Diagnostic Sensitivity of Plasma Endothelin-1 for Cerebral Vasospasm After Subarachnoid Hemorrhage, a Multicentre Double-Blind Study.

The purpose of this study is to establish the diagnostic sensitivity of Endothelin-1 for risk stratification and screening of clinical vasospasm after subarachnoid hemorrhage.This is a multicentre, observational study, correlating daily blood Endothelin-1 with clinical variables. Binary logistic regression used to examine if Endothelin-1 levels could be used to predict clinical vasospasm. Bivariate modelling used to explore associations between patient characteristics and vasospasm. A Receiver Operating Curve used to explore cut-off values for Endothelin-1. Sensitivity and specificity was used to validate the cut-point found in the pilot study. A total of 96 patients were enrolled over two years. Median Endothelin-1 was higher for patients who experienced clinical vasospasm except for day-5, where median endothelin for patients without vasospasm was higher (3.6 IQR = 5.3), compared to patients with vasospasm (3.3 IQR = 8.5) although differences were not significant. The Receiver Operating Curve analysis confirmed that day-5 Endothelin-1 was not a good indicator of vasospasm, with an area under the curve of 0.506 (95% CI: 0.350-0.663, p = 0.938). The levels of Endothelin-1 in blood do not discriminate patients who may develop symptomatic vasospasm. The high variability in Endothelin-1 levels, aligns with the pathophysiological variability of most biomarkers, decreasing their ability to predict a clinical event.

Pharmacokinetics of a novel dosing regimen of oral melatonin in critically ill patients.

BACKGROUND: Loss of circadian rhythms and reduced concentrations of endogenous melatonin are common in critically ill patients. After exogenous administration, supra-physiological concentrations in serum are only ephemeral, which may explain the absence of significant therapeutic effect on sleep. The aim of this study is to describe the pharmacokinetics of enteral melatonin in critically ill patients administered in a novel regimen aiming to simulate endogenous release. METHODS: Thirteen patients in the recovery phase of critical illness were randomised to receive enteral melatonin or placebo. In the melatonin group, a total of 6 mg was administered as solution through their feeding tube, commencing with a 3 mg loading dose at 9 pm and six subsequent 0.5 mg doses hourly. The placebo was administered using a similar regimen. Serial blood samples were taken and measured using a validated chromatographic method. The concentration-time data for serum melatonin concentrations were described using non-linear mixed-effects modelling. RESULTS: The observed concentrations in the melatonin patients were significantly higher than that observed in the placebo patients. The concentrations in the patients administered melatonin were also higher than endogenous melatonin concentrations previously reported in non-critically ill patients. The patients administered melatonin had a mean clearance, volume of distribution and absorption rate constant of melatonin was 55.2 L/h, 767 L and 0.76 h-1, respectively. CONCLUSIONS: Exogenous administration of melatonin with a loading dose of 3 mg followed by an hourly dose of 0.5 mg demonstrates good oral bioavailability and results in supra-physiological and sustained concentrations of serum melatonin during 12 h overnight.

Cerebral microcirculation during mild head injury after a contusion and acceleration experimental model in sheep.

BACKGROUND: Cerebral microcirculation after head injury is heterogeneous and temporally variable. Regions at risk of infarction such as peri-contusional areas are vulnerable to anaemia. However, direct quantification of the cerebral microcirculation is clinically not feasible. This study describes a novel experimental head injury model correlating cerebral microcirculation with histopathology analysis. OBJECTIVE: To test the hypothesis that cerebral microcirculation at the ischaemic penumbrae is reduced over time when compared with non-injured regions. METHODS: Merino sheep were instrumented using a transeptal catheter to inject coded microspheres into the left cardiac atrium, ensuring systemic distribution. After a blunt impact over the left parietal region, cytometric analyses quantified cerebral microcirculation and amyloid precursor protein staining identified axonal injury in pre-defined anatomical regions. A mixed effect regression model assessed the hourly blood flow results during 4 hours after injury. RESULTS: Cerebral microcirculation showed temporal reductions with minimal amyloid staining except for the ipsilateral thalamus and medulla. CONCLUSION: The spatial heterogeneity and temporal reduction of cerebral microcirculation in ovine models occur early, even after mild head injury, independent of the intracranial pressure and the level of haemoglobin. Alternate approaches to ensure recovery of regions with reversible injury require a targeted assessment of cerebral microcirculation.

