Driving Simulator Performance After Administration of Analgesic Doses of Ketamine With Dexmedetomidine or Fentanyl.

PURPOSE/BACKGROUND: As a sole agent, ketamine acutely compromises driving ability; however, performance after coadministration with the adjuvant sedating agents dexmedetomidine or fentanyl is unclear. METHODS/PROCEDURES: Using a randomized within-subject design, 39 participants (mean ± SD age, 28.4 ± 5.8 years) received 0.3 mg/kg bolus followed by 0.15 mg kg h infusion of ketamine (3-hour duration), in addition to either (i) 0.7 µg kg h infusion of dexmedetomidine for 1.5 hours (n = 19; KET/DEX) or (ii) three 25 µg fentanyl injections for 1.5 hours (n = 20; KET/FENT). Whole blood drug concentrations were determined during ketamine only, at coadministration (KET/DEX or KET/FENT) and at 2 hours after treatment. Subjective effects were determined using a standardized visual analog scale. Driving performance was assessed at baseline and at posttreatment using a validated computerized driving simulator. Primary outcomes included SD of lateral position (SDLP) and steering variability (SV). FINDINGS/RESULTS: Administration of ketamine with dexmedetomidine but not fentanyl significantly increased SDLP (F1,18 = 22.60, P < 0.001) and reduced SV (F1,18 = 164.42, P < 0.001) 2 hours after treatment. These deficits were comparatively greater for the KET/DEX group than for the KET/FENT group (t37 = -5.21 [P < 0.001] and t37 = 5.22 [P < 0.001], (respectively). For the KET/DEX group, vehicle control (SV) and self-rated performance (visual analog scale), but not SDLP, was inversely associated with ketamine and norketamine blood concentrations (in nanograms per milliliter). Greater subjective effects were moderately associated with driving deficits. IMPLICATIONS/CONCLUSIONS: Driving simulator performance is significantly compromised after coadministration of analgesic range doses of ketamine with dexmedetomidine but not fentanyl. An extended period of supervised driver abstinence is recommended after treatment, with completion of additional assessments to evaluate home readiness.

Sedation Intensity in the First 48 Hours of Mechanical Ventilation and 180-Day Mortality: A Multinational Prospective Longitudinal Cohort Study.

OBJECTIVES: In the absence of a universal definition of light or deep sedation, the level of sedation that conveys favorable outcomes is unknown. We quantified the relationship between escalating intensity of sedation in the first 48 hours of mechanical ventilation and 180-day survival, time to extubation, and delirium. DESIGN: Harmonized data from prospective multicenter international longitudinal cohort studies SETTING:: Diverse mix of ICUs. PATIENTS: Critically ill patients expected to be ventilated for longer than 24 hours. INTERVENTIONS: Richmond Agitation Sedation Scale and pain were assessed every 4 hours. Delirium and mobilization were assessed daily using the Confusion Assessment Method of ICU and a standardized mobility assessment, respectively. MEASUREMENTS AND MAIN RESULTS: Sedation intensity was assessed using a Sedation Index, calculated as the sum of negative Richmond Agitation Sedation Scale measurements divided by the total number of assessments. We used multivariable Cox proportional hazard models to adjust for relevant covariates. We performed subgroup and sensitivity analysis accounting for immortal time bias using the same variables within 120 and 168 hours. The main outcome was 180-day survival. We assessed 703 patients in 42 ICUs with a mean (SD) Acute Physiology and Chronic Health Evaluation II score of 22.2 (8.5) with 180-day mortality of 32.3% (227). The median (interquartile range) ventilation time was 4.54 days (2.47-8.43 d). Delirium occurred in 273 (38.8%) of patients. Sedation intensity, in an escalating dose-dependent relationship, independently predicted increased risk of death (hazard ratio [95% CI], 1.29 [1.15-1.46]; p < 0.001, delirium hazard ratio [95% CI], 1.25 [1.10-1.43]), p value equals to 0.001 and reduced chance of early extubation hazard ratio (95% CI) 0.80 (0.73-0.87), p value of less than 0.001. Agitation level independently predicted subsequent delirium hazard ratio [95% CI], of 1.25 (1.04-1.49), p value equals to 0.02. Delirium or mobilization episodes within 168 hours, adjusted for sedation intensity, were not associated with survival. CONCLUSIONS: Sedation intensity independently, in an ascending relationship, predicted increased risk of death, delirium, and delayed time to extubation. These observations suggest that keeping sedation level equivalent to a Richmond Agitation Sedation Scale 0 is a clinically desirable goal.

