Dexmedetomidine and Propofol Sedation in Critically Ill Patients and Dose-associated 90-Day Mortality: A Secondary Cohort Analysis of a Randomized Controlled Trial (SPICE III).

Rationale: The SPICE III (Sedation Practice in Intensive Care Evaluation) trial reported significant heterogeneity in mortality with dexmedetomidine treatment. Supplemental propofol was commonly used to achieve desirable sedation. Objectives: To quantify the association of different infusion rates of dexmedetomidine and propofol, given in combination, with mortality and to determine if this is modified by age. Methods: We included 1,177 patients randomized in SPICE III to receive dexmedetomidine and given supplemental propofol, stratified by age (>65 or ⩽65 yr). We used double stratification analysis to produce quartiles of steady infusion rates of dexmedetomidine while escalating propofol dose and vice versa. We used Cox proportional hazard and multivariable regression adjusted for relevant clinical variable to evaluate the association of sedative dose with 90-day mortality. Measurements and Main Results: Younger patients (598 of 1,177 [50.8%]) received significantly higher doses of both sedatives compared with older patients to achieve comparable sedation depth. On double stratification analysis, escalating infusion rates of propofol to 1.27 mg/kg/h at a steady dexmedetomidine infusion rate (0.54 µg/kg/h) was associated with reduced adjusted mortality in younger but not older patients. This was consistent with multivariable regression modeling (hazard ratio, 0.59; 95% confidence interval, 0.43-0.78; P < 0.0001) adjusted for baseline risk and interaction with dexmedetomidine dose. In contrast, among younger patients, using multivariable regression, escalating dexmedetomidine infusion rate was associated with increased adjusted mortality (hazard ratio, 1.30; 95% confidence interval, 1.03-1.65; P = 0.029). Conclusions: In patients ⩽65 years of age sedated with dexmedetomidine and propofol combination, preferentially increasing the dose of propofol was associated with decreased adjusted 90-day mortality. Conversely, increasing dexmedetomidine may be associated with increased mortality. Clinical trial registered with www.clinicaltrials.gov (NCT01728558).

The feasibility and acceptability of a physician-led ICU follow-up service: A prospective cohort study.

BACKGROUND: Increased recognition of post-intensive care syndrome has led to widespread development of intensive care follow-up services internationally. OBJECTIVE: The objective of this study was to determine the feasibility and acceptability of an intensive care unit (ICU) follow-up clinic in Australia for patients and their caregivers and to describe satisfaction with this service. METHODS: This was a prospective cohort study in a mixed tertiary ICU in Australia. Eligible patients were adults admitted to the ICU for 7 days or more and/or ventilated for 48 h or more, as well as their primary caregiver. Patients and their primary caregivers were invited to attend a follow-up clinic 4-8 weeks after hospital discharge. The clinic appointment was attended by an ICU physician and nurse, with multidisciplinary support. Feasibility and acceptability were defined as the proportion of clinic attendance and frequency of interventions initiated at the clinic. Satisfaction was measured by a 5-point satisfaction survey (very dissatisfied to very satisfied). The burden of ongoing disease was reported via multiple validated instruments. RESULTS: From April 2020-July 2021, 386 patients met the inclusion criteria. Only 146 patients were approached for consent due to site staffing limitations. Eighty-three patients and 32 caregivers consented to attend the clinic. Seventy percent (54/77) of patients attended scheduled appointments and 50% (16/32) of caregivers. For patients, 23 medical referrals were made, 8 patients had medication changes, and 10 patients were offered social work support. Satisfaction surveys were completed by 65% (35/54) of attending patients; 97% (34) patients reported either being 'very satisfied' or 'satisfied' with the service. All responding caregivers (10) were either 'very satisfied' or 'satisfied' with the clinic. CONCLUSION: There were a large number of patients meeting the inclusion criteria to the ICU follow-up clinic, and clinic attendance was moderate for patients but lower for caregivers. Reported satisfaction with the service was high for both patients and their caregiver.

Early Sedation with Dexmedetomidine in Critically Ill Patients.