The silent and apparent neurological injury in transcatheter aortic valve implantation study (SANITY): concept, design and rationale.

BACKGROUND: The incidence of clinically apparent stroke in transcatheter aortic valve implantation (TAVI) exceeds that of any other procedure performed by interventional cardiologists and, in the index admission, occurs more than twice as frequently with TAVI than with surgical aortic valve replacement (SAVR). However, this represents only a small component of the vast burden of neurological injury that occurs during TAVI, with recent evidence suggesting that many strokes are clinically silent or only subtly apparent. Additionally, insult may manifest as slight neurocognitive dysfunction rather than overt neurological deficits. Characterisation of the incidence and underlying aetiology of these neurological events may lead to identification of currently unrecognised neuroprotective strategies. METHODS: The Silent and Apparent Neurological Injury in TAVI (SANITY) Study is a prospective, multicentre, observational study comparing the incidence of neurological injury after TAVI versus SAVR. It introduces an intensive, standardised, formal neurologic and neurocognitive disease assessment for all aortic valve recipients, regardless of intervention (SAVR, TAVI), valve-type (bioprosthetic, Edwards SAPIEN-XT) or access route (sternotomy, transfemoral, transapical or transaortic). Comprehensive monitoring of neurological insult will also be recorded to more fully define and compare the neurological burden of the procedures and identify targets for harm minimisation strategies. DISCUSSION: The SANITY study undertakes the most rigorous assessment of neurological injury reported in the literature to date. It attempts to accurately characterise the insult and sustained injury associated with both TAVI and SAVR in an attempt to advance understanding of this complication and associations thus allowing for improved patient selection and procedural modification.

Nimodipine prophylaxis in aneurysmal subarachnoid hemorrhage, a question of tradition or evidence: A scoping review.

BACKGROUND: The prophylactic use of nimodipine following subarachnoid hemorrhage is a practice established four decades ago when clinical management differed from current and the concept of Delayed Cerebral Ischemia (DCI) was not established. The applicability of the original studies is limited by the fact of not reflecting current practice; by utilising a dichotomised outcome measure such as good neurological outcome versus death and vegetative state; by applying variable dosing regimens and including all causes of poor neurological outcome different than DCI. This study aims to review the available evidence to discuss the ongoing role of nimodipine in contemporaneous clinical practice. METHODS: PRISMA guidelines based review, evaluated the evidence on the prophylactic use of nimodipine. The following search engines: Medline, Embase, Cochrane, Web of Science and PubMed, identified Randomized Control Trials (RCTs) with neurological benefit as outcome measure and the impact of fixed versus weight-based nimodipine dosing regimens. RESULTS: Eight RCT were selected. Three of those trials with a total of 349 patients, showed a reduction on death and vegetative state (pooled RR: 0.62; 95 % confidence interval-CI: 0.45, 0.86) related to DCI. Amongst all studies, all cause death (pooled RR = 0.73, [95 % CI: 0.56, 0.97]) favoured a fixed-dose regimen (pooled RR: 0.60; [95 % CI: 0.43, 0.85]). CONCLUSION: Available evidence demonstrates that nimodipine only reduces the risk for DCI-related death or vegetative state and that fixed-dose regimens favour all cause infarct and death independent of DCI. Contemporaneous studies assessing the benefit of nimodipine beyond death or vegetative states and applying individualized dosing are warranted.

PRECISION-TBI: a study protocol for a vanguard prospective cohort study to enhance understanding and management of moderate to severe traumatic brain injury in Australia.

