Non-invasive technology for brain monitoring: definition and meaning of the principal parameters for the International PRactice On TEChnology neuro-moniToring group (I-PROTECT).

Technologies for monitoring organ function are rapidly advancing, aiding physicians in the care of patients in both operating rooms (ORs) and intensive care units (ICUs). Some of these emerging, minimally or non-invasive technologies focus on monitoring brain function and ensuring the integrity of its physiology. Generally, the central nervous system is the least monitored system compared to others, such as the respiratory, cardiovascular, and renal systems, even though it is a primary target in most therapeutic strategies. Frequently, the effects of sedatives, hypnotics, and analgesics are entirely unpredictable, especially in critically ill patients with multiple organ failure. This unpredictability exposes them to the risks of inadequate or excessive sedation/hypnosis, potentially leading to complications and long-term negative outcomes. The International PRactice On TEChnology neuro-moniToring group (I-PROTECT), comprised of experts from various fields of clinical neuromonitoring, presents this document with the aim of reviewing and standardizing the primary non-invasive tools for brain monitoring in anesthesia and intensive care practices. The focus is particularly on standardizing the nomenclature of different parameters generated by these tools. The document addresses processed electroencephalography, continuous/quantitative electroencephalography, brain oxygenation through near-infrared spectroscopy, transcranial Doppler, and automated pupillometry. The clinical utility of the key parameters available in each of these tools is summarized and explained. This comprehensive review was conducted by a panel of experts who deliberated on the included topics until a consensus was reached. Images and tables are utilized to clarify and enhance the understanding of the clinical significance of non-invasive neuromonitoring devices within these medical settings.

Electrophysiological neuromuscular alterations and severe fatigue predict long-term muscle weakness in survivors of COVID-19 acute respiratory distress syndrome.

Introduction: Long-term weakness is common in survivors of COVID-19-associated acute respiratory distress syndrome (CARDS). We longitudinally assessed the predictors of muscle weakness in patients evaluated 6 and 12 months after intensive care unit discharge with in-person visits. Methods: Muscle strength was measured by isometric maximal voluntary contraction (MVC) of the tibialis anterior muscle. Candidate predictors of muscle weakness were follow-up time, sex, age, mechanical ventilation duration, use of steroids in the intensive care unit, the compound muscle action potential of the tibialis anterior muscle (CMAP-TA-S100), a 6-min walk test, severe fatigue, depression and anxiety, post-traumatic stress disorder, cognitive assessment, and body mass index. We also compared the clinical tools currently available for the evaluation of muscle strength (handgrip strength and Medical Research Council sum score) and electrical neuromuscular function (simplified peroneal nerve test [PENT]) with more objective and robust measures of force (MVC) and electrophysiological evaluation of the neuromuscular function of the tibialis anterior muscle (CMAP-TA-S100) for their essential role in ankle control. Results: MVC improved at 12 months compared with 6 months. CMAP-TA-S100 (P = 0.016) and the presence of severe fatigue (P = 0.036) were independent predictors of MVC. MVC was strongly associated with handgrip strength, whereas CMAP-TA-S100 was strongly associated with PENT. Discussion: Electrical neuromuscular abnormalities and severe fatigue are independently associated with reduced MVC and can be used to predict the risk of long-term muscle weakness in CARDS survivors.

Illness Weakness, Polyneuropathy and Myopathy: Diagnosis, treatment, and long-term outcomes.

