Estimated Cerebral Perfusion Pressure and Intracranial Pressure in Septic Patients.

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.

The association between the presence and burden of periodic discharges and outcome in septic patients: an observational prospective study.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is frequent in septic patients. Electroencephalography (EEG) is very sensitive to detect early epileptic abnormalities, such as seizures and periodic discharges (PDs), and to quantify their duration (the so-called burden). However, the prevalence of these EEG abnormalities in septic patients, as well as their effect on morbidity and mortality, are still unclear. The aims of this study were to assess whether the presence of electrographic abnormalities (i.e. the absence of reactivity, the presence and burden of seizures and PDs) was associated with functional outcome and mortality in septic patients and whether these abnormalities were associated with sepsis-associated encephalopathy (SAE). METHODS: We prospectively included septic patients, without known chronic or acute intracranial disease or pre-existing acute encephalopathy, requiring ICU admission in a tertiary academic centre. Continuous EEG monitoring was started within 72 h after inclusion and performed for up to 7 days. A comprehensive assessment of consciousness and delirium was performed twice daily by a trained neuropsychologist. Primary endpoints were unfavourable functional outcome (UO, defined as a Glasgow Outcome Scale-Extended-GOSE-score < 5), and mortality collected at hospital discharge and secondary endpoint was the association of PDs with SAE. Mann-Whitney, Fisher's exact and χ2 tests were used to assess differences in variables between groups, as appropriate. Multivariable logistic regression analysis with in-hospital mortality, functional outcome, SAE or PDs as the dependent variables were performed. RESULTS: We included 92 patients. No seizures were identified. Nearly 25% of patients had PDs. The presence of PDs and PDs burden was associated with UO in univariate (n = 15 [41%], p = 0.005 and p = 0.008, respectively) and, for PDs presence, also in multivariate analysis after correcting for disease severity (OR 3.82, IC 95% [1.27-11.49], p = 0.02). The PDs burden negatively correlated with GOSE (Spearman's coefficient ρ = - 0.2, p = 0.047). The presence of PDs was also independently associated with SAE (OR 8.98 [1.11-72.8], p = 0.04). Reactivity was observed in the majority of patients and was associated with outcomes (p = 0.044 for both functional outcome and mortality). CONCLUSION: Our findings suggest that PDs and PDs burden are associated with SAE and might affect outcome in septic patients.

Renin as a Marker of Tissue-Perfusion and Prognosis in Critically Ill Patients.

OBJECTIVES: To characterize renin in critically ill patients. Renin is fundamental to circulatory homeostasis and could be a useful marker of tissue-perfusion. However, diurnal variation, continuous renal replacement therapy and drug-interference could confound its use in critical care practice. DESIGN: Prospective observational study. SETTING: Single-center, mixed medical-surgical ICU in Europe. PATIENTS: Patients over 18 years old with a baseline estimated glomerular filtration rate greater than 30 mL/min/1.73 m and anticipated ICU stay greater than 24 hours. Informed consent was obtained from the patient or next-of-kin. INTERVENTIONS: Direct plasma renin was measured in samples drawn 6-hourly from arterial catheters in recumbent patients and from extracorporeal continuous renal replacement therapy circuits. Physiologic variables and use of drugs that act on the renin-angiotensin-aldosterone system were recorded prospectively. Routine lactate measurements were used for comparison. MEASUREMENTS AND MAIN RESULTS: One-hundred twelve arterial samples (n = 112) were drawn from 20 patients (65% male; mean ± SD, 60 ± 14 yr old) with septic shock (30%), hemorrhagic shock (15%), cardiogenic shock (20%), or no circulatory shock (35%). The ICU mortality rate was 30%. Renin correlated significantly with urine output (repeated-measures correlation coefficient = -0.29; p = 0.015) and mean arterial blood pressure (repeated-measures correlation coefficient = -0.35; p < 0.001). There was no diurnal variation of renin or significant interaction of renin-angiotensin-aldosterone system drugs with renin in this population. Continuous renal replacement therapy renin removal was negligible (mass clearance ± SD 4% ± 4.3%). There was a significant difference in the rate of change of renin over time between survivors and nonsurvivors (-32 ± 26 µU/timepoint vs +92 ± 57 µU/timepoint p = 0.03; mean ± SEM), but not for lactate (-0.14 ± 0.04 mM/timepoint vs +0.15 ± 0.21 mM/timepoint; p = 0.07). Maximum renin achieved significant prognostic value for ICU mortality (receiver operator curve area under the curve 0.80; p = 0.04), whereas maximum lactate did not (receiver operator curve area under the curve, 0.70; p = 0.17). CONCLUSIONS: In an heterogeneous ICU population, renin measurement was not significantly affected by diurnal variation, continuous renal replacement therapy, or drugs. Renin served as a marker of tissue-perfusion and outperformed lactate as a predictor of ICU mortality.