INTRODUCTION: Traumatic brain injury (TBI) is a heterogeneous condition in terms of pathophysiology and clinical course. Outcomes from moderate to severe TBI (msTBI) remain poor despite concerted research efforts. The heterogeneity of clinical management represents a barrier to progress in this area. PRECISION-TBI is a prospective, observational, cohort study that will establish a clinical research network across major neurotrauma centres in Australia. This network will enable the ongoing collection of injury and clinical management data from patients with msTBI, to quantify variations in processes of care between sites. It will also pilot high-frequency data collection and analysis techniques, novel clinical interventions, and comparative effectiveness methodology. METHODS AND ANALYSIS: PRECISION-TBI will initially enrol 300 patients with msTBI with Glasgow Coma Scale (GCS) <13 requiring intensive care unit (ICU) admission for invasive neuromonitoring from 10 Australian neurotrauma centres. Demographic data and process of care data (eg, prehospital, emergency and surgical intervention variables) will be collected. Clinical data will include prehospital and emergency department vital signs, and ICU physiological variables in the form of high frequency neuromonitoring data. ICU treatment data will also be collected for specific aspects of msTBI care. Six-month extended Glasgow Outcome Scores (GOSE) will be collected as the key outcome. Statistical analysis will focus on measures of between and within-site variation. Reports documenting performance on selected key quality indicators will be provided to participating sites. ETHICS AND DISSEMINATION: Ethics approval has been obtained from The Alfred Human Research Ethics Committee (Alfred Health, Melbourne, Australia). All eligible participants will be included in the study under a waiver of consent (hospital data collection) and opt-out (6 months follow-up). Brochures explaining the rationale of the study will be provided to all participants and/or an appropriate medical treatment decision-maker, who can act on the patient's behalf if they lack capacity. Study findings will be disseminated by peer-review publications. TRIAL REGISTRATION NUMBER: NCT05855252.

The Use of Noninvasive Multimodal Neuromonitoring in Adult Critically Ill Patients With COVID-19 Infection.

INTRODUCTION: Noninvasive neuromonitoring could be a valuable option for bedside assessment of cerebral dysfunction in patients with coronavirus disease-2019 (COVID-19) admitted to intensive care units (ICUs). This systematic review aims to investigate the use of noninvasive multimodal neuromonitoring in critically ill adult patients with COVID-19 infection. METHODS: MEDLINE/PubMed, Scopus, Cochrane, and EMBASE databases were searched for studies investigating noninvasive neuromonitoring in patients with COVID-19 admitted to ICUs. The monitoring included transcranial Doppler ultrasonography (TCD), the Brain4care Corp. cerebral compliance monitor (B4C), optic nerve sheath diameter (ONSD), near infrared spectroscopy, automated pupillometry, and electroencephalography (EEG). RESULTS: Thirty-two studies that investigated noninvasive neuromonitoring techniques in patients with COVID-19 in the ICU were identified from a systematic search of 7001 articles: 1 study investigating TCD, ONSD and pupillometry; 2 studies investigating the B4C device and TCD; 3 studies investigating near infrared spectroscopy and TCD; 4 studies investigating TCD; 1 case series investigating pupillometry, and 21 studies investigating EEG. One hundred and nineteen patients underwent TCD monitoring, 47 pupillometry, 49 ONSD assessment, 50 compliance monitoring with the B4C device, and 900 EEG monitoring. Alterations in cerebral hemodynamics, brain compliance, brain oxygenation, pupillary response, and brain electrophysiological activity were common in patients with COVID-19 admitted to the ICU; these abnormalities were not clearly associated with worse outcome or the development of new neurological complications. CONCLUSIONS: The use of noninvasive multimodal neuromonitoring in critically ill COVID-19 patients could be considered to facilitate the detection of neurological derangements. Determining whether such findings allow earlier detection of neurological complications or guide appropriate therapy requires additional studies.

PREdiction and Diagnosis using Imaging and Clinical biomarkers Trial in Traumatic Brain Injury (PREDICT-TBI) study protocol: an observational, prospective, multicentre cohort study for the prediction of outcome in moderate-to-severe TBI.

INTRODUCTION: Traumatic brain injury (TBI) is a heterogeneous condition with a broad spectrum of injury severity, pathophysiological processes and variable outcomes. For moderate-to-severe TBI survivors, recovery is often protracted and outcomes can range from total dependence to full recovery. Despite advances in medical treatment options, prognosis remains largely unchanged. The objective of this study is to develop a machine learning predictive model for neurological outcomes at 6 months in patients with a moderate-to-severe TBI, incorporating longitudinal clinical, multimodal neuroimaging and blood biomarker predictor variables. METHODS AND ANALYSIS: A prospective, observational, cohort study will enrol 300 patients with moderate-to-severe TBI from seven Australian hospitals over 3 years. Candidate predictors including demographic and general health variables, and longitudinal clinical, neuroimaging (CT and MRI), blood biomarker and patient-reported outcome measures will be collected at multiple time points within the acute phase of injury. The predictor variables will populate novel machine learning models to predict the Glasgow Outcome Scale Extended 6 months after injury. The study will also expand on current prognostic models by including novel blood biomarkers (circulating cell-free DNA), and the results of quantitative neuroimaging such as Quantitative Susceptibility Mapping and Dynamic Contrast Enhanced MRI as predictor variables. ETHICS AND DISSEMINATION: Ethical approval has been obtained by the Royal Brisbane and Women's Hospital Human Research Ethics Committee, Queensland. Participants or their substitute decision-maker/s will receive oral and written information about the study before providing written informed consent. Study findings will be disseminated by peer-review publications and presented at national and international conferences and clinical networks. TRIAL REGISTRATION NUMBER: ACTRN12620001360909.

