Publications by authors named "Marco Carbonara"

20 Publications

  • Page 1 of 1

Brain Temperature Influences Intracranial Pressure and Cerebral Perfusion Pressure After Traumatic Brain Injury: A CENTER-TBI Study.

Neurocrit Care 2021 Jul 30. Epub 2021 Jul 30.

Neurological Intensive Care Unit, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: After traumatic brain injury (TBI), fever is frequent. Brain temperature (BT), which is directly linked to body temperature, may influence brain physiology. Increased body and/or BT may cause secondary brain damage, with deleterious effects on intracranial pressure (ICP), cerebral perfusion pressure (CPP), and outcome.

Methods: Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI), a prospective multicenter longitudinal study on TBI in Europe and Israel, includes a high resolution cohort of patients with data sampled at a high frequency (from 100 to 500 Hz). In this study, simultaneous BT, ICP, and CPP recordings were investigated. A mixed-effects linear model was used to examine the association between different BT levels and ICP. We additionally focused on changes in ICP and CPP during the episodes of BT changes (Δ BT ≥ 0.5 °C lasting from 15 min to 3 h) up or downward. The significance of ICP and CPP variations was estimated with the paired samples Wilcoxon test (also known as Wilcoxon signed-rank test).

Results: Twenty-one patients with 2,435 h of simultaneous BT and ICP monitoring were studied. All patients reached a BT of 38 °C and experienced at least one episode of ICP above 20 mm Hg. The linear mixed-effects model revealed an association between BT above 37.5 °C and higher ICP levels that was not confirmed for lower BT. We identified 149 episodes of BT changes. During BT elevations (n = 79) ICP increased, whereas CPP was reduced; opposite ICP and CPP variations occurred during episodes of BT reduction (n = 70). All these changes were of moderate clinical relevance (increase of ICP of 4.5 and CPP decrease of 7.5 mm Hg for BT rise, and ICP reduction of 1.7 and CPP elevation of 3.7 mm Hg during BT defervescence), even if statistically significant (p < 0.0001). It has to be noted, however, that a number of therapeutic interventions against intracranial hypertension was documented during those episodes.

Conclusions: Patients after TBI usually develop BT > 38 °C soon after the injury. BT may influence brain physiology, as reflected by ICP and CPP. An association between BT exceeding 37.5 °C and a higher ICP was identified but not confirmed for lower BT ranges. The relationship between BT, ICP, and CPP become clearer during rapid temperature changes. During episodes of temperature elevation, BT seems to have a significant impact on ICP and CPP.
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July 2021

Impact of Cardiovascular Failure in Intensive CareUnit-Acquired Pneumonia: A Single-Center, Prospective Study.

Antibiotics (Basel) 2021 Jun 30;10(7). Epub 2021 Jun 30.

Hospital Clinic, IDIBAPS, Universidad de Barcelona, CIBERes, 08036 Barcelona, Spain.

Background: Cardiovascular failure (CVF) may complicate intensive care unit-acquired pneumonia (ICUAP) and radically alters the empirical treatment of this condition. The aim of this study was to determine the impact of CVF on outcome in patients with ICUAP.

Methods: A prospective, single-center, observational study was conducted in six medical and surgical ICUs at a University Hospital. CVS was defined as a score of 3 or more on the cardiovascular component of the Sequential Organ Failure Assessment (SOFA) score. At the onset of ICUAP, CVF was reported as absent, transient (if lasting ≤ 3 days) or persistent (>3 days). The primary outcome was 90-day mortality modelled through a Cox regression analysis. Secondary outcomes were 28-day mortality, hospital mortality, ICU length of stay (LOS) and hospital LOS.

Results: 358 patients were enrolled: 203 (57%) without CVF, 82 (23%) with transient CVF, and 73 (20%) with persistent CVF. Patients with transient and persistent CVF were more severely ill and presented higher inflammatory response than those without CVF. Despite having similar severity and aetiology, the persistent CVF group more frequently received inadequate initial antibiotic treatment and presented more treatment failures than the transient CVF group. In the persistent CVF group, at day 3, a bacterial superinfection was more frequently detected. The 90-day mortality was significantly higher in the persistent CVF group (62%). The 28-day mortality rates for patients without CVF, with transient and with persistent CVF were 19, 35 and 41% respectively and ICU mortality was 60, 38 and 19% respectively. In the multivariate analysis chronic pulmonary conditions, lack of Pa0/FiO improvement at day 3, pulmonary superinfection at day 3 and persistent CVF were independently associated with 90-day mortality in ICUAP patients. : Persistent CVF has a significant impact on the outcome of patients with ICUAP. Patients at risk from persistent CVF should be promptly recognized to optimize treatment and outcomes.
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June 2021

Optic Nerve Sheath Diameter is not Related to Intracranial Pressure in Subarachnoid Hemorrhage Patients.

