Ilaria Alice Crippa

Brain dysfunction is a frequent complication of sepsis. Most likely, sepsis-associated brain dysfunction (SABD) results from the interaction between multiple factors: neurodegeneration due to microglial activation, altered neurotransmission, neuroinflammation and impairment of cerebral macro- and microcirculation. Altered brain perfusion might results from several mechanism: global or regional alterations in cerebral blood flow (CBF); reduced cerebral perfusion pressure - which is the driving force propelling blood through cerebral blood vessels - due to systemic hypotension; global or regional vasoconstriction; dysfunction of the intrinsic regulatory mechanisms of CBF, such as cerebral autoregulation and cerebrovascular reactivity; endothelial and blood-brain barrier dysfunction; autonomic nervous system dysfunction and metabolic uncoupling. Disorders of brain perfusion and CBF regulation are frequently observed in humans with sepsis, and intracranial hemodynamics monitoring can potentially be useful in clinical management of septic patients. The aim of this review is to provide an update of the current knowledge on alterations in brain hemodynamics associated with sepsis, along with physiological and methodological considerations intended to help the reader navigate the diverse results from published literature and a practical guide to apply non-invasive intracranial hemodynamics monitoring to septic patients in clinical practice.

Background Sepsis-associated brain dysfunction (SABD) is frequent and is associated with poor outcome. Changes in brain hemodynamics remain poorly described in this setting. The aim of this study was to investigate the alterations of cerebral perfusion pressure and intracranial pressure in a cohort of septic patients. Methods We conducted a retrospective analysis of prospectively collected data in septic adults admitted to our intensive care unit (ICU). We included patients in whom transcranial Doppler recording performed within 48 h from diagnosis of sepsis was available. Exclusion criteria were intracranial disease, known vascular stenosis, cardiac arrhythmias, pacemaker, mechanical cardiac support, severe hypotension, and severe hypocapnia or hypercapnia. SABD was clinically diagnosed by the attending physician, anytime during the ICU stay. Estimated cerebral perfusion pressure (eCPP) and estimated intracranial pressure (eICP) were calculated from the blood flow velocity of the middle cerebral artery and invasive arterial pressure using a previously validated formula. Normal eCPP was defined as eCPP ≥ 60 mm Hg, low eCPP was defined as eCPP < 60 mm Hg; normal eICP was defined as eICP ≤ 20 mm Hg, and high eICP was defined as eICP > 20 mm Hg. Results A total of 132 patients were included in the final analysis (71% male, median [interquartile range (IQR)] age was 64 [52–71] years, median [IQR] Acute Physiology and Chronic Health Evaluation II score on admission was 21 [15–28]). Sixty-nine (49%) patients developed SABD during the ICU stay, and 38 (29%) were dead at hospital discharge. Transcranial Doppler recording lasted 9 (IQR 7–12) min. Median (IQR) eCPP was 63 (58–71) mm Hg in the cohort; 44 of 132 (33%) patients had low eCPP. Median (IQR) eICP was 8 (4–13) mm Hg; five (4%) patients had high eICP. SABD occurrence and in-hospital mortality did not differ between patients with normal eCPP and patients with low eCPP or between patients with normal eICP and patients with high eICP. Eighty-six (65%) patients had normal eCPP and normal eICP, 41 (31%) patients had low eCPP and normal eICP, three (2%) patients had low eCPP and high eICP, and two (2%) patients had normal eCPP and high eICP; however, SABD occurrence and in-hospital mortality were not significantly different among these subgroups. Conclusions Brain hemodynamics, in particular CPP, were altered in one third of critically ill septic patients at a steady state of monitoring performed early during the course of sepsis. However, these alterations were equally common in patients who developed or did not develop SABD during the ICU stay and in patients with favorable or unfavorable outcome.

