Cell-Free Hemoglobin Is Associated With Increased Vascular Resistance and Reduced Peripheral Perfusion in Severe Malaria

Hugh W.F. Kingston, Aniruddha Ghose, Voravut Rungpradubvong, Sudarat Satitthummanid, M. Trent Herdman, Katherine Plewes, Haruhiko Ishioka, Stije J. Leopold, Ipsita Sinha, Benjamas Intharabut, Kim Piera, Yvette McNeil, Sanjib Mohanty, Richard J. Maude, Nicholas J. White, Nicholas P.J. Day, Tsin W. Yeo, Md Amir Hossain, Nicholas M. Anstey, Arjen M. Dondorp

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    Abstract

    Background: In severe falciparum malaria, unlike sepsis, hypotension on admission is uncommon. We hypothesized that low nitric oxide bioavailability due to the presence of cell-free hemoglobin (CFH) increases vascular tone in severe malaria. 

    Methods: Patients with severe malaria (n = 119), uncomplicated malaria (n = 91), or suspected bacterial sepsis (n = 56), as well as healthy participants (n = 50), were recruited. The systemic vascular resistance index (SVRI) was estimated from the echocardiographic cardiac index and the mean arterial pressure. 

    Results: SVRI and hematocrit levels were lower and plasma CFH and asymmetric dimethylarginine levels were higher in patients with malaria, compared with healthy participants. In multivariate linear regression models for mean arterial pressure or SVRI in patients with severe malaria, hematocrit and CFH but not asymmetric dimethylarginine were significant predictors. The SVRI was lower in patients with suspected bacterial sepsis than in those with severe malaria, after adjustment for hematocrit and age. Plasma CFH levels correlated positively with the core-peripheral temperature gradient and plasma lactate levels and inversely with the perfusion index. Impaired peripheral perfusion, as reflected by a low perfusion index or a high core-peripheral temperature gradient, predicted mortality in patients with severe malaria. 

    Conclusions: CFH is associated with mean arterial pressure, SVRI, and peripheral perfusion in patients with severe malaria. This may be mediated through the nitric oxide scavenging potency of CFH, increasing basal vascular tone and impairing tissue perfusion.

    Original languageEnglish
    Pages (from-to)127-137
    Number of pages11
    JournalThe Journal of infectious diseases
    Volume221
    Issue number1
    DOIs
    Publication statusPublished - 1 Jan 2020

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    Kingston, H. W. F., Ghose, A., Rungpradubvong, V., Satitthummanid, S., Herdman, M. T., Plewes, K., Ishioka, H., Leopold, S. J., Sinha, I., Intharabut, B., Piera, K., McNeil, Y., Mohanty, S., Maude, R. J., White, N. J., Day, N. P. J., Yeo, T. W., Hossain, M. A., Anstey, N. M., & Dondorp, A. M. (2020). Cell-Free Hemoglobin Is Associated With Increased Vascular Resistance and Reduced Peripheral Perfusion in Severe Malaria. The Journal of infectious diseases, 221(1), 127-137. https://doi.org/10.1093/infdis/jiz359