Volunteer peer support frameworks supporting older women living alone.

Volunteer peer support is an approach that enables a supportive connection between volunteers and a sub-set of community members with shared experiences or interests. To implement co-designed strategies to support older women to maintain independence and optimise wellbeing in Australia, a volunteer peer support approach was proposed. There was limited literature describing volunteer peer support frameworks to underpin interventions of this kind; and given the increasing desire for engagement of individuals and communities, articulation of the key components of such a framework is warranted. In this paper, we define volunteers and peer support, and outline existing frameworks for volunteering and peer support. We then describe the volunteer peer support framework developed for this intervention, outlining the key requirements. This information will enable others to develop an effective and sustainable structure for peer support volunteer services.

Quality of life of older Australians receiving home nursing services for complex care needs.

Older Australians may live up to 10 years in ill health, most likely chronic disease-related. Those with multimorbidity report more healthcare visits, poorer health and take more medications compared with people with a single chronic disease. They are also at higher risk of hospital admission and poor quality of life. People living with multimorbidity are considered to have "complex care" needs. A person-centred approach to healthcare has led to increasing use of in-home nursing support, enabling older people to receive care at home. Our prospective observational study describes the profile and management of home-based care for older people with complex care needs and examines changes in their quality of life over 12 months. Routinely collected data were analysed, including demographics, medical history, medications and the visit activity of staff providing care to participants. Additional health-related quality of life and hospitalisation data were collected via quarterly surveys and analysed. Fifty-two participants (mean age 76.6 years, 54% female) with an average of eight diagnosed health conditions, received an average of four home care visits per week. Almost half the participants were hospitalised once during the 12-month period and experienced a significant decline in overall quality of life and in the dimensions measuring independent living and relationships over the study period. If ageing in place with good quality of life is to be realised by older adults with multimorbidity, support services including home nursing need to consider both the biomedical and social determinants perspectives when addressing health and social care needs.

Co-designing Being Your Best program-A holistic approach to frailty in older community dwelling Australians.

Frailty is a condition characterised by increased vulnerability and decline of physical and cognitive reserves, most often affecting older people. This can lead to a cascade of repeated hospitalisations, further decline and ultimately loss of independence. Frailty and pre-frailty are modifiable; interventions such as physical exercise, cognitive training, social connection and improved nutrition, especially in a group setting, can mitigate frailty. Existing healthcare guidelines for managing frailty focus predominantly on falls, delirium, acute confusion and immobility. Uptake of referrals to services following hospital discharge is sub-optimal, indicating that a more proactive, person-centred and integrated approach to frailty is required. The aim was to co-design a program to help pre-frail and frail older people return to their homes following hospital discharge by increasing resilience and promoting independence. We engaged healthcare consumers, and healthcare professionals from three tertiary hospitals in metropolitan Melbourne (Alfred Hospital, Monash Health and Cabrini Health), and from Bolton Clarke home-based support services. Co-design is a process whereby the input of service consumers is included in the development of a program. In the healthcare sector, co-design involves discussions with healthcare consumers alongside healthcare professionals to identify issues and build knowledge to ultimately work on improving the healthcare system. From co-design sessions with 23 healthcare consumers and 17 healthcare professionals, it was apparent that frailty was perceived to affect physical and mental well-being. The co-design process resulted in refinement of the Being Your Best program to incorporate a holistic approach, addressing four domains supported by research evidence, to improve health and well-being through community- or home-based physical activity, cognitive training, social support and nutritional support. Being Your Best was developed in consultation with older people with lived experience as well as healthcare professionals and aims to mitigate the effects of frailty, and will now be tested for feasibility and acceptability.

Being Your Best: protocol for a feasibility study of a codesigned approach to reduce symptoms of frailty in people aged 65 years or more after transition from hospital.

