater than 1SD from normal. A DCM < 20mmHg conferred a relative risk of poor outcome (RR 1.4, 95%CI 1.2–1.9, p = 0.008). Conclusions: CrCP was > 1SD lower or higher than the mean normal value in a significant number of children with CM. A low DCM is associated with a worse prognosis and may serve as a therapeutic target.