An Ambiguous Role for Fever in Worsening Outcome After Intracerebral Hemorrhage

Abstract

Intracerebral hemorrhage (ICH) accounts for 10–15% of all strokes and leaves most survivors with impairments. Fever, a rise in the thermoregulatory set point, complicates ICH. This review summarizes ICH fever studies and employs meta-analytic techniques to explore the relationship between fever and ICH. We discuss methodological considerations for future studies and provide an overview of mechanisms by which fever, and its treatment, may impact ICH. We searched the PubMed database using the following terms: ((fever OR hyperthermia) AND (intracerebral hemorrhage OR intraparenchymal hemorrhage OR intracerebral haemorrhage OR intraparenchymal haemorrhage)). Our search returned 727 studies, of which 21 were included in our final analysis, consisting of 19 clinical, and two preclinical, studies. We conducted a meta-analysis on the clinical data to quantify how fever is related to mortality, functional outcomes, and intraventricular hemorrhage. Analysis of clinical studies suggested that fever causes an increased risk of mortality but does not appear to be associated with poor outcomes among survivors, making it difficult to ascertain the extent of harm caused by post-ICH fever or the benefits of its treatment. Perhaps these inconsistencies stem from variable fever definitions, and temperature measurement and fever treatment protocols. Additionally, the lack of mechanistic data in clinical studies coupled with preclinical studies showing no harmful effects of moderate bouts of hyperthermia raise concerns about the direct contribution of hyperthermia and fever in post ICH outcome. Overall, the significance of temperature increases after ICH is unclear, making this an important area for future research.

Development and validation of a nomogram to predict the 30-day mortality risk of patients with intracerebral hemorrhage

“…An elevated temperature may be caused by the inflammatory response ( Iglesias-Rey et al, 2018 ). Up to 30–40% of ICH patients reportedly have hyperthermia and a poor prognosis ( Honig et al, 2015 ; Liddle et al, 2022 ). However, in the absence of other infection signs, persistent high fever in ICH patients may be induced by perturbation of temperature control ( Rabinstein and Sandhu, 2007 ).…”

Molecular, Pathological, Clinical, and Therapeutic Aspects of Perihematomal Edema in Different Stages of Intracerebral Hemorrhage

“…Aged male animals have more severe brain swelling [ 121 , 122 ]. However, although there is evidence that therapeutic hypothermia may inhibit brain edema formation in animals with ICH, the significance of increases in temperature after ICH is currently unclear [ 123 , 124 ]. However, it is unknown how genetics influences PHE in animals with acute ICH.…”

“…In particular, many studies implied that a large volume of ICH was correlated with the severity and progression of PHE [ 115 , 116 , 138 , 139 ]. Probably due to the ambiguous effects of fever on ICH outcomes, the effects of therapeutic hypothermia on brain edema are currently heterogeneous in patients with ICH [ 123 , 140 , 141 ]. In addition to the demographic and imaging variables discussed above, other clinical variables may also influence the evolution of PHE after ICH.…”

“…Furthermore, research indicates that repeated remote daily ischemic conditioning for 7 days improved hematoma resolution and reduced rPHE after ICH [ 248 ]. Again, although there was recurring evidence of a reduction in therapeutic hypothermia-induced edema, the effects of therapeutic hypothermia on the outcome of patients with ICH were heterogeneous, as it is currently difficult to determine the extent of damage caused by post-ICH fever currently [ 123 , 140 ]. Therefore, researchers should pay more attention to potential treatment strategies targeting PHE.…”

“…Higher glucose [115] Larger initial ICH volume [116,138] Higher admission hematocrit [21] History of hypertension [138] Irregular hematoma or black hole sign [115,116] Higher admission time for partial thromboplastin time [21] Higher admission SBP [144,145] Larger initial EED [115] Absence in warfarin preuse [99,149] Impaired blood pressure regulation [139] Time from symptom onset [138] Higher serum levels of IL-6 and soluble CD163 [150,153] Higher body temperature [123,124,138,140,141] Absence in sulfonylurea drug pretreatment [142,143] Higher serum MMP-3 or MMP-8 levels [151,152] Abbreviations: PHE: perihematomal edema; APOE4: apolipoprotein E; AQP4: aquaporin 4; TIMP-2: tissue inhibitor of metalloproteinases 2; Hp: haptoglobin; SBP: systolic blood pressure; ICH: intracerebral hemorrhage; EED: edema extension distance; MMP: matrix metallopeptidase; AIVF: absent in ipsilateral venous filling; JVR: jugular vein reflex; CVFV: cerebral venous outflow volume. Oxidative Medicine and Cellular Longevity rPHE in patients with ICH [139].…”