Search

peer-reviewed As the Covid-19 pandemic escalates worldwide it is apparent that many patients with more severe illness will also experience delirium. These patients pose a particular challenge in the application of optimal care due to issues with infectious risk, respiratory compromise and potential interactions between medications that can be used to manage delirium with antiviral and other treatments used for Covid-19. We describe a guidance resource adapted from existing guidelines for delirium management that has been tailored to the specific challenge of managing delirium in patients with Covid-19 infection. Issues around the assessment and treatment of these patients are examined and distilled into a simple (one-paged guidance resource that can assist clinicians in managing suspected delirium.

OBJECTIVE To assess the efficacy and safety of closed-loop insulin delivery compared with sensor-augmented pump therapy among older adults with type 1 diabetes. RESEARCH DESIGN AND METHODS This open-label, randomized (1:1), crossover trial compared 4 months of closed-loop versus sensor-augmented pump therapy. Eligible adults were aged ≥60 years, with type 1 diabetes (duration ≥10 years), using an insulin pump. The primary outcome was continuous glucose monitoring (CGM) time in range (TIR; 3.9–10.0 mmol/L). RESULTS There were 30 participants (mean age 67 [SD 5] years), with median type 1 diabetes duration of 38 years (interquartile range [IQR] 20–47), randomized (n = 15 to each sequence); all completed the trial. The mean TIR was 75.2% (SD 6.3) during the closed-loop stage and 69.0% (9.1) during the sensor-augmented pump stage (difference of 6.2 percentage points [95% CI 4.4 to 8.0]; P < 0.0001). All prespecified CGM metrics favored closed loop over the sensor-augmented pump; benefits were greatest overnight. Closed loop reduced CGM time CONCLUSIONS Closed-loop therapy is an effective treatment option for older adults with long-duration type 1 diabetes, and no safety issues were identified. These older adults had higher TIR accompanied by less time below range during closed loop than during sensor-augmented pump therapy. Of particular clinical importance, closed loop reduced the time spent in hypoglycemic range overnight.

ObjectivesTo investigate whether delirium motor subtypes differ in terms of phenomenology and contributory aetiology.DesignCross-sectional study.SettingInternational study incorporating data from Ireland and India across palliative care, old age liaison psychiatry and general adult liaison psychiatry settings.Participants1757 patients diagnosed with delirium using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition (DSM IV).Primary and secondary outcome measuresHyperactive, mixed and hypoactive delirium subtypes were identified using the abbreviated version of the Delirium Motor Subtype Scale. Phenomenology was assessed using the Delirium Rating Scale Revised. Contributory aetiologies were assessed using the Delirium Aetiology Checklist (DEC), with a score >2 indicating that the aetiology was likely or definitely contributory.ResultsHypoactive delirium was associated with dementia, cerebrovascular and systemic infection aetiologies (pConclusionsThis study indicates a pattern of aetiology and symptomatology of delirium motor subtypes across a large international sample that had previously been lacking. It serves to improve our understanding of this complex condition and has implications in terms of early detection and management of delirium.

Microvascular thrombosis and blood–brain barrier (BBB) breakdown are key components of cerebral malaria (CM) pathogenesis in African children and are implicated in fatal brain swelling. How Plasmodium falciparum infection causes this endothelial disruption and why this occurs, particularly in the brain, is not fully understood. In this study, we have demonstrated that circulating extracellular histones, equally of host and parasite origin, are significantly elevated in CM patients. Higher histone levels are associated with brain swelling on magnetic resonance imaging. On postmortem brain sections of CM patients, we found that histones are colocalized with P falciparum–infected erythrocytes sequestered inside small blood vessels, suggesting that histones might be expelled locally during parasite schizont rupture. Histone staining on the luminal vascular surface colocalized with thrombosis and leakage, indicating a possible link between endothelial surface accumulation of histones and coagulation activation and BBB breakdown. Supporting this, patient sera or purified P falciparum histones caused disruption of barrier function and were toxic to cultured human brain endothelial cells, which were abrogated with antihistone antibody and nonanticoagulant heparin. Overall, our data support a role for histones of parasite and host origin in thrombosis, BBB breakdown, and brain swelling in CM, processes implicated in the causal pathway to death. Neutralizing histones with agents such as nonanticoagulant heparin warrant exploration to prevent brain swelling in the development or progression of CM and thereby to improve outcomes.