Impaired cerebral autoregulation (CA) may increase the risk of brain hypoperfusion in septic patients. Sepsis dysregulates the autonomic nervous system (ANS), potentially affecting CA. ANS function can be assessed through the pupillary light reflex (PLR). The aim of this prospective, observational study was to investigate the association between CA and PLR in adult septic patients. Transcranial Doppler was used to assess CA and calculate estimated cerebral perfusion pressure (eCPP) and intracranial pressure (eICP). An automated pupillometer (AP) was used to record Neurological Pupil Index (NPi), constriction (CV) and dilation (DV) velocities. The primary outcome was the relationship between AP-derived variables with CA; the secondary outcome was the association between AP-derived variables with eCPP and/or eICP. Among 40 included patients, 21 (53%) had impaired CA, 22 (55%) had low eCPP (16 mmHg). DV was lower in patients with impaired CA compared to others; DV predicted impaired CA with area under the curve, AUROC= 0.78 [95% Confidence Interval, CI 0.63–0.94]; DV < 2.2 mm/s had sensitivity 85% and specificity 69% for impaired CA. Patients with low eCPP or high eICP had lower NPi values than others. NPi was correlated with eCPP (r = 0.77, p < 0.01) and eICP (r = −0.87, p < 0.01). Automated pupillometry may play a role to assess brain hemodynamics in septic patients.

Introduction: Dynamic cerebral autoregulation (dCA) is frequently altered in patients with sepsis and may be associated with sepsis-associated brain dysfunction. However, the optimal index to quantify dCA in patients with sepsis is currently unknown.Objective: To assess the agreement between two validated dCA indices in patients with sepsis.Methods: Retrospective analysis of prospectively collected data in patients with sepsis; those with acute or chronic intracranial disease, arrhythmias, mechanical cardiac support, or history of supra-aortic vascular disease were excluded. Transcranial Doppler was performed on the right or left middle cerebral artery (MCA) with a 2-MHz probe, and MCA blood flow velocity (FV) and arterial pressure (BP) signals were simultaneously recorded. We calculated two indices of dCA: the mean flow index (Mxa), which is the Pearson correlation coefficient between BP and FV (MATLAB, MathWorks), and the autoregulation index (ARI), which is the transfer function analysis of spontaneous fluctuations in BP and FV (custom-written FORTRAN code). Impaired dCA was defined as Mxa >0.3 or ARI ≤ 4. The agreement between the two indices was assessed by Cohen's kappa coefficient.Results: We included 95 patients (age 64 ± 13 years old; male 74%); ARI was 4.38 [2.83–6.04] and Mxa was 0.32 [0.14–0.59], respectively. There was no correlation between ARI and Mxa (r = −0.08; p = 0.39). dCA was altered in 40 (42%) patients according to ARI and in 50 (53%) patients according to Mxa. ARI and Mxa were concordant in classifying 23 (24%) patients as having impaired dCA and 28 (29%) patients as having intact dCA. Cohen's kappa coefficient was 0.08, suggesting poor agreement. ARI was altered more frequently in patients on mechanical ventilation than others (27/52, 52% vs. 13/43, 30%, p = 0.04), whereas Mxa did not differ between those two groups. On the contrary, Mxa was altered more frequently in patients receiving sedatives than others (23/34, 68% vs. 27/61, 44%, p = 0.03), whereas ARI did not differ between these two groups.Conclusions: Agreement between ARI and Mxa in assessing dCA in patients with sepsis was poor. The identification of specific factors influencing the dCA analysis might lead to a better selection of the adequate cerebral autoregulation (CAR) index in critically ill patients with sepsis.