Neurocrit Care 2020 10;33(2):491-498

Neuroscience Intensive Care Unit, Department of Anesthesia and Critical Care, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: Intracranial pressure (ICP) monitoring is essential after subarachnoid hemorrhage (SAH) to prevent secondary brain insults and to tailor individualized treatments. Optic nerve sheath diameter (ONSD), measured using ultrasound (US), could serve as a noninvasive bedside tool to estimate ICP, avoiding the risks of hemorrhage or infection related to intracranial catheters. The aims of this study were twofold: first, to explore the reliability of US for measuring ONSD; second, to establish whether the US-ONSD can be considered a proxy for ICP in SAH patients early after bleeding. For the first aim, we compared the ONSD measurements given by magnetic resonance imaging (MRI-ONSD) with the US-ONSD findings. For the second aim, we analyzed the relationship between US-ONSD measurements and ICP values.

Methods: Adult patients with diagnosis of aneurysmal SAH and external ventricular drainage system (EVD) were included. Ten patients were examined by MRI to assess ONSD, and the results were compared to the diameter given by US. In 20 patients, the US-ONSD values were related to ICP measured simultaneously through EVD. In ten of these patients, we explored the changes in the US-ONSD at the time of controlled and fairly rapid changes in ICP after cerebrospinal fluid (CSF) drainage.

Results: US-ONSD measurements at the bedside were accurate, very similar to the diameters measured by MRI (the mean difference in the Bland-Altman plot was 0.08 mm, 95% limits of agreement: - 1.13; + 1.23 mm). No clear relationship was detectable between the ICP and US-ONSD, and a linear regression model showed an angular coefficient very close to 0 (p > 0.05). US-ONSD and ICP values were in agreement after CSF drainage and shifts in ICP in a limited number of patients.

Conclusions: US-ONSD measurement does not accurately estimate ICP in SAH patients in the intensive care unit.
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October 2020

Changing care pathways and between-center practice variations in intensive care for traumatic brain injury across Europe: a CENTER-TBI analysis.

Intensive Care Med 2020 05 25;46(5):995-1004. Epub 2020 Feb 25.

Neuroscience Intensive Care Unit, Department of Anesthesia and Critical Care, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy.

Purpose: To describe ICU stay, selected management aspects, and outcome of Intensive Care Unit (ICU) patients with traumatic brain injury (TBI) in Europe, and to quantify variation across centers.

Methods: This is a prospective observational multicenter study conducted across 18 countries in Europe and Israel. Admission characteristics, clinical data, and outcome were described at patient- and center levels. Between-center variation in the total ICU population was quantified with the median odds ratio (MOR), with correction for case-mix and random variation between centers.

Results: A total of 2138 patients were admitted to the ICU, with median age of 49 years; 36% of which were mild TBI (Glasgow Coma Scale; GCS 13-15). Within, 72 h 636 (30%) were discharged and 128 (6%) died. Early deaths and long-stay patients (> 72 h) had more severe injuries based on the GCS and neuroimaging characteristics, compared with short-stay patients. Long-stay patients received more monitoring and were treated at higher intensity, and experienced worse 6-month outcome compared to short-stay patients. Between-center variations were prominent in the proportion of short-stay patients (MOR = 2.3, p < 0.001), use of intracranial pressure (ICP) monitoring (MOR = 2.5, p < 0.001) and aggressive treatments (MOR = 2.9, p < 0.001); and smaller in 6-month outcome (MOR = 1.2, p = 0.01).

Conclusions: Half of contemporary TBI patients at the ICU have mild to moderate head injury. Substantial between-center variations exist in ICU stay and treatment policies, and less so in outcome. It remains unclear whether admission of short-stay patients represents appropriate prudence or inappropriate use of clinical resources.
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May 2020

Cerebrovascular reactivity is not associated with therapeutic intensity in adult traumatic brain injury: a CENTER-TBI analysis.

Acta Neurochir (Wien) 2019 09 25;161(9):1955-1964. Epub 2019 Jun 25.

Division of Anaesthesia, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

Background: Impaired cerebrovascular reactivity in adult traumatic brain injury (TBI) is known to be associated with poor outcome. However, there has yet to be an analysis of the association between the comprehensively assessed intracranial hypertension therapeutic intensity level (TIL) and cerebrovascular reactivity.