Objectives Patients with dementia in the acute setting are generally considered to impose higher costs on the health system compared to those without the disease largely due to longer length of stay (LOS). Many studies exploring the economic impact of the disease extrapolate estimates based on the costs of patients diagnosed using routinely collected hospital discharge data only. However, much dementia is undiagnosed, and therefore in limiting the analysis to this cohort, we believe that LOS and the associated costs of dementia may be overestimated. We examined LOS and associated costs in a cohort of patients specifically screened for dementia in the hospital setting. Methods Using primary data collected from a prospective observational study of patients aged ≥70 years, we conducted a comparative analysis of LOS and associated hospital costs for patients with and without a diagnosis of dementia. Results There was no significant difference in overall length of stay and total costs between those with (μ = 9.9 days, μ = € 8246) and without (μ = 8.25 days, μ = € 6855) dementia. Categorical data analysis of LOS and costs between the two groups provided mixed results. Conclusions The results challenge the basis for estimating the costs of dementia in the acute setting using LOS data from only those patients with a formal dementia diagnosis identified by routinely collected hospital discharge data. Accurate disease prevalence data, encompassing all stages of disease severity, are required to enable an estimation of the true costs of dementia in the acute setting based on LOS.

Background Identifying patients at high risk of delirium is crucial to facilitate prevention. Although dementia is the most consistent risk factor across populations, it remains under-diagnosed. Hence understanding other markers of delirium vulnerability on admission is important. Objective We aimed to identify predictors of incident delirium development in older medical inpatients that were readily identifiable at presentation to the emergency department. Methods Medical inpatients of ≥70 years were assessed on admission for delirium using the Revised Delirium Rating Scale (DRS-R98) and those with prevalent delirium were excluded. Consenting non-delirious patients were then assessed daily using the DRS-R98. Data pertaining to multiple baseline delirium risk factors were collected, including pre-morbid dementia. Multivariable logistic regression was used to examine which factors predicted the development of incident delirium. Results Of 555 patients approached, 184 (33.1%) had prevalent delirium. Following other exclusions, 191 were included in the study and 61 developed incident delirium. Predictors of incident delirium on multivariable analysis, controlling for confounders, were dementia (OR 2.54, 95% CI 1.01-6.43, p = 0.048); Barthel Index score (OR 1.15 for each unit decrease in score, 95% CI 1.06-1.25, p = 0.001), and Modified Cumulative Illness Rating Scale score (OR 1.13 for each unit increase in score, 95% CI 1.05-1.22, p = 0.001). Conclusion Dementia is a well-known risk factor for delirium; however, it too is under-recognized and on admission can be missed. Conversely, the Barthel Index is a simple and widely used measure of functional ability that may prove useful in stratifying those at risk of in-hospital delirium on admission.

Coagulopathy and leak, specific to the brain vasculature, are central pathogenetic components of cerebral malaria (CM). It is unclear how the parasite, Plasmodium falciparum, triggers these processes. Extracellular histones, released from damaged host cells, bind to cell membranes and cause coagulation activation, platelet aggregation and vascular leak in diverse critical illnesses. In CM patients with P. falciparum, serum histones correlate with fibrin formation, thrombocytopenia, and endothelial activation and predict brain swelling on magnetic resonance imaging and fatal outcome. Post-mortem, histones bind to the luminal vascular surface, co-localizing with P. falciparum-infected erythrocytes (IE), and with thrombosis and leak. Purified P. falciparum histones cause toxicity and barrier disruption in cultured human brain microvascular endothelial cells, as does serum from CM patients, reversed by anti-histone antibodies and non-anticoagulant heparin. These data implicate parasite histones as a key trigger of fatal brain swelling in CM. Neutralizing histones with agents such as non-anticoagulant heparin warrant exploration to prevent brain swelling and improve outcome.

Transfer to an Emergency Department (ED) is the safest and most expeditious plan for any geriatric patient with an acute medical event. Of course, consultation with appropriate specialists is useful, but finding and waiting for specialists or consultants should not delay emergency care either on the unit, with an emergency medical team (EMT), or in the ED. The challenge is to manage the acute medical event until more definitive evaluation and treatment can be provided. Many medical events on inpatient geriatric psychiatric units fall within the four domains discussed in this chapter, and an overview of each is offered.

