Feasibility and Safety of Integrating Extended TCD Assessments in a Full Multimodal Neuromonitoring Protocol After Traumatic Brain Injury.

OBJECTIVE: Targeting single monitoring modalities such as intracranial pressure (ICP) or cerebral perfusion pressure alone has shown to be insufficient in improving outcome after traumatic brain injury (TBI). Multimodality monitoring (MMM) allows for a more complete description of brain function and for individualized management. Transcranial Doppler (TCD) represents the gold standard for continuous cerebral blood flow velocity assessment, but requires high levels skill and time. In TBI, the practical aspects of conducting extended TCD monitoring sessions have yet to be evaluated. METHODS: Patients with acute moderate-to-severe TBI admitted to the neurocritical care unit between March 2022 and December 2023 receiving invasive ICP measurements were evaluated for inclusion. Exclusion criteria included trauma incompatible with TCD monitoring and if MMM was unwarranted. Daily MMM sessions (in addition to regular monitoring) were performed using TCD (Delica EMS 9D System or the DWL Doppler Box) for ≤5 d. Quantitative and qualitative feasibility, safety, and quality metrics were assessed. RESULTS: Of 74 patients, 36 (75% male; mean age, 44 ± 17 y) were included. Common reasons for exclusion were skull fractures (n = 12) and decompressive craniectomy (n = 9). We acquired 88 recordings (mean, 275 ± 88 min). Overall monitoring times increased, and set-up times decreased. Physiologic variables (including ICP/brain temperature) did not change with TCD application. A single adverse event (dislodging of a microdialysis catheter) occurred. CONCLUSION: Implementing extended TCD monitoring in MMM protocols is feasible and safe. Considering these results, inclusion of long-term TCD as part of the MMM is strongly encouraged to allow for in-depth description and direct evaluation of hemodynamic changes after TBI.

Acetabular Fractures in older patients Intervention Trial (AceFIT): a feasibility triple-arm randomized controlled study.

Aims: To assess the feasibility of a randomized controlled trial (RCT) that compares three treatments for acetabular fractures in older patients: surgical fixation, surgical fixation and hip arthroplasty (fix-and-replace), and non-surgical treatment. Methods: Patients were recruited from seven UK NHS centres and randomized to a three-arm pilot trial if aged older than 60 years and had a displaced acetabular fracture. Feasibility outcomes included patients' willingness to participate, clinicians' capability to recruit, and dropout rates. The primary clinical outcome measure was the EuroQol five-dimension questionnaire (EQ-5D) at six months. Secondary outcomes were Oxford Hip Score, Disability Rating Index, blood loss, and radiological and mobility assessments. Results: Between December 2017 and December 2019, 60 patients were recruited (median age 77.4 years, range 63.3 to 88.5) (39/21 M/F ratio). At final nine-month follow-up, 4/60 (7%) had withdrawn, 4/60 (7%) had died, and one had been lost to follow-up; a 98% response rate (50/51) was achieved for the EQ-5D questionnaire. Four deaths were recorded during the three-year trial period: three in the non-surgical treatment group and one in the fix-and-replace group. Conclusion: This study has shown a full-scale RCT to be feasible, but will need international recruitment. The Acetabular Fractures in older patients Intervention Trial (AceFIT) has informed the design of a multinational RCT sample size of 1,474 or 1,974 patients for a minimal clinically important difference of 0.06 on EQ-5D, with a power of 0.8 or 0.9, and loss to follow-up of 20%. This observed patient cohort comprises a medically complex group requiring multidisciplinary care; surgeon, anaesthetist, and ortho-geriatrician input is needed to optimize recovery and rehabilitation.

Brain tissue oxygen monitoring in traumatic brain injury-part II: isolated and combined insults in relation to outcome.