Temperature Profile and Adverse Outcomes After Discharge From the Intensive Care Unit.

BACKGROUND: A predictive model that uses the rhythmicity of core body temperature (CBT) could be an easily accessible clinical tool to ultimately improve outcomes among critically ill patients. OBJECTIVES: To assess the relation between the 24-hour CBT profile (CBT-24) before intensive care unit (ICU) discharge and clinical events in the step-down unit within 7 days of ICU discharge. METHODS: This retrospective cohort study in a tertiary ICU at a single center included adult patients requiring acute invasive ventilation for more than 48 hours and assessed major clinical adverse events (MCAEs) and rapid response system activations (RRSAs) within 7 days of ICU discharge (MCAE-7 and RRSA-7, respectively). RESULTS: The 291 enrolled patients had a median mechanical ventilation duration of 139 hours (IQR, 50-862 hours) and at admission had a median Acute Physiology and Chronic Health Evaluation II score of 22 (IQR, 7-42). At least 1 MCAE or RRSA occurred in 64% and 22% of patients, respectively. Independent predictors of an MCAE-7 were absence of CBT-24 rhythmicity (odds ratio, 1.78 [95% CI, 1.07-2.98]; P = .03), Sequential Organ Failure Assessment score at ICU discharge (1.10 [1.00-1.21]; P = .05), male sex (1.72 [1.04-2.86]; P = .04), age (1.02 [1.00-1.04]; P = .02), and Charlson Comorbidity Index (0.87 [0.76-0.99]; P = .03). Age (1.03 [1.01-1.05]; P = .006), sepsis at ICU admission (2.02 [1.13-3.63]; P = .02), and Charlson Comorbidity Index (1.18 [1.02-1.36]; P = .02) were independent predictors of an RRSA-7. CONCLUSIONS: Use of CBT-24 rhythmicity can assist in stratifying a patient's risk of subsequent deterioration during general care within 7 days of ICU discharge.

Circadian Rhythmicity of Vital Signs at Intensive Care Unit Discharge and Outcome of Traumatic Brain Injury.

BACKGROUND: Physiological functions with circadian rhythmicity are often disrupted during illness. OBJECTIVE: To assess the utility of circadian rhythmicity of vital signs in predicting outcome of traumatic brain injury (TBI). METHODS: A retrospective single-center cohort study of adult intensive care unit (ICU) patients with largely isolated TBI to explore the relationship between the circadian rhythmicity of vital signs during the last 24 hours before ICU discharge and clinical markers of TBI severity and score on the Glasgow Outcome Scale 6 months after injury (GOS-6). RESULTS: The 130 study participants had a median age of 39.0 years (IQR, 23.0-59.0 years), a median Glasgow Coma Scale score at the scene of 8.0 (IQR, 3.0-13.0), and a median Rotterdam score on computed tomography of the head of 3 (IQR, 3-3), with 105 patients (80.8%) surviving to hospital discharge. Rhythmicity was present for heart rate (30.8% of patients), systolic blood pressure (26.2%), diastolic blood pressure (20.0%), and body temperature (26.9%). Independent predictors of a dichotomized GOS-6 ≥4 were the Rotterdam score (odds ratio [OR], 0.38 [95% CI, 0.18-0.81]; P = .01), Glasgow Coma Scale score at the scene (OR, 1.22 [95% CI, 1.05-1.41]; P = .008), age (OR, 0.95 [95% CI, 0.92-0.98]; P = .003), oxygen saturation <90% in the first 24 hours (OR, 0.19 [95% CI, 0.05-0.73]; P = .02), serum sodium level <130 mmol/L (OR, 0.20 [95% CI, 0.05-0.70]; P = .01), and active intracranial pressure management (OR, 0.16 [95% CI, 0.04-0.62]; P = .008), but not rhythmicity of any vital sign. CONCLUSION: Circadian rhythmicity of vital signs at ICU discharge is not predictive of GOS-6 in patients with TBI.