Methods: Using the Collaborative European Neuro Trauma Effectiveness Research in TBI (CENTER-TBI) high-resolution intensive care unit (ICU) cohort, we derived pressure reactivity index (PRx) as the moving correlation coefficient between slow-wave in ICP and mean arterial pressure, updated every minute. Mean daily PRx, and daily % time above PRx of 0 were calculated for the first 7 days of injury and ICU stay. This data was linked with the daily TIL-Intermediate scores, including total and individual treatment sub-scores. Daily mean PRx variable values were compared for each TIL treatment score via mean, standard deviation, and the Mann U test (Bonferroni correction for multiple comparisons). General fixed effects and mixed effects models for total TIL versus PRx were created to display the relation between TIL and cerebrovascular reactivity.

Results: A total of 249 patients with 1230 ICU days of high frequency physiology matched with daily TIL, were assessed. Total TIL was unrelated to daily PRx. Most TIL sub-scores failed to display a significant relationship with the PRx variables. Mild hyperventilation (p < 0.0001), mild hypothermia (p = 0.0001), high levels of sedation for ICP control (p = 0.0001), and use vasopressors for CPP management (p < 0.0001) were found to be associated with only a modest decrease in mean daily PRx or % time with PRx above 0.

Conclusions: Cerebrovascular reactivity remains relatively independent of intracranial hypertension therapeutic intensity, suggesting inadequacy of current TBI therapies in modulating impaired autoregulation. These findings support the need for investigation into the molecular mechanisms involved, or individualized physiologic targets (ICP, CPP, or Co2) in order to treat dysautoregulation actively.
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September 2019

Patient-specific ICP Epidemiologic Thresholds in Adult Traumatic Brain Injury: A CENTER-TBI Validation Study.

J Neurosurg Anesthesiol 2021 Jan;33(1):28-38

Brain Physics Laboratory, Division of Neurosurgery, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

Background: Patient-specific epidemiologic intracranial pressure (ICP) thresholds in adult traumatic brain injury (TBI) have emerged, using the relationship between pressure reactivity index (PRx) and ICP, displaying stronger association with outcome over existing guideline thresholds. The goal of this study was to explore this relationship in a multi-center cohort in order to confirm the previous finding.

Methods: Using the Collaborative European Neuro Trauma Effectiveness Research in TBI (CENTER-TBI) high-resolution intensive care unit cohort, we derived individualized epidemiologic ICP thresholds for each patient using the relationship between PRx and ICP. Mean hourly dose of ICP was calculated for every patient for the following thresholds: 20, 22 mm Hg and the patient's individual ICP threshold. Univariate logistic regression models were created comparing mean hourly dose of ICP above thresholds to dichotomized outcome at 6 to 12 months, based on Glasgow Outcome Score-Extended (GOSE) (alive/dead-GOSE≥2/GOSE=1; favorable/unfavorable-GOSE 5 to 8/GOSE 1 to 4, respectively).

Results: Individual thresholds were identified in 65.3% of patients (n=128), in keeping with previous results (23.0±11.8 mm Hg [interquartile range: 14.9 to 29.8 mm Hg]). Mean hourly dose of ICP above individual threshold provides superior discrimination (area under the receiver operating curve [AUC]=0.678, P=0.029) over mean hourly dose above 20 mm Hg (AUC=0.509, P=0.03) or above 22 mm Hg (AUC=0.492, P=0.035) on univariate analysis for alive/dead outcome at 6 to 12 months. The AUC for mean hourly dose above individual threshold trends to higher values for favorable/unfavorable outcome, but fails to reach statistical significance (AUC=0.610, P=0.060). This was maintained when controlling for baseline admission characteristics.

Conclusions: Mean hourly dose of ICP above individual epidemiologic ICP threshold has stronger associations with mortality compared with the dose above Brain Trauma Foundation defined thresholds of 20 or 22 mm Hg, confirming prior findings. Further studies on patient-specific epidemiologic ICP thresholds are required.
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January 2021

Compensatory-reserve-weighted intracranial pressure versus intracranial pressure for outcome association in adult traumatic brain injury: a CENTER-TBI validation study.

Acta Neurochir (Wien) 2019 07 3;161(7):1275-1284. Epub 2019 May 3.

Brain Physics Laboratory, Division of Neurosurgery, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

Background: Compensatory-reserve-weighted intracranial pressure (wICP) has recently been suggested as a supplementary measure of intracranial pressure (ICP) in adult traumatic brain injury (TBI), with a single-center study suggesting an association with mortality at 6 months. No multi-center studies exist to validate this relationship. The goal was to compare wICP to ICP for association with outcome in a multi-center TBI cohort.