BACKGROUND: The primary aim was to explore the concept of isolated and combined threshold-insults for brain tissue oxygenation (pbtO2) in relation to outcome in traumatic brain injury (TBI). METHODS: A total of 239 TBI patients with data on clinical outcome (GOS) and intracranial pressure (ICP) and pbtO2 monitoring for at least 12 h, who had been treated at the neurocritical care unit, Addenbrooke's Hospital, Cambridge, UK, between 2002 and 2022 were included. Outcome was dichotomised into favourable/unfavourable (GOS 4-5/1-3) and survival/mortality (GOS 2-5/1). PbtO2 was studied over the entire monitoring period. Thresholds were analysed in relation to outcome based on median and mean values, percentage of time and dose per hour below critical values and visualised as the combined insult intensity and duration. RESULTS: Median pbtO2 was slightly, but not significantly, associated with outcome. A pbtO2 threshold at 25 and 20 mmHg, respectively, yielded the highest x2 when dichotomised for favourable/unfavourable outcome and mortality/survival in chi-square analyses. A higher dose and higher percentage of time spent with pbtO2 below 25 mmHg as well as lower thresholds were associated with unfavourable outcome, but not mortality. In a combined insult intensity and duration analysis, there was a transition from favourable towards unfavourable outcome when pbtO2 went below 25-30 mmHg for 30 min and similar transitions occurred for shorter durations when the intensity was higher. Although these insults were rare, pbtO2 under 15 mmHg was more strongly associated with unfavourable outcome if, concurrently, ICP was above 20 mmHg, cerebral perfusion pressure below 60 mmHg, or pressure reactivity index above 0.30 than if these variables were not deranged. In a multiple logistic regression, a higher percentage of monitoring time with pbtO2 < 15 mmHg was associated with a higher rate of unfavourable outcome. CONCLUSIONS: Low pbtO2, under 25 mmHg and particularly below 15 mmHg, for longer durations and in combination with disturbances in global cerebral physiological variables were associated with poor outcome and may indicate detrimental ischaemic hypoxia. Prospective trials are needed to determine if pbtO2-directed therapy is beneficial, at what individualised pbtO2 threshold therapies are warranted, and how this may depend on the presence/absence of concurrent cerebral physiological disturbances.

Brain tissue oxygen monitoring in traumatic brain injury: part I-To what extent does PbtO2 reflect global cerebral physiology?

BACKGROUND: The primary aim was to explore the association of global cerebral physiological variables including intracranial pressure (ICP), cerebrovascular reactivity (PRx), cerebral perfusion pressure (CPP), and deviation from the PRx-based optimal CPP value (∆CPPopt; actual CPP-CPPopt) in relation to brain tissue oxygenation (pbtO2) in traumatic brain injury (TBI). METHODS: A total of 425 TBI patients with ICP- and pbtO2 monitoring for at least 12 h, who had been treated at the neurocritical care unit, Addenbrooke's Hospital, Cambridge, UK, between 2002 and 2022 were included. Generalized additive models (GAMs) and linear mixed effect models were used to explore the association of ICP, PRx, CPP, and CPPopt in relation to pbtO2. PbtO2 < 20 mmHg, ICP > 20 mmHg, PRx > 0.30, CPP < 60 mmHg, and ∆CPPopt < - 5 mmHg were considered as cerebral insults. RESULTS: PbtO2 < 20 mmHg occurred in median during 17% of the monitoring time and in less than 5% in combination with ICP > 20 mmHg, PRx > 0.30, CPP < 60 mmHg, or ∆CPPopt < - 5 mmHg. In GAM analyses, pbtO2 remained around 25 mmHg over a large range of ICP ([0;50] mmHg) and PRx [- 1;1], but deteriorated below 20 mmHg for extremely low CPP below 30 mmHg and ∆CPPopt below - 30 mmHg. In linear mixed effect models, ICP, CPP, PRx, and ∆CPPopt were significantly associated with pbtO2, but the fixed effects could only explain a very small extent of the pbtO2 variation. CONCLUSIONS: PbtO2 below 20 mmHg was relatively frequent and often occurred in the absence of disturbances in ICP, PRx, CPP, and ∆CPPopt. There were significant, but weak associations between the global cerebral physiological variables and pbtO2, suggesting that hypoxic pbtO2 is often a complex and independent pathophysiological event. Thus, other variables may be more crucial to explain pbtO2 and, likewise, pbtO2 may not be a suitable outcome measure to determine whether global cerebral blood flow optimization such as CPPopt therapy is successful.

And whatsoever I shall see or hear I will never divulge. Confidentiality and disclosure for intensivists.

Police requests to provide information about unconscious patients frequently cause difficulty for intensivists. This article reviews the circumstances where an intensive care doctor may and should disclose information about unconscious patients to the police. It first considers what constitutes private and confidential information and explains why this information should be protected. The relevant laws and regulations are then examined to identify circumstances in which a disclosure to the police is compulsory and when it is discretionary. It considers the required and permitted extent of the disclosures, and any requirements that must be fulfilled for the disclosure to be lawful. The role of the General Data Protection Regulations in governing all disclosures is reviewed, and a framework is provided which may be adopted to aid decision-making for disclosures to the police.