Background Delirium is prevalent and serious, yet remains under-recognised. Systematic screening could improve detection; however, consensus is lacking as to the best approach. Our aim was to assess the diagnostic accuracy of five simple cognitive tests in delirium screening: six-item cognitive impairment test (6-CIT), clock-drawing test, spatial span forwards, months of the year backwards (MOTYB) and intersecting pentagons (IPT). Methods A cross-sectional study was conducted. Within 36 h of admission, older medical patients were assessed for delirium using the Revised Delirium Rating Scale. They also underwent testing using the five cognitive tests outlined above. Sensitivity, specificity, positive and negative predictive values (PPV; NPV) were calculated for each method. Where appropriate, area under the receiver operating characteristic curve (AUC) was also calculated. Results Four hundred seventy patients were included, and 184 had delirium. Of the tests scored on a scale, the 6-CIT had the highest AUC (0.876), the optimum cut-off for delirium screening being 8/9 (sensitivity 89.9%, specificity 62.7%, NPV 91.2%, PPV 59.2%). The MOTYB, scored in a binary fashion, also performed well (sensitivity 84.6%, specificity 58.4%, NPV 87.4%, PPV 52.8). On discriminant analysis, 6-CIT was the only test to discriminate between patients with delirium and those with dementia (without delirium), Wilks' Lambda = 0.748, p

Introduction: Delirium (acute confusion) affects 1 in 8 acute hospital inpatients and is highly distressing for patients and families. It is associated with increased length of hospital stay, risk of falls, mortality and institutionalisation. Early detection improves outcome, whereas established delirium (present for a few days) is difficult to treat. Thus screening for delirium in at-risk patients is key to early detection and treatment to improve outcomes. Description of policy context and objective: NICE guidelines recommend daily delirium screening for high risk patient groups. However, delirium screening and assessment is poorly performed in Irish hospitals (Irish National Audit of Dementia, 2014). We aimed to develop a simple algorithm for delirium screening on hospital wards, helping staff to identify those patients requiring daily delirium screening and outlining the action to be taken when a patient screened positive for delirium. Targeted population: Hospital in-patients on any general medical or surgical ward (i.e. excluding Intensive Care Unit or orthopaedic/neurosurgery wards), with ward nurses performing the daily delirium screening and hospital doctors acting on the abnormal result. Highlights: (innovation, Impact and outcomes) The interdisciplinary national algorithm development team firstly developed an evidence-based algorithm. Two versions were developed- one using the 4AT test (a well-recognised short delirium screening test) and the other using a quicker, deconstructed form. Both versions were piloted in three hospital sites, in a single ward at each site, with extensive user evaluation of the algorithm. Further modification was performed, followed by a second pilot in a single hospital on four wards. The version using the regular 4AT was preferred by users. Staff required pre-use training particularly on how to score patient refusals and using the tool in a patient with severe dementia. A Frequently Asked Questions guide, and an online training tool were developed, to support staff use of the algorithm, based on the pilot studies. This algorithm is being rolled out nationally in 2017 so impact and outcomes can’t be assessed as yet. Comments on transferability: The delirium algorithm was developed for use in all acute hospitals in Ireland. It is highly transferrable to other countries. Conclusions: Any new policy or guideline requires extensive user engagement at all stages of development. Different hospitals have different resources and training needs. Extensive piloting of our proposed algorithm identified areas that required targeted training. This allowed resources to be developed to facilitate adoption of the national policy, targeted to specific end-users needs.

IntroductionSurvivors of critical illness frequently exhibit acute and chronic neurological complications. The underlying aetiology of this dysfunction remains unknown but may be associated with cerebral ischaemia. This study will use near-infrared spectroscopy to non-invasively quantify regional cerebral oxygenation (rSO2) to assess the association between poor rSO2during the first 72 hours of critical illness with delirium severity, as well as long-term sensorimotor and cognitive impairment among intensive care unit (ICU) survivors. Further, the physiological determinants of rSO2will be examined.Methods and analysisThis multicentre prospective observational study will consider adult patients (≥18 years old) eligible for enrolment if within 24 hours of ICU admission, they require mechanical ventilation and/or vasopressor support. For 72 hours, rSO2will be continuously recorded, while vital signs (eg, heart rate) and peripheral oxygenation saturation will be concurrently captured with data monitoring software. Arterial and central venous gases will be sampled every 12 hours for the 72 hours recording period and will include: pH, PaO2, PaCO2, and haemoglobin concentration. Participants will be screened daily for delirium with the confusion assessment method (CAM)-ICU, whereas the brief-CAM will be used on the ward. At 3 and 12 months post-ICU discharge, neurological function will be assessed with the Repeatable Battery for the Assessment of Neuropsychological Status and KINARM sensorimotor and cognitive robot-based behavioural tasks.Ethics and disseminationThe study protocol has been approved in Ontario by a central research ethics board (Clinical Trials Ontario); non-Ontario sites will obtain local ethics approval. The study will be conducted under the guidance of the Canadian Critical Care Trials Group (CCCTG) and the results of this study will be presented at national meetings of the CCCTG for internal peer review. Results will also be presented at national/international scientific conferences. On completion, the study findings will be submitted for publication in peer-reviewed journals.Trial registration numberNCT03141619