BACKGROUND: Severe weakness associated with critical illness (CIW) is common. This narrative review summarizes the latest scientific insights and proposes a guide for clinicians to optimize the diagnosis and management of the CIW during the various stages of the disease from the ICU to the community stage. MAIN BODY: CIW arises as diffuse, symmetrical weakness after ICU admission, which is an important differentiating factor from other diseases causing non-symmetrical muscle weakness or paralysis. In patients with adequate cognitive function, CIW can be easily diagnosed at the bedside using manual muscle testing, which should be routinely conducted until ICU discharge. In patients with delirium or coma or those with prolonged, severe weakness, specific neurophysiological investigations and, in selected cases, muscle biopsy are recommended. With these exams, CIW can be differentiated into critical illness polyneuropathy or myopathy, which often coexist. On the general ward, CIW is seen in patients with prolonged previous ICU treatment, or in those developing a new sepsis. Respiratory muscle weakness can cause neuromuscular respiratory failure, which needs prompt recognition and rapid treatment to avoid life-threatening situations. Active rehabilitation should be reassessed and tailored to the new patient's condition to reduce the risk of disease progression. CIW is associated with long-term physical, cognitive and mental impairments, which emphasizes the need for a multidisciplinary model of care. Follow-up clinics for patients surviving critical illness may serve this purpose by providing direct clinical support to patients, managing referrals to other specialists and general practitioners, and serving as a platform for research to describe the natural history of post-intensive care syndrome and to identify new therapeutic interventions. This surveillance should include an assessment of the activities of daily living, mood, and functional mobility. Finally, nutritional status should be longitudinally assessed in all ICU survivors and incorporated into a patient-centered nutritional approach guided by a dietician. CONCLUSIONS: Early ICU mobilization combined with the best evidence-based ICU practices can effectively reduce short-term weakness. Multi-professional collaborations are needed to guarantee a multi-dimensional evaluation and unitary community care programs for survivors of critical illnesses.

Evaluation and application of ultra-low-frequency pressure reactivity index in pediatric traumatic brain injury patients.

PURPOSE: While clinical practice suggests that knowing the cerebral autoregulation (CA) status of traumatic brain injury (TBI) patients is crucial in assessing the best treatment, evidence in pediatric TBI (pTBI) is limited. The pressure reactivity index (PRx) is a surrogate method for the continuous estimation of CA in adults; however, calculations require continuous, high-resolution monitoring data. We evaluate an ultra-low-frequency pressure reactivity index (UL-PRx), based on data sampled at ∼5-min periods, and test its association with 6-month mortality and unfavorable outcome in a cohort of pTBI patients. METHODS: Data derived from pTBI patients (0-18 years) requiring intracranial pressure (ICP) monitoring were retrospectively collected and processed in MATLAB using an in-house algorithm. RESULTS: Data on 47 pTBI patients were included. UL-PRx mean values, ICP, cerebral perfusion pressure (CPP), and derived indices showed significant association with 6-month mortality and unfavorable outcome. A value of UL-PRx of 0.30 was identified as the threshold to better discriminate both surviving vs deceased patients (AUC: 0.90), and favorable vs unfavorable outcomes (AUC: 0.70) at 6 months. At multivariate analysis, mean UL-PRx and % time with ICP > 20 mmHg, remained significantly associated with 6-month mortality and unfavorable outcome, even when adjusted for International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT)-Core variables. In six patients undergoing secondary decompressive craniectomy, no significant changes in UL-PRx were found after surgery. CONCLUSIONS: UL-PRx is associated with a 6-month outcome even if adjusted for IMPACT-Core. Its application in pediatric intensive care unit could be useful to evaluate CA and offer possible prognostic and therapeutic implications in pTBI patients. CLINICALTRIALS: GOV: NCT05043545, September 14, 2021, retrospectively registered.

Processed Electroencephalogram-Based Monitoring to Guide Sedation in Critically Ill Adult Patients: Recommendations from an International Expert Panel-Based Consensus.