BACKGROUND: Dexmedetomidine produces sedation while maintaining a degree of arousability and may reduce the duration of mechanical ventilation and delirium among patients in the intensive care unit (ICU). The use of dexmedetomidine as the sole or primary sedative agent in patients undergoing mechanical ventilation has not been extensively studied. METHODS: In an open-label, randomized trial, we enrolled critically ill adults who had been undergoing ventilation for less than 12 hours in the ICU and were expected to continue to receive ventilatory support for longer than the next calendar day to receive dexmedetomidine as the sole or primary sedative or to receive usual care (propofol, midazolam, or other sedatives). The target range of sedation-scores on the Richmond Agitation and Sedation Scale (which is scored from -5 [unresponsive] to +4 [combative]) was -2 to +1 (lightly sedated to restless). The primary outcome was the rate of death from any cause at 90 days. RESULTS: We enrolled 4000 patients at a median interval of 4.6 hours between eligibility and randomization. In a modified intention-to-treat analysis involving 3904 patients, the primary outcome event occurred in 566 of 1948 (29.1%) in the dexmedetomidine group and in 569 of 1956 (29.1%) in the usual-care group (adjusted risk difference, 0.0 percentage points; 95% confidence interval, -2.9 to 2.8). An ancillary finding was that to achieve the prescribed level of sedation, patients in the dexmedetomidine group received supplemental propofol (64% of patients), midazolam (3%), or both (7%) during the first 2 days after randomization; in the usual-care group, these drugs were administered as primary sedatives in 60%, 12%, and 20% of the patients, respectively. Bradycardia and hypotension were more common in the dexmedetomidine group. CONCLUSIONS: Among patients undergoing mechanical ventilation in the ICU, those who received early dexmedetomidine for sedation had a rate of death at 90 days similar to that in the usual-care group and required supplemental sedatives to achieve the prescribed level of sedation. More adverse events were reported in the dexmedetomidine group than in the usual-care group. (Funded by the National Health and Medical Research Council of Australia and others; SPICE III ClinicalTrials.gov number, NCT01728558.).

Prophylactic Intra-Aortic Balloon Counterpulsation in High Risk Cardiac Surgery: The PINBALL Pilot Multicentre, Registry-Linked, Randomised, Controlled Feasibility Trial.

BACKGROUND: Prophylactic intra-aortic balloon counterpulsation (IABC) is commonly used in selected patients undergoing coronary artery bypass graft (CABG) surgery, but definitive evidence is lacking. The aim of the multicentre PINBALL Pilot randomised controlled trial (RCT) was to assess the feasibility of performing a definitive trial to address this question. METHODS: Patients listed for CABG surgery with impaired left ventricular function and at least one additional risk factor for postoperative low cardiac output syndrome were eligible for inclusion if the treating surgical team was uncertain as to the benefit of prophylactic IABC. The primary outcome of feasibility was based on exceeding a pre-specified recruitment rate, protocol compliance and follow-up. RESULTS: The recruitment rate of 0.5 participants per site per month did not meet the feasibility threshold of two participants per site per month and the study was stopped early after enrolment of 24 out of the planned sample size of 40 participants. For 20/24 (83%) participants, preoperative IABC use occurred according to study assignment. Six (6)-month follow-up was available for all enrolled participants, [IABC 1 death (8%) vs. control 1 death (9%), p = 0.95]. CONCLUSION: The PINBALL Pilot recruitment rate was insufficient to demonstrate feasibility of a multicentre RCT of prophylactic IABC in high risk patients undergoing CABG surgery.

Cognitive impairment in intensive care unit patients: A pilot mixed-methods feasibility study exploring incidence and experiences for recovering patients.