Six-Month Outcome of Immunocompromised Patients with Severe Acute Respiratory Distress Syndrome Rescued by Extracorporeal Membrane Oxygenation. An International Multicenter Retrospective Study.

Rationale: Because encouraging rates for hospital and long-term survival of immunocompromised patients in ICUs have been described, these patients are more likely to receive invasive therapies, like extracorporeal membrane oxygenation (ECMO).Objectives: To report outcomes of immunocompromised patients treated with ECMO for severe acute respiratory distress syndrome (ARDS) and to identify their pre-ECMO predictors of 6-month mortality and main ECMO-related complications.Methods: Retrospective multicenter study in 10 international ICUs with high volumes of ECMO cases. Immunocompromised patients, defined as having hematological malignancies, active solid tumor, solid-organ transplant, acquired immunodeficiency syndrome, or long-term or high-dose corticosteroid or immunosuppressant use, and severe ECMO-treated ARDS, from 2008 to 2015 were included.Measurements and Main Results: We collected demographics, clinical data, ECMO-related complications, and ICU- and 6 month-outcome data for 203 patients (median Acute Physiology and Chronic Health Evaluation II score, 28 [25th-75th percentile, 20-33]; age, 51 [38-59] yr; PaO2/FiO2, 60 [50-82] mm Hg before ECMO) who fulfilled our inclusion criteria. Six-month survival was only 30%, with a respective median ECMO duration and ICU stay of 8 (5-14) and 25 (16-50) days. Patients with hematological malignancies had significantly poorer outcomes than others (log-rank P = 0.02). ECMO-related major bleeding, cannula infection, and ventilator-associated pneumonia were frequent (36%, 10%, and 50%, respectively). Multivariate analyses retained fewer than 30 days between immunodeficiency diagnosis and ECMO cannulation as being associated with lower 6-month mortality (odds ratio, 0.32 [95% confidence interval, 0.16-0.66]; P = 0.002), and lower platelet count, higher Pco2, age, and driving pressure as independent pre-ECMO predictors of 6-month mortality.Conclusions: Recently diagnosed immunodeficiency is associated with a much better prognosis in ECMO-treated severe ARDS. However, low 6-month survival of our large cohort of immunocompromised patients supports restricting ECMO to patients with realistic oncological/therapeutic prognoses, acceptable functional status, and few pre-ECMO mortality-risk factors.

Septic Encephalopathy.

PURPOSE OF THE REVIEW: To discuss the diagnostic approach to patients with septic encephalopathy as well as the need for specific neuro-monitoring and the perspectives on future therapeutic approaches in this setting. RECENT FINDINGS: Most of data-concern experimental studies evaluating the pathophysiology of septic encephalopathy. A combination of neurodegenerative pathways with neurovascular injury is the cornerstone for the development of such complication and the long-term neurological sequelae among survivors. Septic encephalopathy is a common complication in septic patients. Clinical presentation may range from mild confusion and disorientation to convulsions and deep coma. The diagnosis of septic encephalopathy is made difficult by the lack of any specific clinical and non-clinical feature, in particular among sedated patients in whom neurological examination is unreliable. In spite of the high mortality rate associated with this condition, there is no prophylactic or targeted therapy to reduce or minimize brain damage in septic patients and clinical management is limited to the treatment of the underlying infection.

Impaired cerebral autoregulation is associated with brain dysfunction in patients with sepsis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Anemia management after acute brain injury.

Anemia is frequent among brain-injured patients, where it has been associated with an increased risk of poor outcome. The pathophysiology of anemia in this patient population remains multifactorial; moreover, whether anemia merely reflects a higher severity of the underlying disease or is a significant determinant of the neurological recovery of such patients remains unclear. Interestingly, the effects of red blood cell transfusions (RBCT) in moderately anemic patients remain controversial; although hemoglobin levels are increased, different studies observed only a modest and inconsistent improvement in cerebral oxygenation after RBCT and raised serious concerns about the risk of increased complications. Thus, considering this "blood transfusion anemia paradox", the optimal hemoglobin level to trigger RBCT in brain-injured patients has not been defined yet; also, there is insufficient evidence to provide strong recommendations regarding which hemoglobin level to target and which associated transfusion strategy (restrictive versus liberal) to select in this patient population. We summarize in this review article the more relevant studies evaluating the effects of anemia and RBCT in patients with an acute neurological condition; also, we propose some potential strategies to optimize transfusion management in such patients.