BACKGROUND: The use of processed electroencephalography (pEEG) for depth of sedation (DOS) monitoring is increasing in anesthesia; however, how to use of this type of monitoring for critical care adult patients within the intensive care unit (ICU) remains unclear. METHODS: A multidisciplinary panel of international experts consisting of 21 clinicians involved in monitoring DOS in ICU patients was carefully selected on the basis of their expertise in neurocritical care and neuroanesthesiology. Panelists were assigned four domains (techniques for electroencephalography [EEG] monitoring, patient selection, use of the EEG monitors, competency, and training the principles of pEEG monitoring) from which a list of questions and statements was created to be addressed. A Delphi method based on iterative approach was used to produce the final statements. Statements were classified as highly appropriate or highly inappropriate (median rating ≥ 8), appropriate (median rating ≥ 7 but < 8), or uncertain (median rating < 7) and with a strong disagreement index (DI) (DI < 0.5) or weak DI (DI ≥ 0.5 but < 1) consensus. RESULTS: According to the statements evaluated by the panel, frontal pEEG (which includes a continuous colored density spectrogram) has been considered adequate to monitor the level of sedation (strong consensus), and it is recommended by the panel that all sedated patients (paralyzed or nonparalyzed) unfit for clinical evaluation would benefit from DOS monitoring (strong consensus) after a specific training program has been performed by the ICU staff. To cover the gap between knowledge/rational and routine application, some barriers must be broken, including lack of knowledge, validation for prolonged sedation, standardization between monitors based on different EEG analysis algorithms, and economic issues. CONCLUSIONS: Evidence on using DOS monitors in ICU is still scarce, and further research is required to better define the benefits of using pEEG. This consensus highlights that some critically ill patients may benefit from this type of neuromonitoring.

Evaluation and Application of Ultra-Low-Resolution Pressure Reactivity Index in Moderate or Severe Traumatic Brain Injury.

BACKGROUND: The pressure reactivity index (PRx) has emerged as a surrogate method for the continuous bedside estimation of cerebral autoregulation and a predictor of unfavorable outcome after traumatic brain injury (TBI). However, calculation of PRx require continuous high-resolution monitoring currently limited to specialized intensive care units. The aim of this study was to evaluate a new index, the ultra-low-frequency PRx (UL-PRx) sampled at ∼0.0033 Hz at ∼5 minutes periods, and to investigate its association with outcome. METHODS: Demographic data, admission Glasgow coma scale, in-hospital mortality and Glasgow outcome scale extended at 12 months were extracted from electronic records. The filtering and preparation of time series of intracranial pressure (ICP), mean arterial pressure and cerebral perfusion pressure (CPP), and calculation of the indices (UL-PRx, Δ-optimal CPP), were performed in MATLAB using an in-house algorithm. RESULTS: A total of 164 TBI patients were included in the study; in-hospital and 12-month mortality was 29.3% and 38.4%, respectively, and 64% of patients had poor neurological outcome at 12 months. On univariate analysis, ICP, CPP, UL-PRx, and ΔCPPopt were associated with 12-month mortality. After adjusting for age, Glasgow coma scale, ICP and CPP, mean UL-PRx and UL-PRx thresholds of 0 and +0.25 remained associated with 12-month mortality. Similar findings were obtained for in-hospital mortality. For mean UL-PRx, the area under the receiver operating characteristic curves for in-hospital and 12-month mortality were 0.78 (95% confidence interval [CI]: 0.69-0.87; P <0.001) and 0.70 (95% CI: 0.61-0.79; P <0.001), respectively, and 0.65 (95% CI: 0.57-0.74; P =0.001) for 12-month neurological outcome. CONCLUSIONS: Our findings indicate that ultra-low-frequency sampling might provide sufficient resolution to derive information about the state of cerebrovascular autoregulation and prediction of 12-month outcome in TBI patients.

Seeking the Light in Intensive Care Unit Sedation: The Optimal Sedation Strategy for Critically Ill Patients.

The clinical approach to sedation in critically ill patients has changed dramatically over the last two decades, moving to a regimen of light or non-sedation associated with adequate analgesia to guarantee the patient's comfort, active interaction with the environment and family, and early mobilization and assessment of delirium. Although deep sedation (DS) may still be necessary for certain clinical scenarios, it should be limited to strict indications, such as mechanically ventilated patients with Acute Respiratory Distress Syndrome (ARDS), status epilepticus, intracranial hypertension, or those requiring target temperature management. DS, if not indicated, is associated with prolonged duration of mechanical ventilation and ICU stay, and increased mortality. Therefore, continuous monitoring of the level of sedation, especially when associated with the raw EEG data, is important to avoid unnecessary oversedation and to convert a DS strategy to light sedation as soon as possible. The approach to the management of critically ill patients is multidimensional, so targeted sedation should be considered in the context of the ABCDEF bundle, a holistic patient approach. Sedation may interfere with early mobilization and family engagement and may have an impact on delirium assessment and risk. If adequately applied, the ABCDEF bundle allows for a patient-centered, multidimensional, and multi-professional ICU care model to be achieved, with a positive impact on appropriate sedation and patient comfort, along with other important determinants of long-term patient outcomes.