BACKGROUND: Despite improvements in survival after critical illness and intensive care unit (ICU) treatment, some recovering patients still face ongoing challenges. There are few investigations exploring the incidence, risk factors, and trajectory for cognitive impairment (CI) in former ICU patients in Australia. OBJECTIVES: To test the feasibility of a study protocol designed to ascertain the incidence and impact of CI during recovery from a critical illness. METHODS: We conducted a mixed-methods longitudinal single-centre pilot study. Participants were adult patients mechanically ventilated for ≥48 h. Cognitive function was assessed during hospitalisation and at 1 week, 2 months, and 6 months after hospital discharge, using the Montreal Cognitive Assessment instrument. Factors potentially affecting cognitive function were also collected, including demographic and clinical variables and fatigue, frailty, and muscle strength. Semistructured interviews were conducted to further explore participants' experiences during recovery. RESULTS: We screened 2068 patients (10% met the inclusion criteria). Participants (n = 20) were mostly male with a mean age 61.9 years and a median of 4 days of mechanical ventilation. Data collection was complete for 14 and 11 participants at 2 months and 6 months, respectively. Pre-illness patients were not cognitively impaired; one patient had delirium in ICU. The proportion of patients with CI ranged from 80% (17/18) while in hospital to 35% (5/14) at 6 months. Participants were challenged by fatigue and sleep disruption during recovery but were not particularly concerned about CI. CONCLUSIONS: Recruitment in ICU was challenging as few patients received prolonged mechanical ventilation. The protocol was feasible, but some attrition was noted. A significant proportion of patients had mild CI, largely confined to recall, and language cognitive domains; quantitative findings were supported by interview findings. Further investigations are required to ascertain the most appropriate inclusion criteria to enable identification of those at highest risk of CI.

Sepsis incidence and mortality are underestimated in Australian intensive care unit administrative data.

OBJECTIVES: To compare estimates of the incidence and mortality of sepsis and septic shock among patients in Australian intensive care units (ICUs) according to clinical diagnoses or binational intensive care database (ANZICS CORE) methodology. DESIGN, SETTING, PARTICIPANTS: Prospective inception cohort study (3-month inception period, 1 October - 31 December 2016, with 60-day follow-up); daily screening of all patients in a tertiary hospital 60-bed multidisciplinary ICU. MAIN OUTCOMES: Diagnoses of sepsis and septic shock according to clinical criteria and database criteria; in-hospital mortality (censored at 60 days). RESULTS: Of 864 patients admitted to the ICU, 146 (16.9%) were diagnosed with sepsis by clinical criteria and 98 (11%) according to the database definition (P < 0.001); the sensitivity of the database criteria for sepsis was 52%, the specificity 97%. Forty-nine patients (5.7%) were diagnosed with septic shock by clinical criteria and 83 patients (9.6%) with the database definition (P < 0.001); the sensitivity of the database criteria for septic shock was 65%, the specificity 94%. In-hospital mortality of patients diagnosed with sepsis was greater in the clinical diagnosis group (39/146, 27%) than in the database group (17/98, 17%; P = 0.12); for septic shock, mortality was significantly higher in the database group (18/49, 37%) than in the clinical diagnosis group (13/83, 16%; P = 0.006). CONCLUSIONS: When compared with the reference standard - prospective clinical diagnosis - ANZICS CORE database criteria significantly underestimate the incidence of sepsis and overestimate the incidence of septic shock, and also result in lower estimated hospital mortality rates for each condition.

Six-Month Outcomes After High-Risk Coronary Artery Bypass Graft Surgery and Preoperative Intra-aortic Balloon Counterpulsation Use: An Inception Cohort Study.

OBJECTIVE: To inform the design of a pivotal randomized controlled trial of prophylactic intra-aortic balloon counterpulsation (IABC) in patients undergoing coronary artery bypass graft (CABG) at high risk of postoperative low cardiac output syndrome (LCOS). DESIGN: Inception cohort study. SETTING: A total of 13 established cardiac centers in Australia, Canada, New Zealand, and the United Kingdom. PARTICIPANTS: Adult patients were eligible for inclusion if they were listed for CABG surgery and had 2 or more LCOS risk factors (low ejection fraction, severe left main coronary artery disease, redo sternotomy, unstable angina). INTERVENTIONS: Outcomes of interest were a composite outcome of in-hospital mortality, postoperative acute myocardial infarction (AMI), acute kidney injury (AKI), or stroke as well as 6-month vital status and quality of life using the EuroQol 5-dimensional questionnaire (EQ5D). MEASUREMENTS AND MAIN RESULTS: The study included 136 participants over a 29-month period. Overall, in-hospital and 6-month mortality occurred in 7 (5%) and 11 (8%) participants, respectively. The composite outcome occurred in 60 (44%). The mean increase in EQ5D summary index at 6 months was 0.10 (standard deviation 0.24, p = 0.01). Perioperative AMI, AKI, or stroke significantly decreased the odds of a clinically meaningful improvement in quality of life (odds ratio 0.32; 95% confidence interval 0.13-0.79; p = 0.014). Preoperative IABC was used in 39 participants and did not predict postoperative outcomes. CONCLUSIONS: The study identified a group of patients at risk of LCOS in whom CABG surgery was associated with a substantial burden of perioperative morbidity. Preoperative IABC use was variable, supporting the need for further research.