Non-Invasive Multimodal Neuromonitoring in Non-Critically Ill Hospitalized Adult Patients With COVID-19: A Systematic Review and Meta-Analysis.

Introduction: Neurological complications are frequent in patients with coronavirus disease-2019 (COVID-19). The use of non-invasive neuromonitoring in subjects without primary brain injury but with potential neurological derangement is gaining attention outside the intensive care unit (ICU). This systematic review and meta-analysis investigates the use of non-invasive multimodal neuromonitoring of the brain in non-critically ill patients with COVID-19 outside the ICU and quantifies the prevalence of abnormal neuromonitoring findings in this population. Methods: A structured literature search was performed in MEDLINE/PubMed, Scopus, Cochrane, and EMBASE to investigate the use of non-invasive neuromonitoring tools, including transcranial doppler (TCD); optic nerve sheath diameter (ONSD); near-infrared spectroscopy (NIRS); pupillometry; and electroencephalography (EEG) inpatients with COVID-19 outside the ICU. The proportion of non-ICU patients with CVOID-19 and a particular neurological feature at neuromonitoring at the study time was defined as prevalence. Results: A total of 6,593 records were identified through literature searching. Twenty-one studies were finally selected, comprising 368 non-ICU patients, of whom 97 were considered for the prevalence of meta-analysis. The pooled prevalence of electroencephalographic seizures, periodic and rhythmic patterns, slow background abnormalities, and abnormal background on EEG was.17 (95% CI 0.04-0.29), 0.42 (95% CI 0.01-0.82), 0.92 (95% CI 0.83-1.01), and.95 (95% CI 0.088-1.09), respectively. No studies investigating NIRS and ONSD outside the ICU were found. The pooled prevalence for abnormal neuromonitoring findings detected using the TCD and pupillometry were incomputable due to insufficient data. Conclusions: Neuromonitoring tools are non-invasive, less expensive, safe, and bedside available tools with a great potential for both diagnosis and monitoring of patients with COVID-19 at risk of brain derangements. However, extensive literature searching reveals that they are rarely used outside critical care settings.Systematic Review Registration: www.crd.york.ac.uk/prospero/display_record.php?RecordID=265617, identifier: CRD42021265617.

Effects of brain tissue oxygen (PbtO2) guided management on patient outcomes following severe traumatic brain injury: A systematic review and meta-analysis.

Monitoring and optimisation of brain tissue oxygen tension (PbtO2) has been associated with improved neurological outcome and survival in observational studies of severe traumatic brain injury (TBI). We carried out a systematic review of randomized controlled trials to determine if PbtO2-guided management is associated with differential neurological outcomes, survival, and adverse events. Searches were carried out to 10 February 2022 in Medline (OvidSP), 11 February in EMBASE (OvidSP) and 8 February in Cochrane library. Randomized controlled trials comparing PbtO2 and ICP-guided management to ICP-guided management alone were included. The primary outcome was survival with favourable neurological outcome at 6-months post injury. Data were extracted by two independent authors and GRADE certainty of evidence assessed. There was no difference in the proportion of patients with favourable neurological outcomes with PbtO2-guided management (relative risk [RR] 1.42, 95% CI 0.97 to 2.08; p = 0.07; I2 = 0%, very low certainty evidence) but PbtO2-guided management was associated with reduced mortality (RR 0.54, 95% CI 0.31 to 0.93; p = 0.03; I2 = 42%; very low certainty evidence) and ICP (mean difference (MD) - 4.62, 95% CI - 8.27 to - 0.98; p = 0.01; I2 = 63%; very low certainty evidence). There was no significant difference in the risk of adverse respiratory or cardiovascular events. PbtO2-guided management in addition to ICP-based care was not significantly associated with increased favourable neurological outcomes, but was associated with increased survival and reduced ICP, with no difference in respiratory or cardiovascular adverse events. However, based on GRADE criteria, the certainty of evidence provided by this meta-analysis was consistently very low. MESH: Brain Ischemia; Intensive Care; Glasgow Outcome Scale; Randomized Controlled Trial; Craniocerebral Trauma.

The effect of Ventricular Assist Devices on cerebral autoregulation: A preliminary study.