Methods: Using the Collaborative European Neuro Trauma Effectiveness Research in TBI (CENTER-TBI) high-resolution intensive care unit (ICU) cohort, we derived ICP and wICP (calculated as wICP = (1 - RAP) × ICP; where RAP is the compensatory reserve index derived from the moving correlation between pulse amplitude of ICP and ICP). Various univariate logistic regression models were created comparing ICP and wICP to dichotomized outcome at 6 to 12 months, based on Glasgow Outcome Score-Extended (GOSE) (alive/dead-GOSE ≥ 2/GOSE = 1; favorable/unfavorable-GOSE 5 to 8/GOSE 1 to 4, respectively). Models were compared using area under the receiver operating curves (AUC) and p values.

Results: wICP displayed higher AUC compared to ICP on univariate regression for alive/dead outcome compared to mean ICP (AUC 0.712, 95% CI 0.615-0.810, p = 0.0002, and AUC 0.642, 95% CI 0.538-746, p < 0.0001, respectively; no significant difference on Delong's test), and for favorable/unfavorable outcome (AUC 0.627, 95% CI 0.548-0.705, p = 0.015, and AUC 0.495, 95% CI 0.413-0.577, p = 0.059; significantly different using Delong's test p = 0.002), with lower wICP values associated with improved outcomes (p < 0.05 for both). These relationships on univariate analysis held true even when comparing the wICP models with those containing both ICP and RAP integrated area under the curve over time (p < 0.05 for all via Delong's test).

Conclusions: Compensatory-reserve-weighted ICP displays superior outcome association for both alive/dead and favorable/unfavorable dichotomized outcomes in adult TBI, through univariate analysis. Lower wICP is associated with better global outcomes. The results of this study provide multi-center validation of those seen in a previous single-center study.
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July 2019

Nebulized Amikacin and Fosfomycin for Severe Pseudomonas aeruginosa Pneumonia: An Experimental Study.

Crit Care Med 2019 06;47(6):e470-e477

CardeasPharma, Seattle, WA.

Objectives: Latest trials failed to confirm merits of nebulized amikacin for critically ill patients with nosocomial pneumonia. We studied various nebulized and IV antibiotic regimens in a porcine model of severe Pseudomonas aeruginosa pneumonia, resistant to amikacin, fosfomycin, and susceptible to meropenem.

Design: Prospective randomized animal study.

Setting: Animal Research, University of Barcelona, Spain.

Subjects: Thirty female pigs.

Interventions: The animals were randomized to receive nebulized saline solution (CONTROL); nebulized amikacin every 6 hours; nebulized fosfomycin every 6 hours; IV meropenem alone every 8 hours; nebulized amikacin and fosfomycin every 6 hours; amikacin and fosfomycin every 6 hours, with IV meropenem every 8 hours. Nebulization was performed through a vibrating mesh nebulizer. The primary outcome was lung tissue bacterial concentration. Secondary outcomes were tracheal secretions P. aeruginosa concentration, clinical variables, lung histology, and development of meropenem resistance.

Measurements And Main Results: We included five animals into each group. Lung P. aeruginosa burden varied among groups (p < 0.001). In particular, IV meropenem and amikacin and fosfomycin + IV meropenem groups presented lower P. aeruginosa concentrations versus amikacin and fosfomycin, amikacin, CONTROL, and fosfomycin groups (p < 0.05), without significant difference between these two groups undergoing IV meropenem treatment. The sole use of nebulized antibiotics resulted in dense P. aeruginosa accumulation at the edges of the interlobular septa. Amikacin, amikacin and fosfomycin, and amikacin and fosfomycin + IV meropenem effectively reduced P. aeruginosa in tracheal secretions (p < 0.001). Pathognomonic clinical variables of respiratory infection did not differ among groups. Resistance to meropenem increased in IV meropenem group versus amikacin and fosfomycin + meropenem (p = 0.004).

Conclusions: Our findings corroborate that amikacin and fosfomycin alone efficiently reduced P. aeruginosa in tracheal secretions, with negligible effects in pulmonary tissue. Combination of amikacin and fosfomycin with IV meropenem does not increase antipseudomonal pulmonary tissue activity, but it does reduce development of meropenem-resistant P. aeruginosa, in comparison with the sole use of IV meropenem. Our findings imply potential merits for preemptive use of nebulized antibiotics in order to reduce resistance to IV meropenem.
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June 2019

Neuroprotection in Traumatic Brain Injury: Mesenchymal Stromal Cells can Potentially Overcome Some Limitations of Previous Clinical Trials.

Front Neurol 2018 24;9:885. Epub 2018 Oct 24.