Transcranial Doppler as a screening test to exclude intracranial hypertension in brain-injured patients: the IMPRESSIT-2 prospective multicenter international study.

BACKGROUND: Alternative noninvasive methods capable of excluding intracranial hypertension through use of transcranial Doppler (ICPtcd) in situations where invasive methods cannot be used or are not available would be useful during the management of acutely brain-injured patients. The objective of this study was to determine whether ICPtcd can be considered a reliable screening test compared to the reference standard method, invasive ICP monitoring (ICPi), in excluding the presence of intracranial hypertension. METHODS: This was a prospective, international, multicenter, unblinded, diagnostic accuracy study comparing the index test (ICPtcd) with a reference standard (ICPi), defined as the best available method for establishing the presence or absence of the condition of interest (i.e., intracranial hypertension). Acute brain-injured patients pertaining to one of four categories: traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH) or ischemic stroke (IS) requiring ICPi monitoring, were enrolled in 16 international intensive care units. ICPi measurements (reference test) were compared to simultaneous ICPtcd measurements (index test) at three different timepoints: before, immediately after and 2 to 3 h following ICPi catheter insertion. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) were calculated at three different ICPi thresholds (> 20, > 22 and > 25 mmHg) to assess ICPtcd as a bedside real-practice screening method. A receiver operating characteristic (ROC) curve analysis with the area under the curve (AUC) was used to evaluate the discriminative accuracy and predictive capability of ICPtcd. RESULTS: Two hundred and sixty-two patients were recruited for final analysis. Intracranial hypertension (> 22 mmHg) occurred in 87 patients (33.2%). The total number of paired comparisons between ICPtcd and ICPi was 687. The NPV was elevated (ICP > 20 mmHg = 91.3%, > 22 mmHg = 95.6%, > 25 mmHg = 98.6%), indicating high discriminant accuracy of ICPtcd in excluding intracranial hypertension. Concordance correlation between ICPtcd and ICPi was 33.3% (95% CI 25.6-40.5%), and Bland-Altman showed a mean bias of -3.3 mmHg. The optimal ICPtcd threshold for ruling out intracranial hypertension was 20.5 mmHg, corresponding to a sensitivity of 70% (95% CI 40.7-92.6%) and a specificity of 72% (95% CI 51.9-94.0%) with an AUC of 76% (95% CI 65.6-85.5%). CONCLUSIONS AND RELEVANCE: ICPtcd has a high NPV in ruling out intracranial hypertension and may be useful to clinicians in situations where invasive methods cannot be used or not available. TRIAL REGISTRATION: NCT02322970 .

Long-term complications of COVID-19 in ICU survivors: what do we know?