BACKGROUND: The insertion of Ventricular Assist Devices is a common strategy for cardiovascular support in patients with refractory cardiogenic shock. This study sought to determine the impact of ventricular assist devices on the dynamic relationship between arterial blood pressure and cerebral blood flow velocity. METHODS: A sample of 5 patients supported with a pulsatile ventricular assist device was compared with 5 control patients. Controls were matched for age, co-morbidities, current diagnosis and cardiac output state, to cases. Beat-to-beat recordings of mean arterial pressure and cerebral blood flow velocity, using transcranial Doppler were obtained. Transfer function analysis was performed on the lowpass filtered pressure and flow signals, to assess gain, phase and coherence of the relationship between mean arterial blood pressure and cerebral blood flow velocity. These parameters were derived from the very low frequency (0.02-0.07 Hz), low frequency (0.07-0.2 Hz) and high frequency (0.2-0.35 Hz). RESULTS: No significant difference was found in gain and phase values between the two groups, but the low frequency coherence was significantly higher in cases compared with controls (mean ± SD: 0.65 ± 0.16 vs 0.38 ± 0.19, P = 0.04). The two cases with highest coherence (~0.8) also had much higher spectral power in mean arterial blood pressure. CONCLUSIONS: Pulsatile ventricular assist devices affect the coherence but not the gain or phase of the cerebral pressure-flow relationship in the low frequency range; thus whether there was any significant disruption of cerebral autoregulation mechanism was not exactly clear. The augmentation of input pressure fluctuations might contribute in part to the higher coherence observed.

Temperature rhythms and ICU sleep: the TRIS study.

BACKGROUND: Core body temperature (CBT) patterns associated with sleep have not been described in the critically ill. This study aimed to characterize night-time sleep and its relationship to CBT in ICU patients. METHODS: A prospective study was performed in a 27-bed tertiary adult intensive care unit of 20 mechanically ventilated patients in the weaning stage of their critical illness. The study assessed sleep by polysomnography (PSG) during the evening between 21:00-7:00 hours, nursing interventions using the Therapeutic Intervention Scoring System (TISS), illness severity using SOFA and APACHE II scores and CBT 24-hour pattern. RESULTS: Patients were awake for approximately half the study period (45.04%, IQR 13.81-77-17) with no REM (0%, IQR 0-0.04%) and median arousals of 19.5/hour (IQR 7.1-40.9). The 24-hour CBT had a rhythmic pattern in 13 (65%) patients with a highly variable phase of median peak time at 17:35 hours (IQR 12:40-19:39). No significant associations were found between CBT rhythmicity, sleep stages, sleep EEG frequency density, illness severity scores or TISS on the day of PSG. There was no relationship between time awake and CBT rhythmicity (P=0.48) or CBT peak time (P=0.82). The relationship between circadian rhythms and sleep patterns in the critically ill is complex. CONCLUSIONS: Patients recovering in ICU commonly have CBT loss of rhythmicity or a significant phase shift with loss of normal night-time patterns of sleep architecture. Appropriate care plans to promote sleep and circadian rhythm require further investigation of contributing factors such as environment, clinical care routines, illness type and severity.

Neurological Manifestations of Coronavirus Disease 2019: A Comprehensive Review and Meta-Analysis of the First 6 Months of Pandemic Reporting.

Background: There is growing evidence that SARS-Cov-2 infection is associated with severe neurological complications. Understanding the nature and prevalence of these neurologic manifestations is essential for identifying higher-risk patients and projecting demand for ongoing resource utilisation. This review and meta-analysis report the neurologic manifestations identified in hospitalised COVID-19 patients and provide a preliminary estimate of disease prevalence. Methods: MEDLINE, Embase and Scopus were searched for studies reporting the occurrence of neurological complications in hospitalised COVID-19 patients. Results: A total of 2,207 unique entries were identified and screened, among which 14 cohort studies and 53 case reports were included, reporting on a total of 8,577 patients. Central nervous system manifestations included ischemic stroke (n = 226), delirium (n = 79), intracranial haemorrhage (ICH, n = 57), meningoencephalitis (n = 13), seizures (n = 3), and acute demyelinating encephalitis (n = 2). Peripheral nervous system manifestations included Guillain-Barrè Syndrome (n = 21) and other peripheral neuropathies (n = 3). The pooled period prevalence of ischemic stroke from identified studies was 1.3% [95%CI: 0.9-1.8%, 102/7,715] in all hospitalised COVID-19 patients, and 2.8% [95%CI: 1.0-4.6%, 9/318] among COVID-19 patients admitted to ICU. The pooled prevalence of ICH was estimated at 0.4% [95%CI: 0-0.8%, 6/1,006]. Conclusions: The COVID-19 pandemic exerts a substantial neurologic burden which may have residual effects on patients and healthcare systems for years. Low quality evidence impedes the ability to accurately predict the magnitude of this burden. Robust studies with standardised screening and case definitions are required to improve understanding of this disease and optimise treatment of individuals at higher risk for neurologic sequelae.

