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

    Research output: Contribution to journalArticle

    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

    Fingerprint

    Vascular Resistance
    Malaria
    Hemoglobins
    Perfusion
    Hematocrit
    Sepsis
    Arterial Pressure
    Plasma Cells
    Blood Vessels
    Linear Models
    Healthy Volunteers
    Nitric Oxide
    Temperature
    Falciparum Malaria
    Hypotension
    Biological Availability
    Lactic Acid
    Mortality

    Cite this

    Kingston, H. W. F., Ghose, A., Rungpradubvong, V., Satitthummanid, S., Herdman, M. T., Plewes, K., ... 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
    Kingston, Hugh W.F. ; Ghose, Aniruddha ; Rungpradubvong, Voravut ; Satitthummanid, Sudarat ; Herdman, M. Trent ; Plewes, Katherine ; Ishioka, Haruhiko ; Leopold, Stije J. ; Sinha, Ipsita ; Intharabut, Benjamas ; Piera, Kim ; McNeil, Yvette ; Mohanty, Sanjib ; Maude, Richard J. ; White, Nicholas J. ; Day, Nicholas P.J. ; Yeo, Tsin W. ; Hossain, Md Amir ; Anstey, Nicholas M. ; Dondorp, Arjen M. / Cell-Free Hemoglobin Is Associated With Increased Vascular Resistance and Reduced Peripheral Perfusion in Severe Malaria. In: The Journal of infectious diseases. 2020 ; Vol. 221, No. 1. pp. 127-137.
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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.",
    keywords = "cell-free hemoglobin, hemodynamics, nitric oxide, Severe malaria, vascular resistance, vascular tone",
    author = "Kingston, {Hugh W.F.} and Aniruddha Ghose and Voravut Rungpradubvong and Sudarat Satitthummanid and Herdman, {M. Trent} and Katherine Plewes and Haruhiko Ishioka and Leopold, {Stije J.} and Ipsita Sinha and Benjamas Intharabut and Kim Piera and Yvette McNeil and Sanjib Mohanty and Maude, {Richard J.} and White, {Nicholas J.} and Day, {Nicholas P.J.} and Yeo, {Tsin W.} and Hossain, {Md Amir} and Anstey, {Nicholas M.} and Dondorp, {Arjen M.}",
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    Kingston, HWF, Ghose, A, Rungpradubvong, V, Satitthummanid, S, Herdman, MT, Plewes, K, Ishioka, H, Leopold, SJ, Sinha, I, Intharabut, B, Piera, K, McNeil, Y, Mohanty, S, Maude, RJ, White, NJ, Day, NPJ, Yeo, TW, Hossain, MA, Anstey, NM & Dondorp, AM 2020, 'Cell-Free Hemoglobin Is Associated With Increased Vascular Resistance and Reduced Peripheral Perfusion in Severe Malaria', The Journal of infectious diseases, vol. 221, no. 1, pp. 127-137. https://doi.org/10.1093/infdis/jiz359

    Cell-Free Hemoglobin Is Associated With Increased Vascular Resistance and Reduced Peripheral Perfusion in Severe Malaria. / Kingston, Hugh W.F.; Ghose, Aniruddha; Rungpradubvong, Voravut; Satitthummanid, Sudarat; Herdman, M. Trent; Plewes, Katherine; Ishioka, Haruhiko; Leopold, Stije J.; Sinha, Ipsita; Intharabut, Benjamas; Piera, Kim; McNeil, Yvette; Mohanty, Sanjib; Maude, Richard J.; White, Nicholas J.; Day, Nicholas P.J.; Yeo, Tsin W.; Hossain, Md Amir; Anstey, Nicholas M.; Dondorp, Arjen M.

    In: The Journal of infectious diseases, Vol. 221, No. 1, 01.01.2020, p. 127-137.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Cell-Free Hemoglobin Is Associated With Increased Vascular Resistance and Reduced Peripheral Perfusion in Severe Malaria

    AU - Kingston, Hugh W.F.

    AU - Ghose, Aniruddha

    AU - Rungpradubvong, Voravut

    AU - Satitthummanid, Sudarat

    AU - Herdman, M. Trent

    AU - Plewes, Katherine

    AU - Ishioka, Haruhiko

    AU - Leopold, Stije J.

    AU - Sinha, Ipsita

    AU - Intharabut, Benjamas

    AU - Piera, Kim

    AU - McNeil, Yvette

    AU - Mohanty, Sanjib

    AU - Maude, Richard J.

    AU - White, Nicholas J.

    AU - Day, Nicholas P.J.

    AU - Yeo, Tsin W.

    AU - Hossain, Md Amir

    AU - Anstey, Nicholas M.

    AU - Dondorp, Arjen M.

    PY - 2020/1/1

    Y1 - 2020/1/1

    N2 - 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.

    AB - 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.

    KW - cell-free hemoglobin

    KW - hemodynamics

    KW - nitric oxide

    KW - Severe malaria

    KW - vascular resistance

    KW - vascular tone

    UR - http://www.scopus.com/inward/record.url?scp=85076505939&partnerID=8YFLogxK

    U2 - 10.1093/infdis/jiz359

    DO - 10.1093/infdis/jiz359

    M3 - Article

    C2 - 31693729

    AN - SCOPUS:85076505939

    VL - 221

    SP - 127

    EP - 137

    JO - Journal of Infectious Diseases

    JF - Journal of Infectious Diseases

    SN - 0022-1899

    IS - 1

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