Pulmonary embolism following complex trauma: UK MTC observational study.

OBJECTIVES: To describe the incidence of pulmonary embolism (PE) in a critically ill UK major trauma centre (MTC) patient cohort. METHODS: A retrospective, multidataset descriptive study of all trauma patients requiring admission to level 2 or 3 care in the East of England MTC from 1 November 2014 to 1 May 2017. Data describing demographics, the nature and extent of injuries, process of care, timing of PE prophylaxis, tranexamic acid (TXA) administration and CT scanner type were extracted from the Trauma Audit and Research Network database and hospital electronic records. PE presentation was categorised as immediate (diagnosed on initial trauma scan), early (within 72 hours of admission but not present initially) and late (diagnosed after 72 hours). RESULTS: Of the 2746 trauma patients, 1039 were identified as being admitted to level 2 or 3 care. Forty-eight patients (4.6%) were diagnosed with PE during admission with 14 immediate PEs (1.3%). Of 32.1% patients given TXA, 6.3% developed PE compared with 3.8% without TXA (p=0.08). CONCLUSION: This is the largest study of the incidence of PE in UK MTC patients and describes the greatest number of immediate PEs in a civilian complex trauma population to date. Immediate PEs are a rare phenomenon whose clinical importance remains unclear. Tranexamic acid was not significantly associated with an increase in PE in this population following its introduction into the UK trauma care system.

Probable Catastrophic Antiphospholipid Syndrome with Intracerebral Hemorrhage Secondary to Epstein-Barr Viral Infection.

BACKGROUND: Catastrophic antiphospholipid syndrome (CAPS) is a rare, severe variant of antiphospholipid syndrome with a high mortality rate. We report a unique case of CAPS secondary to Epstein-Barr viral (EBV) infection complicated by pulmonary and intracerebral hemorrhage. A review of the CAPS literature relevant to intensive care practice is used to outline a rational approach to diagnosis and management. METHODS: All data are from a single patient admitted to the Neurosciences Critical Care Unit in Addenbrooke's Hospital, Cambridge, in March 2016. Medline, Web of Science, PubMed, and the Cochrane Library were searched through September 2016 without restrictions for cases of CAPS, management of CAPS in the intensive care unit, and hemorrhage complicating CAPS. The patient gave express written consent to access and publish these data. RESULTS: This is only the second reported case of probable CAPS secondary to EBV infection. Furthermore, pulmonary and intracerebral hemorrhage is rare manifestations of this multisystem prothrombotic state which provided unique challenges to the management. CONCLUSIONS: While rare, CAPS should be considered in any patient presenting with rapidly progressive multiorgan failure, evidence of thrombotic microangiopathy, and antiphospholipid antibodies. A high index of suspicion is required as early, aggressive, multimodal treatment with anticoagulation, and immunosuppression improves outcomes.

Cambridge Polytrauma Pathway: Are we making appropriately guided decisions?

Addenbrooke's Hospital, the Major Trauma Centre for the East of England Trauma Network, received 1070 major trauma patients between 1st January and 31st December 2014. In order to improve care, an audit was performed of 59 patients meeting our own selection criteria for orthopaedic polytrauma between 1st January 2013 and 31st December 2013. The Cambridge Polytrauma Pathway was devised through NCEPOD guidelines, literature review, internal and external discussion. It facilitates provision of best practice Early Appropriate Care, encompassing - multidisciplinary consultant decisions around the patient in our Neurological and Trauma Critical Care Unit, early full body trauma CT scans, serial measurements of lactate and fibrinogen levels, and out-of-hours orthopaedic theatre reserved for life-and-limb threatening injuries. Re-audit was conducted of 15 patients meeting selection criteria, admitted between 1st October 2014 and 31st March 2015. Significant improvements in recording of lactate and fibrinogen were demonstrated, both on admission (lactate - p<0.000, fibrinogen - p=0.015), and preoperatively (lactate - p=0.003, fibrinogen - p=0.030). Time to trauma CT was unchanged (p=0.536) with a median time to CT of 0.53h at re-audit (IQR 0.48-0.75). The number of patients receiving definitive orthopaedic intervention out-of-hours reduced from 8 to zero (p=0.195). The approach of facilitating management decisions to be made at early daytime MDT meetings has been adopted. It is anticipated that this pathway will improve outcomes in orthopaedic polytrauma patients and it is recommended that either the GOS-E, or the EQ-5D scoring systems be introduced to assess this.