Background: Little is known about the prevalence of altered CAR in anoxic brain injury and the association with patients’ outcome. We aimed at investigating CAR in cardiac arrest survivors treated by targeted temperature management and its association to outcome. Methods: Retrospective analysis of prospectively collected data. Inclusion criteria: adult cardiac arrest survivors treated by targeted temperature management (TTM). Exclusion criteria: trauma; sepsis, intoxication; acute intra-cranial disease; history of supra-aortic vascular disease; severe hemodynamic instability; cardiac output mechanical support; arterial carbon dioxide partial pressure (PaCO₂) > 60 mmHg; arrhythmias; lack of acoustic window. Middle cerebral artery flow velocitiy (FV) was assessed by transcranial Doppler (TCD) once during hypothermia (HT) and once during normothermia (NT). FV and blood pressure (BP) were recorded simultaneously and Mxa calculated (MATLAB). Mxa is the Pearson correlation coefficient between FV and BP. Mxa > 0.3 defined altered CAR. Survival was assessed at hospital discharge. Cerebral Performance Category (CPC) 3–5 assessed 3 months after CA defined unfavorable neurological outcome (UO). Results: We included 50 patients (Jan 2015–Dec 2018). All patients had out-of-hospital cardiac arrest, 24 (48%) had initial shockable rhythm. Time to return of spontaneous circulation was 20 [10–35] min. HT (core body temperature 33.7 [33.2–34] °C) lasted for 24 [23–28] h, followed by rewarming and NT (core body temperature: 36.9 [36.6–37.4] °C). Thirty-one (62%) patients did not survive at hospital discharge and 36 (72%) had UO. Mxa was lower during HT than during NT (0.33 [0.11–0.58] vs. 0.58 [0.30–0.83]; p = 0.03). During HT, Mxa did not differ between outcome groups. During NT, Mxa was higher in patients with UO than others (0.63 [0.43–0.83] vs. 0.31 [− 0.01–0.67]; p = 0.03). Mxa differed among CPC values at NT (p = 0.03). Specifically, CPC 2 group had lower Mxa than CPC 3 and 5 groups. At multivariate analysis, initial non-shockable rhythm, high Mxa during NT and highly malignant electroencephalography pattern (HMp) were associated with in-hospital mortality; high Mxa during NT and HMp were associated with UO. Conclusions: CAR is frequently altered in cardiac arrest survivors treated by TTM. Altered CAR during normothermia was independently associated with poor outcome.

Brain dysfunction is associated with poor outcome in critically ill patients. In a post hoc analysis of the Intensive Care over Nations (ICON) database, we investigated the effect of brain dysfunction on hospital mortality in critically ill patients. Brain failure was defined as a neurological sequential organ failure assessment (nSOFA) score of 3–4, based on the assumed Glasgow Coma Scale (GCS) score. Multivariable analyses were performed to assess the independent roles of nSOFA and change in nSOFA from admission to day 3 (ΔnSOFA) for predicting hospital mortality. Data from 7192 (2096 septic and 5096 non-septic) patients were analyzed. Septic patients were more likely than non-septic patients to have brain failure on admission (434/2095 (21%) vs. 617/4665 (13%), p < 0.001) and during the ICU stay (625/2063 (30%) vs. 736/4665 (16%), p < 0.001). The presence of sepsis (RR 1.66 (1.31–2.09)), brain failure (RR 4.85 (3.33–7.07)), and both together (RR 5.61 (3.93–8.00)) were associated with an increased risk of in-hospital death, but nSOFA was not. In the 3280 (46%) patients in whom ΔnSOFA was available, sepsis (RR 2.42 (1.62–3.60)), brain function deterioration (RR 6.97 (3.71–13.08)), and the two together (RR 10.24 (5.93–17.67)) were associated with an increased risk of in-hospital death, whereas improvement in brain function was not.

Sepsis-associated brain dysfunction (SABD) is associated with high morbidity and mortality. The pathophysiology of SABD is multifactorial. One hypothesis is that impaired cerebral autoregulation (CAR) may result in brain hypoperfusion and neuronal damage leading to SABD. We studied 100 adult patients with sepsis (July 2012–March 2017) (age = 62 [52–71] years; Acute Physiology and Chronic Health Evaluation II score on admission = 21 [15–26]). Exclusion criteria were acute or chronic intracranial disease, arrhythmias, extracorporeal membrane oxygenation, and known intra- or extracranial supra-aortic vessel disease. The site of infection was predominantly abdominal (46%) or pulmonary (28%). Transcranial Doppler was performed, insonating the left middle cerebral artery with a 2-MHz probe. Middle cerebral artery blood flow velocity (FV) and arterial blood pressure (ABP) signals were recorded simultaneously; Pearson’s correlation coefficient (mean flow index [Mxa]) between ABP and FV was calculated using MATLAB. Impaired CAR was defined as Mxa > 0.3. Mxa was 0.29 [0.05–0.62]. CAR was impaired in 50 patients (50%). In a multiple linear regression analysis, low mean arterial pressure, history of chronic kidney disease and fungal infection were associated with high Mxa. SABD was diagnosed in 57 patients (57%). In a multivariable analysis, altered cerebral autoregulation, mechanical ventilation and history of vascular disease were independent predictors of SABD. Cerebral autoregulation was altered in half of the patients with sepsis and was associated with the development of SABD. These findings support the concept that cerebral hypoxia could contribute to the development of SABD.