Severe Plasmodium falciparum malaria remains a leading cause of mortality, particularly in sub-Saharan Africa where it accounts for up to 1 million deaths per annum. In spite of the significant mortality and morbidity associated with cerebral malaria (CM), the molecular mechanisms involved in the pathophysiology of severe malaria remain surprisingly poorly understood. Previous studies have demonstrated that sequestration of P falciparum–infected erythrocytes within the microvasculature of the brain plays a key role in the development of CM. In addition, there is convincing evidence that both endothelial cell activation and platelets play critical roles in the modulating the pathogenesis of severe P falciparum malaria. In this review, we provide an overview of recent studies that have identified novel roles through which hemostatic dysfunction may directly influence malaria pathogenesis. In particular, we focus on emerging data suggesting that von Willebrand factor, coagulation cascade activation, and dysfunction of the protein C pathway may be of specific importance in this context. These collective insights underscore a growing appreciation of the important, but poorly understood, role of hemostatic dysfunction in malaria progression and, importantly, illuminate potential approaches for novel therapeutic strategies. Given that the mortality rate associated with CM remains on the order of 20% despite the availability of effective antimalarial therapy, development of adjunctive therapies that can attenuate CM progression clearly represents a major unmet need. These emerging data are thus not only of basic scientific interest, but also of direct clinical significance.

Summary Adherence of infected erythrocytes to vascular endothelium causes acute endothelial cell (EC) activation during Plasmodium falciparum infection. Consequently, proteins stored in Weibel-Palade (WP) bodies within EC are secreted into the plasma. Osteoprotegerin (OPG) binds to VWF and consequently is stored within WP bodies. Given the critical role of EC activation in the pathogenesis of severe malaria, we investigated plasma OPG levels in children with P. falciparum malaria. At presentation, plasma OPG levels were significantly elevated in children with cerebral malaria (CM) compared to healthy controls (means 16.0 vs 0.8 ng/ml; p

Plasmodium falciparum malaria infection is associated with an early marked increase in plasma von Willebrand factor (VWF) levels, together with a pathological accumulation of hyperreactive ultra-large VWF (UL-VWF) multimers. Given the established critical role of platelets in malaria pathogenesis, these increases in plasma VWF raise the intriguing possibility that VWF may play a direct role in modulating malaria pathogenesis. To address this hypothesis, we used an established murine model of experimental cerebral malaria (ECM), in which wild-type (WT) C57BL/6J mice were infected with Plasmodium berghei ANKA. In keeping with findings in children with P falciparum malaria, acute endothelial cell activation was an early and consistent feature in the murine model of cerebral malaria (CM), resulting in significantly increased plasma VWF levels. Despite the fact that murine plasma ADAMTS13 levels were not significantly reduced, pathological UL-VWF multimers were also observed in murine plasma following P berghei infection. To determine whether VWF plays a role in modulating the pathogenesis of CM in vivo, we further investigated P berghei infection in VWF(-/-) C57BL/6J mice. Clinical ECM progression was delayed, and overall survival was significantly prolonged in VWF(-/-) mice compared with WT controls. Despite this protection against ECM, no significant differences in platelet counts or blood parasitemia levels were observed between VWF(-/-) and WT mice. Interestingly, however, the degree of ECM-associated enhanced blood-brain barrier permeability was significantly attenuated in VWF(-/-) mice compared with WT controls. Given the significant morbidity and mortality associated with CM, these novel data may have direct translational significance.

Hypoactive delirium is most commonly missed and yields the worst outcomes. Little is known about longitudinal course of motor subtypes, as most studies are cross-sectional in nature. We aimed to investigate the frequency and stability of motor subtypes in incident delirium in older medical inpatients. Medical inpatients of ≥70 years without prevalent delirium on admission underwent daily assessment for ≤7 days for incident delirium. Motor activity profile was established using the Delirium Motor Subtype Scale-4 (DMSS-4). Longitudinal subtypes were ascertained by examining the daily profiles of each delirious patient. In total, 1219 assessments were performed in 191 patients, 61 with incident delirium. Hypoactive subtype was most prevalent on any given delirium day (n= 75/113, 66.4%) and was the most common longitudinal subtype (n=38/61, 62.3%). Hypoactive delirium is highly prevalent in older medical inpatients. Hence, delirium education programmes should focus on improving understanding and awareness of this subtle presentation amongst clinicians.