Optimizing sedation in patients with acute brain injury.

Daily interruption of sedative therapy and limitation of deep sedation have been shown in several randomized trials to reduce the duration of mechanical ventilation and hospital length of stay, and to improve the outcome of critically ill patients. However, patients with severe acute brain injury (ABI; including subjects with coma after traumatic brain injury, ischaemic/haemorrhagic stroke, cardiac arrest, status epilepticus) were excluded from these studies. Therefore, whether the new paradigm of minimal sedation can be translated to the neuro-ICU (NICU) is unclear. In patients with ABI, sedation has 'general' indications (control of anxiety, pain, discomfort, agitation, facilitation of mechanical ventilation) and 'neuro-specific' indications (reduction of cerebral metabolic demand, improved brain tolerance to ischaemia). Sedation also is an essential therapeutic component of intracranial pressure therapy, targeted temperature management and seizure control. Given the lack of large trials which have evaluated clinically relevant endpoints, sedative selection depends on the effect of each agent on cerebral and systemic haemodynamics. Titration and withdrawal of sedation in the NICU setting has to be balanced between the risk that interrupting sedation might exacerbate brain injury (e.g. intracranial pressure elevation) and the potential benefits of enhanced neurological function and reduced complications. In this review, we provide a concise summary of cerebral physiologic effects of sedatives and analgesics, the advantages/disadvantages of each agent, the comparative effects of standard sedatives (propofol and midazolam) and the emerging role of alternative drugs (ketamine). We suggest a pragmatic approach for the use of sedation-analgesia in the NICU, focusing on some practical aspects, including optimal titration and management of sedation withdrawal according to ABI severity.

Variability in brain death determination in europe: looking for a solution.

BACKGROUND: Criteria for determining brain death (BD) vary between countries. We report the results of an investigation designed to compare procedures to determine BD in different European countries. METHODS: We developed a web-based questionnaire that was sent to representatives of 33 European countries. Responses were reviewed, and individual respondents were contacted if clarification was required. RESULTS: Responses were received from 28 (85 %) of the 33 countries to which the questionnaire was sent. Each country has either a law (93 %) or national guidance (89 %) for defining BD. Clinical examination is sufficient to determine BD in 50 % of countries; coma, apnea, absence of corneal, and cough reflexes are mandatory criteria in all. Confirmation of apnea is required in all countries but not defined in 4 (14 %). In the 24 (86 %) of countries with a formal definition of the apnea test, a target pCO2 level (23/24, 96 %) is the pre-specified end point in most. The (median, range) number of clinical examinations (2, 1-3) and minimum observation time between tests (3 h, 0-12 h) vary greatly between countries. Additional (confirmatory) tests are required in 50 % of countries. Hypothermia (4 %), anoxic injury (7 %), inability to complete clinical examination (61 %), toxic drug levels (57 %), and inconclusive apnea test (54 %) are among the most common indications for confirmatory tests. Cerebral blood flow (CBF) investigation is mandatory in 18 % of countries, but optional or indicated only in selected cases in 82 %. Conventional angiography is the preferred method of determining absent CBF (50 %), followed by transcranial Doppler sonography (43 %), computerized tomography (CT) angiography (39 %), CT perfusion, and magnetic resonance imaging (MRI) angiography (11 %). Electroencephalography is always (21 %) or optionally (14 %) recorded. CONCLUSIONS: Although legislation or professional guidance is available to standardize nationally the BD diagnosis process in all European countries, there are still disparities between countries. The current variation in practice makes an international consensus for the definition of BD imperative.

Correlation between heart rate variability and cerebral autoregulation in septic patients.