Coronavirus disease 2019 (COVID-19) has caused more than 175 million persons infected and 3.8 million deaths so far and is having a devastating impact on both low and high-income countries, in particular on hospitals and Intensive Care Units (ICU). The ICU mortality during the first pandemic wave ranged from 40% to 85% during the busiest ICU period for admissions around the peak of the surge, and those surviving are frequently faced with impairments affecting physical, cognitive, and mental health status, complicating the postacute phase of COVID-19, which in the pre-COVID period, were defined collectively as postintensive care syndrome (PICS). Long COVID is defined as four weeks of persisting symptoms after the acute illness, and post-COVID syndrome and chronic COVID-19 are the proposed terms to describe continued symptomatology for more than 12 weeks. Overall, 50% of ICU survivors suffer from new physical, mental, and/or cognitive problems at 1 year after ICU discharge. The prevalence, severity, and duration of the various impairments in ICU survivors are poorly defined, with substantial variations among published series, and may reflect differences in the timing of assessment, the outcome measured, the instruments utilized, and thresholds adopted to establish the diagnosis, the qualification of personnel delivering the tests, the resource availability as well diversity in patients' case-mix. Future longitudinal studies of adequate sample size with repeated assessments of validated outcomes and comparison with non-COVID-19 ICU patients are needed to fully explore the long-term outcome of ICU patients with COVID-19. In this article, we focus on chronic COVID-19 in ICU survivors and present state-of-the-art data regarding long-term complications related to critical illness and the treatments and organ support received.

Management of intracranial hypertension following traumatic brain injury: a best clinical practice adoption proposal for intracranial pressure monitoring and decompressive craniectomy. Joint statements by the Traumatic Brain Injury Section of the Italian Society of Neurosurgery (SINch) and the Neuroanesthesia and Neurocritical Care Study Group of the Italian Society of Anesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI).

No robust evidence is provided by literature regarding the management of intracranial hypertension following severe traumatic brain injury (TBI). This is mostly due to the lack of prospective randomized controlled trials (RCTs), the presence of studies containing extreme heterogeneously collected populations and controversial considerations about chosen outcome. A scientific society should provide guidelines for care management and scientific support for those areas for which evidence-based medicine has not been identified. However, RCTs in severe TBI have failed to establish intervention effectiveness, arising the need to make greater use of tools such as Consensus Conferences between experts, which have the advantage of providing recommendations based on experience, on the analysis of updated literature data and on the direct comparison of different logistic realities. The Italian scientific societies should provide guidelines following the national laws ruling the best medical practice. However, many limitations do not allow the collection of data supporting high levels of evidence for intracranial pressure (ICP) monitoring and decompressive craniectomy (DC) in patients with severe TBI. This intersociety document proposes best practice guidelines for this subsetting of patients to be adopted on a national Italian level, along with joint statements from "TBI Section" of the Italian Society of Neurosurgery (SINch) endorsed by the Neuroanesthesia and Neurocritical Care Study Group of the Italian Society of Anesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI). Presented here is a recap of recommendations on management of ICP and DC supported a high level of available evidence and rate of agreement expressed by the assemblies during the more recent consensus conferences, where members of both groups have had a role of active participants and supporters. The listed recommendations have been sent to a panel of experts consisting of the 107 members of the "TBI Section" of the SINch and the 111 members of the Neuroanesthesia and Neurocritical Care Study Group of the SIAARTI. The aim of the survey was to test a preliminary evaluation of the grade of predictable future adherence of the recommendations following this intersociety proposal. The following recommendations are suggested as representing best clinical practice, nevertheless, adoption of local multidisciplinary protocols regarding thresholds of ICP values, drug therapies, hemostasis management and perioperative care of decompressed patients is strongly recommended to improve treatment efficiency, to increase the quality of data collection and to provide more powerful evidence with future studies. Thus, for this future perspective a rapid overview of the role of the multimodal neuromonitoring in the optimal severe TBI management is also provided in this document. It is reasonable to assume that the recommendations reported in this paper will in future be updated by new observations arising from future trials. They are not binding, and this document should be offered as a guidance for clinical practice through an intersociety agreement, taking in consideration the low level of evidence.

High-mobility group box-1 protein as a novel biomarker to diagnose healthcare-associated ventriculitis and meningitis: a pilot study.