Neuroscience Intensive Care Unit, Department of Anaesthesia and Critical Care, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. In the last 30 years several neuroprotective agents, attenuating the downstream molecular and cellular damaging events triggered by TBI, have been extensively studied. Even though many drugs have shown promising results in the pre-clinical stage, all have failed in large clinical trials. Mesenchymal stromal cells (MSCs) may offer a promising new therapeutic intervention, with preclinical data showing protection of the injured brain. We selected three of the critical aspects identified as possible causes of clinical failure: the window of opportunity for drug administration, the double-edged contribution of mechanisms to damage and recovery, and the oft-neglected role of reparative mechanisms. For each aspect, we briefly summarized the limitations of previous trials and the potential advantages of a newer approach using MSCs.
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October 2018

Comparison of Performance of Different Optimal Cerebral Perfusion Pressure Parameters for Outcome Prediction in Adult Traumatic Brain Injury: A Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) Study.

J Neurotrauma 2019 05 17;36(10):1505-1517. Epub 2018 Dec 17.

4 Brain Physics Laboratory, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.

It has been postulated previously that individualized cerebral perfusion pressure (CPP) targets can be derived from cerebrovascular reactivity indices. Differences between real CPP and target CPP (named generically optimal CPP) has been linked to global outcome in adult traumatic brain injury (TBI). Different vascular reactivity indices can be utilized in the determination. The goal of this study is to evaluate CPPopt parameters, derived from three intracranial pressure (ICP)-derived cerebrovascular reactivity indices, and determine which one is superior for 6- to 12-month outcome prediction. Using the prospectively collected data from the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) study, the following indices of cerebrovascular reactivity were derived: pressure reactivity index (PRx; correlation between ICP and mean arterial pressure [MAP]), pulse amplitude index (PAx; correlation between pulse amplitude of ICP [AMP] and MAP), and RAC (correlation between AMP and CPP). CPPopt was derived using each index. Univariate logistic regression models were created to assess the association between CPPopt with global dichotomized outcome at 6 to 12 months, as assessed by Glasgow Outcome Score-Extended. Models were compared via area under the receiver operating curve (AUC) and Delong's Test. A total of 204 patients had available data. CPPopt derived from PRx, PAx, and RAC performed variably in their association with outcomes. PRx- and RAC-based CPPopt performed similarly, with RAC parameters trending towards highest AUC values. PAx-based CPPopt parameters failed to reach significant associations with dichotomized outcomes at 6 to 12 months. CPPopt parameters derived from PRx and RAC appear similar in their overall ability for 6- to 12-month outcome prediction in moderate/severe adult TBI.
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May 2019

Fluid Management in Acute Brain Injury.

Curr Neurol Neurosci Rep 2018 09 11;18(11):74. Epub 2018 Sep 11.

Neuro ICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.

Purpose Of The Review: The aims of fluid management in acute brain injury are to preserve or restore physiology and guarantee appropriate tissue perfusion, avoiding potential iatrogenic effects. We reviewed the literature, focusing on the clinical implications of the selected papers. Our purposes were to summarize the principles regulating the distribution of water between the intracellular, interstitial, and plasma compartments in the normal and the injured brain, and to clarify how these principles could guide fluid administration, with special reference to intracranial pressure control.

Recent Findings: Although a considerable amount of research has been published on this topic and in general on fluid management in acute illness, the quality of the evidence tends to vary. Intravascular volume management should aim for euvolemia. There is evidence of harm with aggressive administration of fluid aimed at achieving hypervolemia in cases of subarachnoid hemorrhage. Isotonic crystalloids should be the preferred agents for volume replacement, while colloids, glucose-containing hypotonic solutions, and other hypotonic solutions or albumin should be avoided. Osmotherapy seems to be effective in intracranial hypertension management; however, there is no clear evidence regarding the superiority of hypertonic saline over mannitol. Fluid therapy plays an important role in the management of acute brain injury patients. However, fluids are a double-edged weapon because of the potential risk of hyper-hydration, hypo- or hyper-osmolar conditions, which may unfavorably affect the clinical course and the outcome.
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September 2018

External ventricular drain causes brain tissue damage: an imaging study.

Acta Neurochir (Wien) 2017 10 8;159(10):1981-1989. Epub 2017 Aug 8.

Neuroscience Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza, 35, 20122, Milan, Italy.

Background: An external ventricular drain (EVD) is used to measure intracranial pressure (ICP) and to drain cerebrospinal fluid (CSF). The procedure is generally safe, but parenchymal sequelae are reported as a possible side effect, with variable incidence. We investigated the mechanical sequelae of EVD insertion and their clinical significance in acute brain-injured patients, with a special focus on hemorrhagic lesions.