Intraaortic Balloon Pump Counterpulsation and Cerebral Autoregulation: an observational study.

BACKGROUND: The use of Intra-aortic counterpulsation is a well established supportive therapy for patients in cardiac failure or after cardiac surgery. Blood pressure variations induced by counterpulsation are transmitted to the cerebral arteries, challenging cerebral autoregulatory mechanisms in order to maintain a stable cerebral blood flow. This study aims to assess the effects on cerebral autoregulation and variability of cerebral blood flow due to intra-aortic balloon pump and inflation ratio weaning. METHODS: Cerebral blood flow was measured using transcranial Doppler, in a convenience sample of twenty patients requiring balloon counterpulsation for refractory cardiogenic shock (N = 7) or a single inotrope to maintain mean arterial pressure following an elective placement of an intra-aortic balloon pump for cardiac surgery (N = 13). Simultaneous blood pressure at the aortic root was recorded via the intra-aortic balloon pump. Cerebral blood flow velocities were recorded for six minute intervals at a 1:1 balloon inflation-ratio (augmentation of all cardiac beats) and during progressive reductions of the inflation-ratio to 1:3 (augmentation of one every third cardiac beat). Real time comparisons of peak cerebral blood flow velocities with systolic blood pressure were performed using cross-correlation analysis. The primary endpoint was assessment of cerebral autoregulation using the time delay between the peak signals for cerebral blood flow velocity and systolic blood pressure, according to established criteria. The variability of cerebral blood flow was also assessed using non-linear statistics. RESULTS: During the 1:1 inflation-ratio, the mean time delay between aortic blood pressure and cerebral blood flow was -0.016 seconds (95% CI: -0.023,-0.011); during 1:3 inflation-ratio mean time delay was significantly longer at -0.010 seconds (95% CI: -0.016, -0.004, P < 0.0001). Finally, upon return to a 1:1 inflation-ratio, time delays recovered to those measured at baseline. During inflation-ratio reduction, cerebral blood flow irregularities reduced over time, whilst cerebral blood flow variability at end-diastole decreased in patients with cardiogenic shock. CONCLUSIONS: Weaning counterpulsation from 1:1 to 1:3 inflation ratio leads to a progressive reduction in time delays between systolic blood pressure and peak cerebral blood flow velocities suggesting that although preserved, there is a significant delay in the establishment of cerebral autoregulatory mechanisms. In addition, cerebral blood flow irregularities (i.e. surrogate of flow adaptability) decrease and a loss of cerebral blood flow chaotic pattern occurs during the end-diastolic phase of each beat in patients with cardiogenic shock.

Effect of Exogenous Melatonin Administration in Critically Ill Patients on Delirium and Sleep: A Randomized Controlled Trial.

INTRODUCTION: Sleep deprivation is a contributor for delirium in intensive care. Melatonin has been proposed as a pharmacological strategy to improve sleep, but studies have shown that the increase in plasma levels of melatonin do not correlate to a beneficial clinical effect; in addition, melatonin's short half-life may be a major limitation to achieving therapeutic levels. This study applies a previously published novel regimen of melatonin with proven sustained levels of melatonin during a 12 h period. In this study, the aim is to determine if such melatonin dosing positively influences on the sleep architecture and the incidence of delirium in intensive care. METHODS: Single center, randomized control trial with consecutive recruitment over 5 years. Medical and surgical patients were in a recovery phase, all weaning from mechanical ventilation. Randomized allocation to placebo or enteral melatonin, using a previously described regimen (loading dose of 3 mg at 21 h, followed by 0.5 mg hourly maintenance dose until 03am through a nasogastric tube). Sleep recordings were performed using polysomnogram at baseline (prior to intervention) and the third night on melatonin (postintervention recording). Delirium was assessed using the Richmond Agitation and the Confusion Assessment Method Scales. Environmental light and noise levels were recorded using a luxmeter and sound meter. RESULTS: 80 patients were screened, but 33 were recruited. Sleep studies showed no statistical differences on arousal index or length of sleep. Baseline delirium scores showed no difference between groups when compared to postintervention scores. RASS scores were 1 in both groups at baseline, compared to zero (drug group) and 0.5 (placebo group) posttreatment. CAM scores were zero (drug group) and 1 (placebo group) at baseline, compared to zero (in both groups) postintervention. CONCLUSION: High levels of plasma melatonin during the overnight period of intensive care cohort patients did not improve sleep nor decreased the prevalence of delirium. This trial is registered with Anzctr.org.au/ACTRN12620000661976.aspx.