BACKGROUND: The diagnosis of healthcare-associated ventriculitis and meningitis (HAVM) is challenging in the ICU setting. Traditional cerebrospinal fluid (CSF) markers and clinical signs of infection fail to diagnose HAVM in the critically ill setting. We sought to determine the diagnostic accuracy of measuring levels of high-mobility group box 1 (HMGB1) protein in cerebrospinal fluid (CSF) for the diagnosis of HAVM. METHODS: In this prospective observational cohort study, we enrolled 29 patients with an implanted external ventricular drainage (EVD). We tested the accuracy of CSF-HMGB1 as a diagnostic test for HAVM when compared to standard CSF parameters. RESULTS: HAVM was diagnosed in 11/29 (37.9%) patients. These patients had significantly higher CSF-HMGB1 levels compared to patients without HAVM (median [IQR] 43.39 [83.51] ng/mL vs 6.46 ng/mL [10.94]; P<0.001). CSF-HMGB1 and CSF-glucose were independently related to HAVM, with OR's (95% CI) of 15.43 (15.37 to 15.48, P<0.0001) and 0.31 (0.30 to 0.32, P<0.0001), respectively. The AUC [CI] of CSF-HMGB1 to predict HAVM was 0.83 [0.72 to 0.94]. CONCLUSIONS: HMGB1 is an accurate marker of HAVM and it adds incremental diagnostic value when paired with CSF-glucose measurements. Future larger and multicenter studies should assess the incremental diagnostic value of HMGB1 data when used alongside other established CSF markers of infection, and the external validity of these preliminary results.

Essential Noninvasive Multimodality Neuromonitoring for the Critically Ill Patient.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2020. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2020. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.

Brain Ultrasonography Consensus on Skill Recommendations and Competence Levels Within the Critical Care Setting.

BACKGROUND: To report a consensus on the different competency levels for the elaboration of skill recommendations in performing brain ultrasonography within the neurocritical care setting. METHODS: Four brain ultrasound experts, supported by a methodologist, performed a preselection of indicators and skills based on the current literature and clinical expertise. An international panel of experts was recruited and subjected to web-based questionnaires according to a Delphi method presented in three separate rounds. A pre-defined threshold of agreement was established on expert subjective opinions, > 84% of votes was set to support a strong recommendation and > 68% for a weak recommendation. Below these thresholds, no recommendation reached. RESULTS: We defined four different skill levels (basic, basic-plus, pre-advanced, advanced). Twenty-five experts participated to the full process. After four rounds of questions, two items received a strong recommendation in the basic skill category, three in the advanced, twelve in the basic-plus, and seven in the pre-advanced. Two items in the pre-advanced category received a weak recommendation and three could not be collocated and were excluded from the list. CONCLUSIONS: Results from this consensus permitted stratification of the different ultrasound examination skills in four levels with progressively increasing competences. This consensus can be useful as a guide for beginners in brain ultrasonography and for the development of specific training programs within this field.

Transcranial Doppler and Optic Nerve Sonography.

Transcranial Doppler is a bedside procedure that measures linear cerebral blood flow velocity (CBFV) and the pulsatility index through the intracranial circulation. Transcranial color-coded duplex Doppler (TCCD) provides both CBFV and B-mode functions. In this review they are both referred to as brain ultrasound TCCD. Brain ultrasound can be applied in various environments, including out-of-hospital, emergency room, surgery, intensive care, and ward settings. The most common neurologic disease processes evaluated with TCCD are subarachnoid hemorrhage, traumatic brain injury, and ischemic and hemorrhagic stroke. However, TCCD also is used outside the neuroenvironment for diseases such as sickle cell anemia or for cerebral hemodynamic assessment during the cardiovascular perioperative period. In these applications, TCCD can be used for the detection of cerebral vessel occlusion, estimation of cerebrovascular reactivity, right-to-left cardiac shunts, noninvasive estimation of cerebral perfusion and intracranial pressure, optic nerve sheath diameter, midline shift, hydrocephalus, and the presence of foreign objects. Finally, TCCD has a high accuracy in confirming total cerebral circulatory arrest and has been used as an ancillary test to support clinical diagnosis of brain death. Other indications for TCCD include assessment of collateral blood flow and embolization during carotid endarterectomy, assessment of patterns and extent of collateral circulation in severe stenosis or occlusion, assessment of patent foramen ovale/paradoxical embolism, assessment of arteriovenous malformations and studying their supply arteries and flow patterns, assessment of noncardiac right-to-left shunts, assessment of severe stenosis in the arteries of the circle of Willis, and assessment of vertebral artery dissection.