Methods: Mechanical sequelae of EVD insertion were detected in patients by computed tomography (CT) and magnetic resonance imaging (MRI), performed for clinical purposes.

Results: In 155 patients we studied the brain tissue surrounding the EVD by CT scan (all patients) and MRI (16 patients); 53 patients were studied at three time points (day 1-2, day 3-10, >10 days after EVD placement) to document the lesion time course. Small hemorrhages, with a hyperdense core surrounded by a hypodense area, were identified by CT scan in 33 patients. The initial average (hyper- + hypodense) lesion volume was 8.16 ml, increasing up to 15 ml by >10 days after EVD insertion. These lesions were not accompanied by neurologic deterioration or ICP elevation. History of arterial hypertension, coagulation abnormalities and multiple EVD insertions were significantly associated with hemorrhages. In 122 non-hemorrhagic patients, we detected very small hypodense areas (average volume 0.38 ml) surrounding the catheter. At later times these hypodensities slightly increased. MRI studies in 16 patients identified both intra- and extracellular edema around the catheters. The extracellular component increased with time.

Conclusion: EVD insertion, even when there are no clinically important complications, causes a tissue reaction with minimal bleedings and small areas of brain edema.
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October 2017

Rethinking Neuroprotection in Severe Traumatic Brain Injury: Toward Bedside Neuroprotection.

Front Neurol 2017 24;8:354. Epub 2017 Jul 24.

Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Department of Anesthesia and Critical Care, Neuroscience Intensive Care Unit, Milan, Italy.

Neuroprotection after traumatic brain injury (TBI) is an important goal pursued strenuously in the last 30 years. The acute cerebral injury triggers a cascade of biochemical events that may worsen the integrity, function, and connectivity of the brain cells and decrease the chance of functional recovery. A number of molecules acting against this deleterious cascade have been tested in the experimental setting, often with preliminary encouraging results. Unfortunately, clinical trials using those candidate neuroprotectants molecules have consistently produced disappointing results, highlighting the necessity of improving the research standards. Despite repeated failures in pharmacological neuroprotection, TBI treatment in neurointensive care units has achieved outcome improvement. It is likely that intensive treatment has contributed to this progress offering a different kind of neuroprotection, based on a careful prevention and limitations of intracranial and systemic threats. The natural course of acute brain damage, in fact, is often complicated by additional adverse events, like the development of intracranial hypertension, brain hypoxia, or hypoperfusion. All these events may lead to additional brain damage and worsen outcome. An approach designed for early identification and prompt correction of insults may, therefore, limit brain damage and improve results.
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July 2017

Severe traumatic brain injury: targeted management in the intensive care unit.

Lancet Neurol 2017 06;16(6):452-464

Addenbrooke's Hospital, Division of Anaesthesia, University of Cambridge, Cambridge, UK.

Severe traumatic brain injury (TBI) is currently managed in the intensive care unit with a combined medical-surgical approach. Treatment aims to prevent additional brain damage and to optimise conditions for brain recovery. TBI is typically considered and treated as one pathological entity, although in fact it is a syndrome comprising a range of lesions that can require different therapies and physiological goals. Owing to advances in monitoring and imaging, there is now the potential to identify specific mechanisms of brain damage and to better target treatment to individuals or subsets of patients. Targeted treatment is especially relevant for elderly people-who now represent an increasing proportion of patients with TBI-as preinjury comorbidities and their therapies demand tailored management strategies. Progress in monitoring and in understanding pathophysiological mechanisms of TBI could change current management in the intensive care unit, enabling targeted interventions that could ultimately improve outcomes.
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June 2017

Intracranial pressure management in patients with traumatic brain injury: an update.

Curr Opin Crit Care 2017 Apr;23(2):110-114

aNeuroscience Intensive Care Unit, Department of Anesthesia and Critical Care, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico bDepartment of Pathophysiology and Transplants, University of Milan, Milan, Italy.

Purpose Of Review: Intracranial pressure (ICP) monitoring and treatment is central in the management of traumatic brain injury. Despite 4 decades of clinical use, several aspects remain controversial, including the indications for ICP and treatment options.

Recent Findings: Two major trials tested surgical decompression and mild hypothermia as treatments for high ICP. Both were rigorous, randomized, multicenter studies, with different designs. Decompression was tested for ICP refractory to conventional treatment, whereas hypothermia was offered as an alternative to conventional medical therapy. Decompression reduced mortality, but at the expense of more disability. The hypothermia trial was stopped because of a worse outcome in the treated arm. Indications for ICP monitoring have been reviewed and new international guidelines issued. New contributions published in 2016 have dealt with computerized analysis for predicting ICP crises; noninvasive or innovative methods for measuring ICP; reassessment of standard therapeutic interventions, such as hypertonic solutions and the level of intensity of ICP therapy.