The incidence of ventriculostomy-related infections as diagnosed by 16S rRNA polymerase chain reaction: A prospective observational study.

BACKGROUND: Ventriculostomy-related infections (VRIs) are reported in about 10 % of patients with external ventricular drains (EVDs). VRIs are difficult to diagnose due to clinical and laboratory abnormalities caused by the primary neurological injury which led to insertion of the EVD. Polymerase chain reaction (PCR) of the cerebrospinal fluid (CSF) may enable more accurate diagnosis of VRI. We performed a prospective cohort study to measure the incidence of VRI as diagnosed by 16S rRNA PCR. METHODS: Patients admitted to intensive care with a primary diagnosis of subarachnoid haemorrhage (SAH), traumatic brain injury (TBI), or intracerebral haemorrhage (ICH), who required an EVD, were assessed for inclusion in this study. Data were extracted from the electronic medical record, bedside charts, or from a prospectively collected database, the Neuroscience Outcomes in Intensive CarE database (NOICE). 16S rRNA PCR was performed on routinely collected CSF as per laboratory protocol. VRI was also diagnosed based on pre-existing definitions. RESULTS: 237 CSF samples from 39 patients were enrolled in the study. The mean patient age was 55.7 years, and 56.4 % were female. The most common primary neurological diagnosis was SAH (61.5 %). The incidence of a positive PCR was 2.6 % of patients (1 in 39) and 0.8 % of CSF samples (2 in 237). The incidence of VRI according to pre-published diagnostic criteria was 2.6 % - 41 % of patients and 0.4 % - 17.6 % of CSF samples. 28.2 % of patients were treated for VRI. Pre-published definitions which relied on CSF culture results had higher specificity and lower false positive rates for predicting a PCR result when compared to definitions incorporating non-microbiological markers of VRI. In CSF samples with a negative 16S rRNA PCR, there was a high proportion of non-microbiological markers of infection, and a high incidence of fever on the day the CSF sample was taken. CONCLUSIONS: The incidence of VRI as defined as a positive PCR was lower than the incidence of VRI according to several published definitions, and lower than the incidence of VRI as defined as treatment by the clinical team. Non-microbiological markers of VRI may be less reliable than a positive CSF culture in diagnosing VRI.

A Pilot Study of the Adoption and Guardianship Enhanced Support (AGES) Program: Preventing Discontinuity by Walking Alongside Adoptive and Guardianship Families Who are Struggling.

PURPOSE: There is a strong preference for evidence-based child welfare services, however, there are few well-researched programs for families that struggle post-permanence. Following adoption or guardianship, some families experience significant challenges, struggle to find effective programs, and run the risk of family instability. This study described the process used to develop the Adoption and Guardianship Enhanced Support (AGES) intervention and explored: 1) the needs of families participating in the program and 2) how AGES worked with families to address those challenges. METHODS: This descriptive study utilized quantitative structured assessment data and qualitative data from case records to explore the needs of families and provide context for qualitative, in-depth interviews with families regarding their experiences with the AGES program, presented using thematic analysis. RESULTS: Pre-service structured assessments indicated multiple dimensions of parenting strain, with case record reviews and interviews with families providing a nuanced picture of multiple sources of strain, suggesting the project was reaching the intended audience. Record review and interviews demonstrated strong alignment between needs of families and the support provided by AGES workers. Intended analysis of quantitative post-assessment data was not possible, due to lower enrollment and higher staff turnover than expected, as well as study timeframes. DISCUSSION AND CONCLUSION: The approach utilized by AGES workers, one that walked alongside families and provided flexible responses to identified needs, showed promise for adoptive and guardianship families. Replication and additional research are needed to assess the program with a larger sample and more rigorous methods.