Daptomycin Plasma and CSF Levels in Patients with Healthcare-Associated Meningitis.

BACKGROUND: There are currently few data concerning the cerebrospinal fluid (CSF) penetration of daptomycin in patients with healthcare-associated meningitis. This study aims (1) to better characterize the pharmacokinetics of daptomycin in humans during a 7-day intravenous (IV) therapy course, and (2) to study the penetration of daptomycin in the CSF after IV infusion at the dose of 10 mg/kg. RESULTS: In this prospective observational study, we enrolled nine patients with an implanted external ventricular drainage and a diagnosis of a healthcare-associated meningitis. Daptomycin was administered at 10 mg/kg for a maximum of 7 days. The pharmacokinetic of daptomycin was studied using a two-compartment population/pharmacokinetic (POP/PK) model and by means of a nonlinear mixed effects modeling approach. A large inter-individual variability in plasma area under the curve (Range: 574.7-1366.3 h mg/L), paralleled by high-peak plasma concentration (Cmax) (all values > 60 mg/L), was noted. The inter-individual variability of CSF-AUC although significant (range: 1.17-6.81 h mg/L) was narrower than previously reported and with a late occurrence of CSF-Cmax (range: 6.04-9.54 h). The terminal half-life between plasma and CSF was similar. tmax values in CSF did not show a high inter-individual variability, and the fluctuations of predicted CSF concentrations were minimal. The mean value for daptomycin penetration obtained from our model was 0.45%. CONCLUSIONS: Our POP/PK model was able to describe the pharmacokinetics of daptomycin in both plasma and CSF, showing that daptomycin (up to 7 days at 10 mg/kg) has minimal penetration into central nervous system. Furthermore, the observed variability of AUC, tmax and predicted concentration in CSF was lower than what previously reported in the literature. Based on the present findings, it is unlikely that daptomycin could reach CSF concentrations high enough to have clinical efficacy; this should be tested in future studies.

The accuracy of transcranial Doppler in excluding intracranial hypertension following acute brain injury: a multicenter prospective pilot study.

BACKGROUND: Untimely diagnosis of intracranial hypertension may lead to delays in therapy and worsening of outcome. Transcranial Doppler (TCD) detects variations in cerebral blood flow velocity which may correlate with intracranial pressure (ICP). We investigated if intracranial hypertension can be accurately excluded through use of TCD. METHOD: This was a multicenter prospective pilot study in patients with acute brain injury requiring invasive ICP (ICPi) monitoring. ICP estimated with TCD (ICPtcd) was compared with ICPi in three separate time frames: immediately before ICPi placement, immediately after ICPi placement, and 3 hours following ICPi positioning. Sensitivity and specificity, and concordance correlation coefficient between ICPi and ICPtcd were calculated. Receiver operating curve (ROC) and the area under the curve (AUC) analyses were estimated after measurement averaging over time. RESULTS: A total of 38 patients were enrolled, and of these 12 (31.6%) had at least one episode of intracranial hypertension. One hundred fourteen paired measurements of ICPi and ICPtcd were gathered for analysis. With dichotomized ICPi (≤20 mmHg vs >20 mmHg), the sensitivity of ICPtcd was 100%; all measurements with high ICPi (>20 mmHg) also had a high ICPtcd values. Bland-Altman plot showed an overestimation of 6.2 mmHg (95% CI 5.08-7.30 mmHg) for ICPtcd compared to ICPi. AUC was 96.0% (95% CI 89.8-100%) and the estimated best threshold was at ICPi of 24.8 mmHg corresponding to a sensitivity 100% and a specificity of 91.2%. CONCLUSIONS: This study provides preliminary evidence that ICPtcd may accurately exclude intracranial hypertension in patients with acute brain injury. Future studies with adequate power are needed to confirm this result.