Summary: Aggressive strategies for ICP control, like surgical decompression or hypothermia, carefully tested, have controversial effects on outcome. Several articles have made worthwhile contributions to important clinical issues, but with no real breakthroughs.
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April 2017

Polymicrobial intensive care unit-acquired pneumonia: prevalence, microbiology and outcome.

Crit Care 2015 Dec 23;19:450. Epub 2015 Dec 23.

Department of Pneumology, Thorax Institute, Hospital Clinic, Villarroel 170, 08036, Barcelona, Spain.

Background: Microbial aetiology of intensive care unit (ICU)-acquired pneumonia (ICUAP) determines antibiotic treatment and outcomes. The impact of polymicrobial ICUAP is not extensively known. We therefore investigated the characteristics and outcomes of polymicrobial aetiology of ICUAP.

Method: Patients with ICUAP confirmed microbiologically were prospectively compared according to identification of 1 (monomicrobial) or more (polymicrobial) potentially-pathogenic microorganisms. Microbes usually considered as non-pathogenic were not considered for the etiologic diagnosis. We assessed clinical characteristics, microbiology, inflammatory biomarkers and outcome variables.

Results: Among 441 consecutive patients with ICUAP, 256 (58%) had microbiologic confirmation, and 41 (16%) of them polymicrobial pneumonia. Methicillin-sensitive Staphylococcus aureus, Haemophilus influenzae, and several Enterobacteriaceae were more frequent in polymicrobial pneumonia. Multi-drug and extensive-drug resistance was similarly frequent in both groups. Compared with monomicrobial, patients with polymicrobial pneumonia had less frequently chronic heart disease (6, 15% vs. 71, 33%, p = 0.019), and more frequently pleural effusion (18, 50%, vs. 54, 25%, p = 0.008), without any other significant difference. Appropriate empiric antimicrobial treatment was similarly frequent in the monomicrobial (185, 86%) and the polymicrobial group (39, 95%), as were the initial response to the empiric treatment, length of stay and mortality. Systemic inflammatory response was similar comparing monomicrobial with polymicrobial ICUAP.

Conclusion: The aetiology of ICUAP confirmed microbiologically was polymicrobial in 16% cases. Pleural effusion and absence of chronic heart disease are associated with polymicrobial pneumonia. When empiric treatment is frequently appropriate, polymicrobial aetiology does not influence the outcome of ICUAP.
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December 2015

An acceleromyographic train-of-four ratio of 1.0 reliably excludes respiratory muscle weakness after major abdominal surgery: a randomized double-blind study.

Can J Anaesth 2014 Jul 17;61(7):641-9. Epub 2014 Apr 17.

Department of Anesthesia, Intensive Care and Palliative Care, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, Milan, 20133, Italy,

Purpose: This randomized double-blind study was designed to determine if respiratory muscle weakness - measured by maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) - persists even if an acceleromyographic train-of-four ratio (TOFR) of 1.0 is reached after major abdominal surgery.

Methods: Twenty patients underwent respiratory function tests before induction of anesthesia. Rocuronium was given, and the tests were repeated after extubation when the TOFR reached 1.0. The patients were then randomized to receive sugammadex 1 mg·kg(-1) or placebo, and the same tests were repeated five and 20 min later. Between-group comparisons were carried out with a mixed-model analysis of variance analysis.

Results: After anesthesia and adequate epidural analgesia, MIP and MEP decreased by 60% in both groups. In the placebo group, MIP decreased from a pre-induction value (median [range]) of 61.8 [31.3-96.1] to 19.6 [8.3-58.3] cm H2O after extubation without significant variation five and 20 min after placebo. In the sugammadex group, MIP decreased from a pre-induction value of 57.8 [13.0-96.4] to 20.5 [6.4-67.3] cm H2O after extubation. No differences were recorded after sugammadex administration (P = 0.246 between groups). In the placebo group, MEP decreased from 88.8 [65.1-120.3] before induction to 37.6 [13.4-70.6] cm H2O after extubation. In the sugammadex group, MEP decreased from 85.5 [58.6-132.7] to 30.8 [10.5-60.5] cm H2O, with no improvement five and 20 min after either placebo or sugammadex administration (P = 0.648). Similarly, the FCV and FEV1 decreased 30-40% after extubation in both study groups.