Early goal-directed sedation versus standard sedation in mechanically ventilated critically ill patients: a pilot study*.

OBJECTIVE: To assess the feasibility and safety of delivering early goal-directed sedation compared with standard sedation. DESIGN: Pilot prospective, multicenter, randomized, controlled trial. SETTING: Six ICUs. PATIENTS: Critically ill adults mechanically ventilated for greater than 24 hours. INTERVENTIONS: Patients randomized to early goal-directed sedation received a dexmedetomidine-based algorithm targeted to light sedation (Richmond Agitation Sedation Score of -2 to 1). Patients randomized to standard sedation received propofol and/or midazolam-based sedation as clinically appropriate. MEASUREMENTS AND MAIN RESULTS: The main feasibility outcomes were time to randomization and proportion of Richmond Agitation Sedation Score assessments in the first 48 hours in the light and deep sedation range. Safety outcomes were delirium-free days, vasopressor and physical restraints use, and device removal. Randomization occurred within a median (interquartile range) of 1.1 hours (0.46-1.9) after intubation or ICU admission for out of ICU intubation. Patients in the early goal-directed sedation (n = 21) mean (SD) Acute Physiology and Chronic Health Evaluation II score was 20.2 (6.2) versus 18.6 (8.8; p = 0.53) in the standard sedation (n = 16). A significantly higher proportion of patients was lightly sedated on days 1, 2, and 3 (12/19 [63.2%], 19/21 [90.5%], and 18/20 [90%] vs 2/14 [14.3%], 8/15 [53.3%], and 9/15 [60%]; p = 0.005, 0.011, 0.036) and more Richmond Agitation Sedation Scale assessments between (-2 and 1), in the first 48 hours (203/307 [66%] versus (74/197 [38%]; p = 0.01) in the early goal-directed sedation versus standard sedation, respectively. Early goal-directed sedation patients received midazolam on 6 of 173 (3.5%) versus 4 of 114 (3.5%) standard sedation patient-days when dexmedetomidine was given. Propofol was given to 16 of 21 (76%) of early goal-directed sedation versus 16 of 16 (100%) of standard sedation patients (p = 0.04). Early goal-directed sedation patients had 101 of 175 (58%) versus 54 of 114 (47%; p = 0.27) delirium-free days and required significantly less physical restraints 1 (5%) versus 5 (31%; p = 0.03) than standard sedation patients. There were no differences in vasopressor use and self-extubation. CONCLUSIONS: Delivery of early goal-directed sedation was feasible, appeared safe, achieved early light sedation, minimized benzodiazepines and propofol, and decreased the need for physical restraints. The findings of this pilot study justify further investigation of early goal-directed sedation.

Early intensive care sedation predicts long-term mortality in ventilated critically ill patients.

RATIONALE: Choice and intensity of early (first 48 h) sedation may affect short- and long-term outcome. OBJECTIVES: To investigate the relationships between early sedation and time to extubation, delirium, and hospital and 180-day mortality among ventilated critically ill patients in the intensive care unit (ICU). METHODS: Multicenter (25 Australia and New Zealand hospitals) prospective longitudinal (ICU admission to 28 d) cohort study of medical/surgical patients ventilated and sedated 24 hours or more. We assessed administration of sedative agents, ventilation time, sedation depth using Richmond Agitation Sedation Scale (RASS, four hourly), delirium (daily), and hospital and 180-day mortality. We used multivariable Cox regression to quantify relationships between early deep sedation (RASS, -3 to -5) and patients' outcomes. MEASUREMENTS AND MAIN RESULTS: We studied 251 patients (mean age, 61.7 ± 15.9 yr; mean Acute Physiology and Chronic Health Evaluation [APACHE] II score, 20.8 ± 7.8), with 21.1% (53) hospital and 25.8% (64) 180-day mortality. Over 2,678 study days, we completed 14,736 RASS assessments. Deep sedation occurred in 191 (76.1%) patients within 4 hours of commencing ventilation and in 171 (68%) patients at 48 hours. Delirium occurred in 111 (50.7%) patients with median (interquartile range) duration of 2 (1-4) days. After adjusting for diagnosis, age, sex, APACHE II, operative, elective, hospital type, early use of vasopressors, and dialysis, early deep sedation was an independent predictor of time to extubation (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.87-0.94; P < 0.001), hospital death (HR, 1.11; 95% CI, 1.02-1.20; P = 0.01), and 180-day mortality (HR, 1.08; 95% CI, 1.01-1.16; P = 0.026) but not delirium occurring after 48 hours (P = 0.19). CONCLUSIONS: Early sedation depth independently predicts delayed extubation and increased mortality, making it a potential target for interventional studies.