BACKGROUND: Heart rate variability (HRV) may provide an estimation of the autonomous nervous system (ANS) integrity in critically ill patients. Disturbances of cerebral autoregulation (CAR) may share common pathways of ANS dysfunction. AIM: To explore whether changes in HRV and CAR index correlate in critically ill septic patients. METHODS: Prospectively collected data on septic adult (> 18 years) patients admitted into a mixed Intensive Care between February 2016 and August 2019 with a recorded transcranial doppler CAR assessment. CAR was assessed calculating the Pearson's correlation coefficient (i.e. mean flow index, Mxa) between the left middle cerebral artery flow velocity (FV), insonated with a 2-MHz probe, and invasive blood pressure (BP) signal, both recorded simultaneously through a Doppler Box (DWL, Germany). MATLAB software was used for CAR assessment using a validated script; a Mxa >0.3 was considered as impaired CAR. HRV was assessed during the same time period using a specific software (Kubios HRV 3.2.0) and analyzed in both time-domain and frequency domain methods. Correlation between HRV-derived variables and Mxa were assessed using the Spearman's coefficient. RESULTS: A total of 141 septic patients was studied; median Mxa was 0.35 [0.13-0.60], with 77 (54.6 %) patients having an impaired CAR. Mxa had a significant although weak correlation with HRV time domain (SDNN, r = 0.17, p = 0.04; RMSSD, r = 0.18, p = 0.03; NN50, r = 0.23, p = 0.006; pNN50, r = 0.23, p = 0.007), frequency domain (FFT-HF, r = 0.21; p = 0.01; AR-HF, r = 0.19; p = 0.02), and non-linear domain (SD1, r = 0.18, p = 0.03) parameters. Impaired CAR patients had also all of these HRV-derived parameters higher than those with intact CAR. CONCLUSIONS: In this exploratory study, a potential association of ANS dysfunction and impaired CAR during sepsis was observed.

Critically ill patients with acute kidney injury: clinical determinants and post-mortem histology.

Background: Acute kidney injury (AKI) requiring renal replacement therapy (RRT) in the intensive care unit (ICU) portends a poor prognosis. We aimed to better characterize predictors of survival and the mechanism of kidney failure in these patients. Methods: This was a retrospective observational study using clinical and radiological electronic health records, analysed by univariable and multivariable binary logistic regression. Histopathological examination of post-mortem renal tissue was performed. Results: Among 157 patients with AKI requiring RRT, higher serum creatinine at RRT initiation associated with increased ICU survival [odds ratio (OR) 0.33, 95% confidence interval (CI) 0.17-0.62, P = .001]; however, muscle mass (a marker of frailty) interacted with creatinine (P = .02) and superseded creatinine as a predictor of survival (OR 0.26, 95% CI 0.08-0.82; P = .02). Achieving lower cumulative fluid balance (mL/kg) predicted ICU survival (OR 1.01, 95% CI 1.00-1.01, P < .001), as supported by sensitivity analyses showing improved ICU survival with the use of furosemide (OR 0.40, 95% CI 0.18-0.87, P = .02) and increasing net ultrafiltration (OR 0.97, 95% CI 0.95-0.99, P = .02). A urine output of >500 mL/24 h strongly predicted successful liberation from RRT (OR 0.125, 95% CI 0.05-0.35, P < .001). Post-mortem reports were available for 32 patients; clinically unrecognized renal findings were described in 6 patients, 1 of whom had interstitial nephritis. Experimental staining of renal tissue from patients with sepsis-associated AKI (S-AKI) showed glomerular loss of synaptopodin (P = .02). Conclusions: Confounding of creatinine by muscle mass undermines its use as a marker of AKI severity in clinical studies. Volume management and urine output are key determinants of outcome. Loss of synaptopodin implicates glomerular injury in the pathogenesis of S-AKI.

Cerebral Autoregulation Indices Are Not Interchangeable in Patients With Sepsis.

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.

Automated Pupillometry as an Assessment Tool for Intracranial Hemodynamics in Septic Patients.

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 (<60 mmHg) and 15 (38%) had high eICP (>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.

Delay of cerebral autoregulation in traumatic brain injury patients.