INTRODUCTION: The population is ageing, with increasing health and supportive care needs. For older people, complex chronic health conditions and frailty can lead to a cascade of repeated hospitalisations and further decline. Existing solutions are fragmented and not person centred. The proposed Being Your Best programme integrates care across hospital and community settings to address symptoms of frailty. METHODS AND ANALYSIS: A multicentre pragmatic mixed methods study aiming to recruit 80 community-dwelling patients aged ≥65 years recently discharged from hospital. Being Your Best is a codesigned 6-month programme that provides referral and linkage with existing services comprising four modules to prevent or mitigate symptoms of physical, nutritional, cognitive and social frailty. Feasibility will be assessed in terms of recruitment, acceptability of the intervention to participants and level of retention in the programme. Changes in frailty (Modified Reported Edmonton Frail Scale), cognition (Mini-Mental State Examination), functional ability (Barthel and Lawton), loneliness (University of California Los Angeles Loneliness Scale-3 items) and nutrition (Malnutrition Screening Tool) will also be measured at 6 and 12 months. ETHICS AND DISSEMINATION: The study has received approval from Monash Health Human Research Ethics Committee (RES-19-0000904L). Results will be disseminated through peer-reviewed journals, conference and seminar presentations. TRIAL REGISTRATION NUMBER: ACTRN12620000533998; Pre-results.

Neurocognitive performance under combined regimens of ketamine-dexmedetomidine and ketamine-fentanyl in healthy adults: A randomised trial.

Analgesic doses of ketamine affects neurocognition; however, deficits under co-administration regimens are unknown. This study evaluated the effects of ketamine, alone and in combination with dexmedetomidine or fentanyl on neurocognition. Using a randomised, within-subjects gender stratified design, 39 participants (mean age = 28.4, SD ±â€¯5.8) received a ketamine bolus of 0.3 mg/kg followed by 0.15 mg/kg/h infusion of ketamine (3 h duration). At 1.5 h post-ketamine infusion commencement, participants received either: i) 0.7 µg/kg/h infusion of dexmedetomidine (n = 19) (KET/DEX) or (ii) three 25 µg fentanyl injections over 1.5 h (n = 20) (KET/FENT). Reaction and Movement time (RTI, Simple and 5Choice), Visuospatial Working Memory (SWM) and Verbal Recognition Memory (VRM) were assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Whole blood drug concentrations were determined during ketamine-only infusion, at co-administration (KET/DEX or KET/FENT) and at 2-h post-treatment. Ketamine-only administration impaired psychomotor response speed (Simple and 5Choice) and impaired memory (all p < .001), however did not alter executive function abilities. Independent of sedation, co-administration of dexmedetomidine produced synergistic performance and memory deficits which persisted at post-treatment (KET/DEX) (all p < .001), and were comparatively greater than for KET/FENT (all p < .05). Ketamine, norketamine and dexmedetomidine concentrations were modestly associated with reduced psychomotor speed and accuracy (all p < .05), and an inverse relationship was found between blood concentrations of ketamine, norketamine and dexmedetomidine and performance on memory tasks. Co-administration of ketamine with dexmedetomidine but not with fentanyl exerts synergistic effects on psychomotor performance and memory without executive dysfunction. Assessment of these effects in clinical groups is warranted.

Neurocognitive and behavioural performance of healthy volunteers receiving an increasing analgesic-range infusion of ketamine.

BACKGROUND: The acute and delayed effect of analgesic-range doses of ketamine on neurocognitive and behavioural outcomes is understudied. Using a non-controlled open-labelled design, three (1-h duration) increasing intravenous (IV) ketamine infusions comprising (i) 30 mg bolus of ketamine + 8 mg/h IV infusion, (ii) 12 mg/h IV infusion and (iii) 20 mg/h infusion were administered to 20 participants (15 male, 5 female, mean age = 30.8 years). Whole-blood ketamine and norketamine concentrations were determined at each treatment step and post-infusion. METHODS: The Cambridge Neuropsychological Test Automated Battery (CANTAB) was used to assess reaction/movement time (RTI, Simple and 5-Choice), visuospatial working memory (SWM), spatial planning (SOC) and subjective effects (visual analogue scale; VAS) during treatment and at post-treatment. RESULTS: Significant main effects were reported for time (dose) on CANTAB RTI 5-Choice reaction (F(4,18) = 3.41, p = 0.029) and movement time (F(4,18) = 4.42, p = 0.011), SWM (F(4,18) = 4.19, p = 0.014) and SOC (F(4,18) = 4.13, p = 0.015), but not RTI Simple reaction or movement time. Post hoc analyses revealed dose-dependent effects for both RTI 5-Choice reaction and movement time (all p < 0.05). Post-treatment performance on all neurocognitive and behavioural tasks returned to baseline levels. Regression analyses revealed a weak positive linear association between SWM 'strategy' score (R2 = 0.103, p < 0.001), all performance-based CANTAB VAS items (R2 range 0.005-0.137, all p < 0.05) and ketamine blood concentrations. DISCUSSION: The open-label, non-controlled trial design somewhat precludes the ability to adequately account for random treatment effects. Notwithstanding, these results suggest that analgesic doses of ketamine produce acute, selective, dose-dependent deficits in higher-order neurocognitive and behavioural domains.