Acute assessment of spinal cord injury in New South Wales: A retrospective study of current practice in two spinal cord injury referral centers.

INTRODUCTION: Interventions provided in the early phases after spinal cord injury (SCI) may improve neurological recovery and provide for best possible functional outcomes. Knowing this relies on early and clear documentation of the level and grade of the spinal cord injury. Guidelines advocate for early documentation of neurological status within 72 h of injury to allow early prognostication and to help guide initial management. It is unclear whether this is current practice in New South Wales (NSW). METHODS: Patients with acute SCI who were admitted to two SCI referral centers during 2018-2019 in NSW were included. Data relating to documentation of neurological status, timing of imaging, surgery and transfer to spinal cord injury center were collected and summarized using descriptive statistics. RESULTS: Only 18 percent of patients had an acceptable neurological examination according to the International Standards for Classification of Spinal Cord Injury (ISNCSCI) within 72 h of injury (either not done, or unable to determine the neurological level of injury). At the first neurological examination, the neurological level of injury and grade was unable to be determined in 26.8% of patients and 29.9% of patients respectively. At discharge from acute care and transfer to rehabilitation, the neurological level was undetermined in 28.9% of patients and grade undetermined in 26.8%. ISNCSCI examination was most commonly performed by spinal rehabilitation doctors after patients were discharged from the intensive care unit (ICU). CONCLUSIONS: Documentation of neurological level and grade of SCI within 72 h of injury is not being performed in the large majority of this cohort, which may impede evaluation of neurological improvement in response to acute treatment, and hinder prognostication.

Effects of Hypothermia vs Normothermia on Societal Participation and Cognitive Function at 6 Months in Survivors After Out-of-Hospital Cardiac Arrest: A Predefined Analysis of the TTM2 Randomized Clinical Trial.

Importance: The Targeted Hypothermia vs Targeted Normothermia After Out-of-Hospital Cardiac Arrest (TTM2) trial reported no difference in mortality or poor functional outcome at 6 months after out-of-hospital cardiac arrest (OHCA). This predefined exploratory analysis provides more detailed estimation of brain dysfunction for the comparison of the 2 intervention regimens. Objectives: To investigate the effects of targeted hypothermia vs targeted normothermia on functional outcome with focus on societal participation and cognitive function in survivors 6 months after OHCA. Design, Setting, and Participants: This study is a predefined analysis of an international multicenter, randomized clinical trial that took place from November 2017 to January 2020 and included participants at 61 hospitals in 14 countries. A structured follow-up for survivors performed at 6 months was by masked outcome assessors. The last follow-up took place in October 2020. Participants included 1861 adult (older than 18 years) patients with OHCA who were comatose at hospital admission. At 6 months, 939 of 1861 were alive and invited to a follow-up, of which 103 of 939 declined or were missing. Interventions: Randomization 1:1 to temperature control with targeted hypothermia at 33 °C or targeted normothermia and early treatment of fever (37.8 °C or higher). Main outcomes and measures: Functional outcome focusing on societal participation assessed by the Glasgow Outcome Scale Extended ([GOSE] 1 to 8) and cognitive function assessed by the Montreal Cognitive Assessment ([MoCA] 0 to 30) and the Symbol Digit Modalities Test ([SDMT] z scores). Higher scores represent better outcomes. Results: At 6 months, 836 of 939 survivors with a mean age of 60 (SD, 13) (range, 18 to 88) years (700 of 836 male [84%]) participated in the follow-up. There were no differences between the 2 intervention groups in functional outcome focusing on societal participation (GOSE score, odds ratio, 0.91; 95% CI, 0.71-1.17; P = .46) or in cognitive function by MoCA (mean difference, 0.36; 95% CI,-0.33 to 1.05; P = .37) and SDMT (mean difference, 0.06; 95% CI,-0.16 to 0.27; P = .62). Limitations in societal participation (GOSE score less than 7) were common regardless of intervention (hypothermia, 178 of 415 [43%]; normothermia, 168 of 419 [40%]). Cognitive impairment was identified in 353 of 599 survivors (59%). Conclusions: In this predefined analysis of comatose patients after OHCA, hypothermia did not lead to better functional outcome assessed with a focus on societal participation and cognitive function than management with normothermia. At 6 months, many survivors had not regained their pre-arrest activities and roles, and mild cognitive dysfunction was common. Trial Registration: ClinicalTrials.gov Identifier: NCT02908308.