INTRODUCTION: Adequate cerebral perfusion prevents secondary insult after traumatic brain injury (TBI). Cerebral autoregulation (CAR) keeps cerebral blood flow (CBF) constant when arterial blood pressure (ABP) changes. Aim of the study was to evaluate the existence of delayed CAR in TBI patients and its possible association with outcome. METHODS: We retrospectively analysed TBI patients. Flow velocity (FV) in middle cerebral artery, invasive intra-cranial pressure (ICP) and ABP were recorded. Cerebral perfusion pressure (CPP) was calculated as ABP - ICP. Mean flow index (Mx) > 0.3 defined altered CAR. Samples from patients with altered CAR were further analysed: FV signal was shifted backward relative to CPP; Mx was calculated after each shift (MxD). Mx > 0.3 plus MxD ≤ 0.3 defined delayed CAR. Favourable outcome (FO) at 6 months was defined as Glasgow Outcome Scale 4-5. RESULTS: 154 patients were included. GCS was 6 [4-9], ICP was 14 [9-20] mmHg. Data on 6 months outcome were available for 131 patients: 104/131 patients (79 %) were alive; GOS was 4 [3-5]; 70/131 (53 %) had FO. Mx was 0.07 [-0.19 to 0.28] overall. Mx was lower in patients with FO compared others (0.00 [-0.21 to 0.20] vs 0.17 [-0.12 to 0.37], p = 0.02). 118 (77 %) patients had intact CAR and 36 (23 %) patients had altered CAR; 23 patients - 15 % of the general cohort and 64 % of patients with altered CAR - had delayed CAR. Delay in the autoregulatory response was 2 [1-4] seconds. 80/98 (82 %) of patients with intact CAR survived, compared to 16/21 (76 %) with delayed and 8/12 (67 %) with altered CAR (p = 0.20). 80/98 (58 %) patients with intact, 10/21 (48 %) patients with delayed and 3/12 (25 %) patients with altered CAR had FO (p = 0.03). CONCLUSION: A subgroup of TBI patients with delayed CAR was identified. Delayed CAR was associated with better neurological outcome than altered CAR.

Cerebral autoregulation in anoxic brain injury patients treated with targeted temperature management.

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.

The use of automated pupillometry to assess cerebral autoregulation: a retrospective study.

BACKGROUND: Critically ill patients are at high risk of developing neurological complications. Among all the potential aetiologies, brain hypoperfusion has been advocated as one of the potential mechanisms. Impairment of cerebral autoregulation (CAR) can result in brain hypoperfusion. However, assessment of CAR is difficult at bedside. We aimed to evaluate whether the automated pupillometer might be able to detect impaired CAR in critically ill patients. METHODS: We included 92 patients in this retrospective observational study; 52 were septic. CAR was assessed using the Mxa index, which is the correlation index between continuous recording of cerebral blood flow velocities using the transcranial Doppler and invasive arterial blood pressure over 8 ± 2 min. Impaired CAR was defined as an Mxa > 0.3. Automated pupillometer (Neuroptics, Irvine, CA, USA) was used to assess the pupillary light reflex concomitantly to the CAR assessment. RESULTS: The median Mxa was 0.33 in the whole cohort (0.33 in septic patients and 0.31 in the non-septic patients; p = 0.77). A total of 51 (55%) patients showed impaired CAR, 28 (54%) in the septic group and 23 (58%) in the non-septic group. We found a statistically significant although weak correlation between Mxa and the Neurologic Pupil Index (r 2 = 0.04; p = 0.048) in the whole cohort as in septic patients (r 2 = 0.11; p = 0.026); no correlation was observed in non-septic patients and for other pupillometry-derived variables. CONCLUSIONS: Automated pupillometry cannot predict CAR indices such as Mxa in a heterogeneous population of critically ill patients.

Neuroprotective strategies and neuroprognostication after cardiac arrest.

Neurocognitive disturbances are common among survivors of cardiac arrest (CA). Although initial management of CA, including bystander cardiopulmonary resuscitation, optimal chest compression, and early defibrillation, has been implemented continuously over the last years, few therapeutic interventions are available to minimize or attenuate the extent of brain injury occurring after the return of spontaneous circulation. In this review, we discuss several promising drugs that could provide some potential benefits for neurological recovery after CA. Most of these drugs have been investigated exclusively in experimental CA models and only limited clinical data are available. Further research, which also considers combined neuroprotective strategies that target multiple pathways involved in the pathophysiology of postanoxic brain injury, is certainly needed to demonstrate the effectiveness of these interventions in this setting. Moreover, the evaluation of neurological prognosis of comatose patients after CA remains an important challenge that requires the accurate use of several tools. As most patients with CA are currently treated with targeted temperature management (TTM), combined with sedative drug therapy, especially during the hypothermic phase, the reliability of neurological examination in evaluating these patients is delayed to 72-96 h after admission. Thus, additional tests, including electrophysiological examinations, brain imaging and biomarkers, have been largely implemented to evaluate earlier the extent of brain damage in these patients.