Delirium is extremely common, and leads to adverse outcomes. Delirium can be preventable, but is frequently missed. Much remains unknown about management of actively delirious individuals. In this symposium, we present the results of novel research from five centres, focusing on risk stratification, case identification and interventions for delirium. Our first abstract reports the prevalence of hypoactive delirium in older medical inpatients, the most underdetected and prognostically serious form. Our second abstract describes a brief two-step diagnostic approach which shows promise as a sensitive delirium identification method. Thirdly, we present a novel delirium risk stratification method for pre-operative cardiac surgery patients, using frailty assessment. Next, we report findings which indicate improvement in delirium symptoms with physical therapy. Finally we highlight the potential harm related to the oft-prescibed antibiotic treatment of asymptomatic bacteruria in delirious patients. This symposium will highlight new research, across a breadth of issues related to delirium.

Cerebral malaria (CM) is a major cause of death in young children in sub-Saharan Africa. Although the pathogenesis of this condition remains poorly understood, Plasmodium falciparum infection results in adhesion of infected erythrocytes (IE) to microvascular endothelium, and acute endothelial cell (EC) activation. Recent studies have shown that plasma VWF:Ag and VWF propeptide levels are markedly elevated in children with severe falciparum malaria. Moreover elevated VWF:Ag levels inversely correlate with clinical outcomes. In addition, circulating ultra-large VWF multimers have also been observed in children with severe malaria. Importantly, platelet-decorated UL-VWF strings have been shown to recruit trophozoite-stage falciparum-IE to EC surfaces in shear-based assays. Collectively, these emerging data suggest that VWF may play a novel role in the pathogenesis of CM. To further investigate this hypothesis, we utilized an established murine model of experimental CM which involves wild type (WT) C57BL/6J mice infected with Plasmodium berghei ANKA. In brief, WT C57Bl/6J mice were inoculated with 2x106P. berghei ANKA via I.P. injection. These mice typically developed CM and died within 6-8 days. In keeping with findings in children with falciparum malaria, acute EC activation was also an early and consistent feature in the murine model of CM. Mean plasma VWF:Ag levels were significantly elevated from Day+3 in infected mice compared to controls (Day +3 1.8 fold increase; Day +5 2.5 fold increase; p To determine whether VWF plays a direct role in modulating the pathogenesis of CM in vivo, we further investigated P. berghei infection in VWF-/- C57BL/6J mice. Importantly, although there was no difference in blood parasitaemia levels, overall survival was significantly prolonged in VWF-/- mice compared to wild type mice (6 versus 7.25 days; p=0.0106). Moreover, a significant delay in malaria clinical progression in the VWF-/- mice was also observed using a previously validated clinical scoring algorithm for experimental cerebral malaria. (Amante et al, Am J Path 2007). Recent studies have demonstrated that platelets may play a direct role in modulating malaria parasite killing. Consequently, to investigate potential mechanisms through which VWF-/- mice are protected against experimental CM, daily platelet counts were determined in WT and VWF-/- mice following infection. In keeping with observations in human patients infected with falciparum malaria, significant thrombocytopenia was also a consistent feature in the murine model. For example, by Day +4 following inoculation of WT mice mean platelet count had fallen by 71.6 ± 26 %. Interestingly however, significant thrombocytopenia was also observed in VWF-/- mice infected with P. berghei (84.2 ± 9 %). Despite the significant differences in clinical progression and overall survival no significant differences in platelet counts were observed between VWF-/- and WT mice at any time point. These findings suggest that VWF-/-mice are protected against CM through a platelet-independent mechanism. In conclusion, we demonstrate that early and consistent EC activation is a feature of the murine model of experimental CM similar to previous findings of children infected with P. falciparum. In addition, our findings show that marked elevation of VWF:Ag, and the appearance of pathological UL-VWF multimers in the plasma, both represent hallmarks of human and murine severe malaria infection. Finally, we report that VWF-/- mice exhibit significantly prolonged survival against CM, and that this effect is mediated through a platelet-independent mechanism. Given the significant morbidity and mortality associated with CM, these novel data have direct translational significance. Disclosures No relevant conflicts of interest to declare.