Early sedation with dexmedetomidine in ventilated critically ill patients and heterogeneity of treatment effect in the SPICE III randomised controlled trial.

PURPOSE: To quantify potential heterogeneity of treatment effect (HTE), of early sedation with dexmedetomidine (DEX) compared with usual care, and identify patients who have a high probability of lower or higher 90-day mortality according to age, and other identified clusters. METHODS: Bayesian analysis of 3904 critically ill adult patients expected to receive invasive ventilation > 24 h and enrolled in a multinational randomized controlled trial comparing early DEX with usual care sedation. RESULTS: HTE was assessed according to age and clusters (based on 12 baseline characteristics) using a Bayesian hierarchical models. DEX was associated with lower 90-day mortality compared to usual care in patients > 65 years (odds ratio [OR], 0.83 [95% credible interval [CrI] 0.68-1.00], with 97.7% probability of reduced mortality across broad categories of illness severity. Conversely, the probability of increased mortality in patients ≤ 65 years was 98.5% (OR 1.26 [95% CrI 1.02-1.56]. Two clusters were identified: cluster 1 (976 patients) mostly operative, and cluster 2 (2346 patients), predominantly non-operative. There was a greater probability of benefit with DEX in cluster 1 (OR 0.86 [95% CrI 0.65-1.14]) across broad categories of age, with 86.4% probability that DEX is more beneficial in cluster 1 than cluster 2. CONCLUSION: In critically ill mechanically ventilated patients, early sedation with dexmedetomidine exhibited a high probability of reduced 90-day mortality in older patients regardless of operative or non-operative cluster status. Conversely, a high probability of increased 90-day mortality was observed in younger patients of non-operative status. Further studies are needed to confirm these findings.

Prevalence of delirium with dexmedetomidine compared with morphine based therapy after cardiac surgery: a randomized controlled trial (DEXmedetomidine COmpared to Morphine-DEXCOM Study).