Dysregulated intracellular signaling impairs CTGF-stimulated responses in human mesangial cells exposed to high extracellular glucose.

High ambient glucose activates intracellular signaling pathways to induce the expression of extracellular matrix and cytokines such as connective tissue growth factor (CTGF). Cell responses to CTGF in already glucose-stressed cells may act to transform the mesangial cell phenotype leading to the development of glomerulosclerosis. We analyzed cell signaling downstream of CTGF in high glucose-stressed mesangial cells to model signaling in the diabetic milieu. The addition of CTGF to primary human mesangial cells activates cell migration which is associated with a PKC-zeta-GSK3beta signaling axis. In high ambient glucose basal PKC-zeta and GSK3beta phosphorylation levels are selectively increased and CTGF-stimulated PKC-zeta and GSK3beta phosphorylation was impaired. These effects were not induced by osmotic changes. CTGF-driven profibrotic cell signaling as determined by p42/44 MAPK and Akt phosphorylation was unaffected by high glucose. Nonresponsiveness of the PKC-zeta-GSK3beta signaling axis suppressed effective remodeling of the microtubule network necessary to support cell migration. However, interestingly the cells remain plastic: modulation of glucose-induced PKC-beta activity in human mesangial cells reversed some of the pathological effects of glucose damage in these cells. We show that inhibition of PKC-beta with LY379196 and PKC-beta siRNA reduced basal PKC-zeta and GSK3beta phosphorylation in human mesangial cells exposed to high glucose. CTGF stimulation under these conditions again resulted in PKC-zeta phosphorylation and human mesangial cell migration. Regulation of PKC-zeta by PKC-beta in this instance may establish PKC-zeta as a target for constraining the progression of mesangial cell dysfunction in the pathogenesis of diabetic nephropathy.

Fucoidan modulates the effect of transforming growth factor (TGF)-beta1 on fibroblast proliferation and wound repopulation in in vitro models of dermal wound repair.

Aberrant wound healing, either causing scarring or chronic wounds, is a significant cause of morbidity. There is therefore, considerable interest in agents which can modulate certain aspects of the wound healing process. Fucoidans, sulphated polyfucose polysaccharides which may be extracted from Fucus spp., have been shown to modulate the effects of a variety of growth factors through mechanisms thought to be similar to the action of heparin. We investigated the interaction between two commercial preparations of fucoidan and transforming growth factor (TGF)-beta(1). These preparations of fucoidan, as well as heparin, inhibited fibroblast proliferation at concentrations from 0.01 to 100 mg/ml. The anti-proliferative effects of 1 ng/ml TGF-beta(1) on dermal fibroblasts were abrogated by fucoidan preparation F7 when used at concentrations over 1 mg/ml. In a three dimensional in vitro model of wound repair, the fibroblast populated collagen lattice or "dermal equivalent", TGF-beta(1) reduced the rate of fibroblast repopulation of a wound defect created by punch biopsy. Addition of fucoidan to the model in the presence of TGF-beta(1) increased the rate of fibroblast repopulation of the wound and at 10 mg/ml of fucoidan the number of cells which had migrated into the wounded defect was similar to that of control cultures. These data suggest that fucoidan has properties which may be beneficial in the treatment of wound healing.

Characterization of the living skin equivalent as a model of cutaneous re-epithelialization.

The living skin equivalent, a three-dimensional organotypic model, has been widely used to investigate many aspects of cutaneous biology. However, there are relatively few studies assessing how faithfully the skin equivalent reproduces normal skin biology. The skin equivalent was fabricated by seeding human epidermal keratinocytes onto the upper surface of a hydrated collagen lattice populated with human dermal fibroblasts and subsequently raised to the air-liquid interface where keratinocyte stratification and differentiation led to the formation of a tissue which showed many common morphological features to that of normal skin. Histology and immunohistochemical detection of keratinocyte integrins and matrix metalloproteinases (MMPs) were used as cytological markers to assess the accuracy of the model during cutaneous re-epithelialization. Analysis of expression of keratinocyte integrins revealed that whilst there were a number of similarities to normal skin, skin equivalent keratinocytes appeared to be 'activated' and hyper-proliferating. Wounding of the skin equivalent, by complete bisection, induced re-epithelialization from both wound edges within 8-12 h, which completely restored the epidermis within 4 days. This migration, like that in vivo, was associated with nascent expression of MMPs and upregulation of certain integrins. However, whilst integrin expression, was similar to in vivo re-epithelialization, there were subtle differences in the level of expression and distribution of certain integrins.