Circadian Hygiene in the ICU Environment (CHIE) study.

Objective: To investigate the environment and care in the intensive care unit (ICU) and its relationship to patient circadian temperature disruption. Design: 30-day, prospective period prevalence study. Setting: 27-bed tertiary ICU. Participants: Patients expected to remain in the ICU for at least 24 hours. Main outcome measures: Temperature, relative humidity, light and sound intensity in the ICU; nursing interventions (using the Therapeutic Intervention Scoring System-28); and core body temperature of ICU patients. Results: Of 28 patients surveyed, 20 (71%) were mechanically ventilated. Median (interquartile range [IQR]) light intensity peaked at 07:00 at 165 (12-1218) lux with a trough at 23:00 of 15 (12-51) lux and was consistently < 100 lux between 21:00 and 06:00. Peak median (IQR) sound intensity was at 07:00 (62.55 [57.87-68.03] dB) while 58.84 (54.81-64.71) dB at 02:00. Ambient temperature and humidity varied with median (IQR) peaks of 23.11°C (22.74-23.31°C) at 16:00 and 44.07% (32.76-51.08%) at 11:00 and median troughs of 22.37°C (21.79-22.88°C) at 05:00 and 39.95% (31.53-47.95%) at 14:00, respectively. Disturbances to sleep during the night occurred due to care activities including linen changes (15 patients, 54%) and bathing (13, 46%). On the day before and the day of the study, 13 patients (47%) and 10 patients (36%), respectively, had a circadian rhythm on core body temperature without an association with illness severity, nursing intervention or environmental measures. Conclusions: The ICU has low light intensity with relative humidity and ambient temperature not aligned to normal human circadian timing. Noise levels are commonly equivalent to conversational speech while patient care procedures interrupt overnight sleep. The contribution of these factors to disrupted CBT rhythmicity is unclear.

Cerebral Microcirculation and Histological Mapping After Severe Head Injury: A Contusion and Acceleration Experimental Model.

BACKGROUND: Cerebral microcirculation after severe head injury is heterogeneous and temporally variable. Microcirculation is dependent upon the severity of injury, and it is unclear how histology relates to cerebral regional blood flow. OBJECTIVE: This study assesses the changes of cerebral microcirculation blood flow over time after an experimental brain injury model in sheep and contrasts these findings with the histological analysis of the same regions with the aim of mapping cerebral flow and tissue changes after injury. METHODS: Microcirculation was quantified using flow cytometry of color microspheres injected under intracardiac ultrasound to ensure systemic and homogeneous distribution. Histological analysis used amyloid precursor protein staining as a marker of axonal injury. A mapping of microcirculation and axonal staining was performed using adjacent layers of tissue from the same anatomical area, allowing flow and tissue data to be available from the same anatomical region. A mixed effect regression model assessed microcirculation during 4 h after injury, and those results were then contrasted to the amyloid staining qualitative score. RESULTS: Microcirculation values for each subject and tissue region over time, including baseline, ranged between 20 and 80 ml/100 g/min with means that did not differ statistically from baseline flows. However, microcirculation values for each subject and tissue region were reduced from baseline, although their confidence intervals crossing the horizontal ratio of 1 indicated that such reduction was not statistically significant. Histological analysis demonstrated the presence of moderate and severe score on the amyloid staining throughout both hemispheres. CONCLUSION: Microcirculation at the ipsilateral and contralateral site of a contusion and the ipsilateral thalamus and medulla showed a consistent decline over time. Our data suggest that after severe head injury, microcirculation in predefined areas of the brain is reduced from baseline with amyloid staining in those areas reflecting the early establishment of axonal injury.