Cerebral autoregulation and neurovascular coupling are progressively impaired during septic shock: an experimental study

Lorenzo Ferlini,Nicolas Gaspard,Fuhong Su,Jacques Creteur,Fabio Silvio Taccone

doi:10.1186/s40635-020-00332-0

Lorenzo Ferlini, Nicolas Gaspard + Show 3 more

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https://doi.org/10.1186/s40635-020-00332-0

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Abstract

BackgroundAlteration of the mechanisms of cerebral blood flow (CBF) regulation might contribute to the pathophysiology of sepsis-associated encephalopathy (SAE). However, previous clinical studies on dynamic cerebral autoregulation (dCA) in sepsis had several cofounders. Furthermore, little is known on the potential impairment of neurovascular coupling (NVC) in sepsis. The aim of our study was to determine the presence and time course of dCA and NVC alterations in a clinically relevant animal model and their potential impact on the development of SAE.MethodsThirty-six anesthetized, mechanically ventilated female sheep were randomized to sham procedures (sham, n = 15), sepsis (n = 14), or septic shock (n = 7). Blood pressure, CBF, and electrocorticography were continuously recorded. Pearson’s correlation coefficient Lxa and transfer function analysis were used to estimate dCA. NVC was assessed by the analysis of CBF variations induced by cortical gamma activity (Eγ) peaks and by the magnitude-squared coherence (MSC) between the spontaneous fluctuations of CBF and Eγ. Cortical function was estimated by the alpha-delta ratio. Wilcoxon signed rank and rank sum tests, Friedman tests, and RMANOVA test were used as appropriate.ResultsSepsis and sham animals did not differ neither in dCA nor in NVC parameters. A significant impairment of dCA occurred only after septic shock (Lxa, p = 0.03, TFA gain p = 0.03, phase p = 0.01). Similarly, NVC was altered during septic shock, as indicated by a lower MSC in the frequency band 0.03–0.06 Hz (p < 0.001). dCA and NVC impairments were associated with cortical dysfunction (reduction in the alpha-delta ratio (p = 0.03)).ConclusionsA progressive loss of dCA and NVC occurs during septic shock and is associated with cortical dysfunction. These findings indicate that the alteration of mechanisms controlling cortical perfusion plays a late role in the pathophysiology of SAE and suggest that alterations of CBF regulation mechanisms in less severe phases of sepsis reported in clinical studies might be due to patients’ comorbidities or other confounders. Furthermore, a mean arterial pressure targeting therapy aiming to optimize dCA might not be sufficient to prevent neuronal dysfunction in sepsis since it would not improve NVC.

Highlights

Sepsis-associated encephalopathy (SAE) is defined as cerebral dysfunction that accompanies sepsis in the absence of direct central nervous system infection, structural abnormality, or other causes of encephalopathy [1]
Neurovascular coupling We found no significant difference in the percentage of Envelope of the cortical high gamma activity (Eγ) peaks followed by cerebral blood flow velocity (CBFv) peaks, the amplitude and lag of the CBFv peaks, between or within the sham and sepsis groups, there was a trend towards a decrease in Eγ peaks followed by CBFv peaks in the last time point in the sepsis group (Supplemental Figure S2)
Whereas earlier studies assessed neurovascular coupling (NVC) in stimuli-induced conditions both in septic patients and animals models [22, 23], little is known about NVC during spontaneous brain activity. In contrast to these studies, which found a reduction in amplitude [22] and a delay [23] in the CBFv response to stimulus-induced cortical activity, we found no significant variations in the amplitude or in the time lag of the CBFv response, independently from the EEG frequency band assessed, even if a trend in the reduction of the CBFv response was observed when comparing the percentage of EEG peaks followed by a CBFv peak

Summary

Introduction

Sepsis-associated encephalopathy (SAE) is defined as cerebral dysfunction that accompanies sepsis in the absence of direct central nervous system infection, structural abnormality, or other causes of encephalopathy [1]. While its physiopathology is not completely understood [1], in addition to a BBB dysfunction [4–6], several studies suggested alterations of cerebral blood flow (CBF) regulation mechanisms as key factors for SAE [7–11]. In response to variations of CPP, an adaptation of vascular resistance allows CBF to remain stable, a mechanism known as cerebral autoregulation (CA) [16]. It was originally found that CBF remains constant over a wide range of CPP changes (static cerebral autoregulation, sCA) [16]. Alteration of the mechanisms of cerebral blood flow (CBF) regulation might contribute to the pathophysiology of sepsis-associated encephalopathy (SAE).

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