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

Nicole F O'Brien; Madiha Q Raees; Hunter J Wynkoop; Mengxin Yu; Dylan Small; Karl B Seydel; Montfort Bernard Gushu; Tusekile Phiri; Sylvester June; Terrie E Taylor

doi:10.1007/s12028-025-02245-w

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

Neurocrit Care. 2025 Apr 21. doi: 10.1007/s12028-025-02245-w. Online ahead of print.

Authors

Affiliations

¹ Department of Pediatrics, Division of Critical Care Medicine, Nationwide Children's Hospital, The Ohio State University, 700 Children's Drive, Columbus, OH, 43502, USA. Nicole.obrien@Nationwidechildrens.org.
² Department of Anesthesiology and Critical Care Medicine, Division of Critical Care Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, 3401 Civic Center Blvd, Rm 9NW103, Philadelphia, PA, 19104, USA.
³ Department of Pediatrics, Division of Critical Care Medicine, Nationwide Children's Hospital, The Ohio State University, 700 Children's Drive, Columbus, OH, 43502, USA.
⁴ Department of Statistics and Data Science, The Wharton School, University of Pennsylvania, 3733 Spruce St, Philadelphia, PA, 19104, USA.
⁵ The Wharton School, University of Pennsylvania, 3733 Spruce St, Philadelphia, PA, 19104, USA.
⁶ Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, 909 Wilson Road, B309-B W. Fee Hall, East Lansing, MI, 48824, USA.
⁷ The Blantyre Malaria Project, Queen Elizabeth Central Hospital, Private Bag 360, Chichiri, Blantyre 3, Malawi.

PMID: 40257726
DOI: 10.1007/s12028-025-02245-w

Abstract

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.

Keywords: Cerebral malaria; CrCP; Critical closing pressure; Diastolic closing margin; Optimal cerebral perfusion pressure; TCD; Transcranial doppler ultrasound.

Grants and funding

5U01AI126610-02/National Institute of Health