The acute and residual effects of escalating, analgesic-range doses of ketamine on driving performance: A simulator study.

Ketamine hydrochloride elicits potent psychotomimetic and neurobehavioural effects which make it incompatible with driving; however, the direct effect on driving performance is yet to be assessed. Using an open label, within-subjects protocol, 15 males and 5 females (mean age = 30.8 years) were administered three fixed, stepwise increasing sub-anaesthetic doses of intravenous (IV) ketamine solution [(i) 8 mg/h IV infusion plus 30 mg bolus, (ii) 12 mg/h IV infusion and (iii) 20 mg/h infusion]. Whole blood ketamine and norketamine concentrations were determined at each treatment step and at 2 h post-infusion. Driving performance was assessed at baseline, at each treatment step and at 2 h post-treatment using a validated computerised driving simulator. Standard Deviation of Lateral Position (SDLP) and Steering Variability (SV) were assessed. Linear Fixed Effect Modelling indicated a main effect for time (dose) for SDLP (F[4,72] = 33.22, p < 0.0001) and SV (F[4,72] = 4.65, p < 0.002). Post-hoc analyses revealed significant differences from baseline at each treatment step for SDLP (all p < 0.001), and for 12 mg/h treatment step for SV (p = 0.049). Post-treatment driving performance returned to baseline levels. Weak positive linear associations were observed between SDLP and whole blood ketamine concentrations (R2 = 0.11, ß = 29.96, p = 0.001) and norketamine (R2 = 0.09, ß = 28.87, p = 0.003). These findings suggest that even under highly controlled conditions, ketamine intoxication significantly alters simulated driving performance. At the highest dose, ketamine produced changes to SDLP considered incompatible with safe driving, highlighting how ketamine consumption may translate to an increased risk of road trauma.

Data on the DNA damaging and mutagenic potential of the BH3-mimetics ABT-263/Navitoclax and TW-37.

Unfortunately, the mutagenic activities of chemotherapy and radiotherapy can provoke development of therapy-induced malignancies in cancer survivors. Non-mutagenic anti-cancer therapies may be less likely to trigger subsequent malignant neoplasms. Here we present data regarding the DNA damaging and mutagenic potential of two drugs that antagonize proteins within the Bcl-2 family: ABT-263/Navitoclax and TW-37. Our data reveal that concentrations of these agents that stimulated Bax/Bak-dependent signaling provoked little DNA damage and failed to trigger mutations in surviving cells. The data supplied in this article is related to the research work entitled "Inhibition of Bcl-2 or IAP proteins does not provoke mutations in surviving cells" [1].

Inhibition of Bcl-2 or IAP proteins does not provoke mutations in surviving cells.

Chemotherapy and radiotherapy can cause permanent damage to the genomes of surviving cells, provoking severe side effects such as second malignancies in some cancer survivors. Drugs that mimic the activity of death ligands, or antagonise pro-survival proteins of the Bcl-2 or IAP families have yielded encouraging results in animal experiments and early phase clinical trials. Because these agents directly engage apoptosis pathways, rather than damaging DNA to indirectly provoke tumour cell death, we reasoned that they may offer another important advantage over conventional therapies: minimisation or elimination of side effects such as second cancers that result from mutation of surviving normal cells. Disappointingly, however, we previously found that concentrations of death receptor agonists like TRAIL that would be present in vivo in clinical settings provoked DNA damage in surviving cells. In this study, we used cell line model systems to investigate the mutagenic capacity of drugs from two other classes of direct apoptosis-inducing agents: the BH3-mimetic ABT-737 and the IAP antagonists LCL161 and AT-406. Encouragingly, our data suggest that IAP antagonists possess negligible genotoxic activity. Doses of ABT-737 that were required to damage DNA stimulated Bax/Bak-independent signalling and exceeded concentrations detected in the plasma of animals treated with this drug. These findings provide hope that cancer patients treated by BH3-mimetics or IAP antagonists may avoid mutation-related illnesses that afflict some cancer survivors treated with conventional DNA-damaging anti-cancer therapies.