Conclusion: Acceleromyographic TOFR of 1.0 excludes residual neuromuscular paralysis. However, major respiratory dysfunction is observed after abdominal surgery. This trial was registered at NCT01503840.
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July 2014


Neurosurgery 2012 Oct;71(4):771-2

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October 2012

Relationship between systemic glucose and cerebral glucose is preserved in patients with severe traumatic brain injury, but glucose delivery to the brain may become limited when oxidative metabolism is impaired: implications for glycemic control.

Crit Care Med 2012 Jun;40(6):1785-91

Department of Anesthesia and Intensive Care, Fondazione IRCCS Cà Granda-Ospedale Maggiore Policlinico, Milan, Italy.

Objective: To clarify the dynamics of glucose delivery to the brain and the effects of changes in blood glucose after severe traumatic brain injury.

Design: Retrospective analysis of a prospective observational cohort study.

Setting: Neurosurgical intensive care unit of a university hospital.

Patients: Seventeen patients with acute traumatic brain injury monitored with cerebral and subcutaneous microdialysis.

Interventions: None.

Measurements And Main Results: For continuous, accurate systemic monitoring, glucose was measured in the interstitial space of subcutaneous adipose tissue using microdialysis, and 39 specific episodes of spontaneous rises in glucose were identified. During these episodes, there was a significant positive linear relationship between systemic glucose levels and brain glucose concentrations measured by microdialysis (p < .0001). The basal lactate/pyruvate ratio, with a threshold of 25, was adopted to distinguish between disturbed and presumably preserved cerebral oxidative metabolism. Using normal vs. elevated lactate/pyruvate ratio as variable factor, the relationship between brain and systemic glucose during the episodes could be described by two significantly distinct parallel lines (p = .0001), which indicates a strong additive effect of subcutaneous glucose and lactate/pyruvate ratio in determining brain glucose. The line describing the relationship under disturbed metabolic conditions was lower than in presumably intact metabolic conditions, with a significant difference of 0.648 ± 0.192 mM (p = .002). This let us to accurately predict that in this situation systemic glucose concentrations in the lower range of normality would result in critical brain glucose levels.

Conclusions: The linear relationship between systemic and brain glucose in healthy subjects is preserved in traumatic brain-injured patients. As a consequence, in brain tissue where oxidative metabolism is disturbed, brain glucose concentrations might possibly drop below the critical threshold of 0.8 mM to 1.0 mM when there is a reduction in systemic glucose toward the lower limits of the "normal" range.
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June 2012

Tau elevations in the brain extracellular space correlate with reduced amyloid-β levels and predict adverse clinical outcomes after severe traumatic brain injury.

Brain 2012 Apr 23;135(Pt 4):1268-80. Epub 2011 Nov 23.

Department of Anaesthesia and Intensive Care, Fondazione IRCCS Ca Granda-Ospedale Maggiore Policlinico, Milan University, Milano 20100, Italy.

Axonal injury is believed to be a major determinant of adverse outcomes following traumatic brain injury. However, it has been difficult to assess acutely the severity of axonal injury in human traumatic brain injury patients. We hypothesized that microdialysis-based measurements of the brain extracellular fluid levels of tau and neurofilament light chain, two low molecular weight axonal proteins, could be helpful in this regard. To test this hypothesis, 100 kDa cut-off microdialysis catheters were placed in 16 patients with severe traumatic brain injury at two neurological/neurosurgical intensive care units. Tau levels in the microdialysis samples were highest early and fell over time in all patients. Initial tau levels were >3-fold higher in patients with microdialysis catheters placed in pericontusional regions than in patients in whom catheters were placed in normal-appearing right frontal lobe tissue (P = 0.005). Tau levels and neurofilament light-chain levels were positively correlated (r = 0.6, P = 0.013). Neurofilament light-chain levels were also higher in patients with pericontusional catheters (P = 0.04). Interestingly, initial tau levels were inversely correlated with initial amyloid-β levels measured in the same samples (r = -0.87, P = 0.000023). This could be due to reduced synaptic activity in areas with substantial axonal injury, as amyloid-β release is closely coupled with synaptic activity. Importantly, high initial tau levels correlated with worse clinical outcomes, as assessed using the Glasgow Outcome Scale 6 months after injury (r = -0.6, P = 0.018). Taken together, our data add support for the hypothesis that axonal injury may be related to long-term impairments following traumatic brain injury. Microdialysis-based measurement of tau levels in the brain extracellular space may be a useful way to assess the severity of axonal injury acutely in the intensive care unit. Further studies with larger numbers of patients will be required to assess the reproducibility of these findings and to determine whether this approach provides added value when combined with clinical and radiological information.
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April 2012