BACKGROUND: Commonly used sedatives/analgesics can increase the risk of postoperative complications, including delirium. This double-blinded study assessed the neurobehavioral, hemodynamic, and sedative characteristics of dexmedetomidine compared with morphine-based regimen after cardiac surgery at equivalent levels of sedation and analgesia. METHODS: A total of 306 patients at least 60 yr old were randomized to receive dexmedetomidine (0.1-0.7 microg x kg(-1) x h(-1)) or morphine (10-70 microg x kg(-1) x h(-1)) with open-label propofol titrated to a target Motor Activity Assessment Scale of 2-4. Primary outcome was the prevalence of delirium measured daily via Confusion Assessment Method for intensive care. Secondary outcomes included ventilation time, additional sedation/analgesia, and hemodynamic and adverse effects. RESULTS: Of all sedation assessments, 75.2% of dexmedetomidine and 79.6% (P = 0.516) of morphine treatment were in the target range. Delirium incidence was comparable between dexmedetomidine 13 (8.6%) and morphine 22 (15.0%) (relative risk 0.571, 95% confidence interval [CI] 0.256-1.099, P = 0.088), however, dexmedetomidine-managed patients spent 3 fewer days (2 [1-7] versus 5 [2-12]) in delirium (95% CI 1.09-6.67, P = 0.0317). The incidence of delirium was significantly less in a small subgroup requiring intraaortic balloon pump and treated with dexmedetomidine (3 of 20 [15%] versus 9 of 25 [36%]) (relative risk 0.416, 95% CI 0.152-0.637, P = 0.001). Dexmedetomidine-treated patients were more likely to be extubated earlier (relative risk 1.27, 95% CI 1.01-1.60, P = 0.040, log-rank P = 0.036), experienced less systolic hypotension (23% versus 38.1%, P = 0.006), required less norepinephrine (P < 0.001), but had more bradycardia (16.45% versus 6.12%, P = 0.006) than morphine treatment. CONCLUSION: Dexmedetomidine reduced the duration but not the incidence of delirium after cardiac surgery with effective analgesia/sedation, less hypotension, less vasopressor requirement, and more bradycardia versus morphine regimen.

Randomised evaluation of active control of temperature versus ordinary temperature management (REACTOR) trial.

PURPOSE: It is unknown whether protocols targeting systematic prevention and treatment of fever achieve lower mean body temperature than usual care in intensive care unit (ICU) patients. The objective of the Randomised Evaluation of Active Control of temperature vs. ORdinary temperature management trial was to confirm the feasibility of such a protocol with a view to conducting a larger trial. METHODS: We randomly assigned 184 adults without acute brain pathologies who had a fever in the previous 12 h, and were expected to be ventilated beyond the calendar day after recruitment, to systematic prevention and treatment of fever or usual care. The primary outcome was mean body temperature in the ICU within 7 days of randomisation. Secondary outcomes included in-hospital mortality, ICU-free days and survival time censored at hospital discharge. RESULTS: Compared with usual temperature management, active management significantly reduced mean temperature. In both groups, fever generally abated within 72 h. The mean temperature difference between groups was greatest in the first 48 h, when it was generally in the order of 0.5 °C. Overall, 23 of 89 patients assigned to active management (25.8%) and 23 of 89 patients assigned to usual management (25.8%) died in hospital (odds ratio 1.0, 95% CI 0.51-1.96, P = 1.0). There were no statistically significant differences between groups in ICU-free days or survival to day 90. CONCLUSIONS: Active temperature management reduced body temperature compared with usual care; however, fever abated rapidly, even in patients assigned to usual care, and the magnitude of temperature separation was small. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry Number, ACTRN12616001285448.

Internet health information use by surrogate decision makers of patients admitted to the intensive care unit: a multicentre survey.

OBJECTIVES: To investigate the use, understanding, trust and influence of the internet and other sources of health information used by the next of kin (NOK) of patients admitted to the intensive care unit (ICU). DESIGN: Multicentre structured survey. SETTING: The ICUs of 13 public and private Australian hospitals. PARTICIPANTS: NOK who self-identified as the primary surrogate decision maker for a patient admitted to the ICU. MAIN OUTCOME MEASURES: The frequency, understanding, trust and influence of online sources of health information, and the quality of health websites visited using the Health on the Net Foundation Code of Conduct (HONcode) for medical and health websites. RESULTS: There were 473 survey responses. The median ICU admission days and number of ICU visits by the NOK at the time of completing the survey was 3 (IQR, 2-6 days) and 4 (IQR, 2-7), respectively. The most commonly reported sources of health information used very frequently were the ICU nurse (55.6%), ICU doctor (38.7%), family (23.3%), hospital doctor (21.4%), and the internet (11.3%). Compared with the 243 NOK (51.6%) not using the internet, NOK using the internet were less likely to report complete understanding (odds ratio [OR], 0.57; 95% CI, 0.38-0.88), trust (OR, 0.34; 95% CI, 0.19-0.59), or influence (OR, 0.58; 95% CI, 0.38-0.88) associated with the ICU doctor. Overall, the quality of the 40 different reported websites accessed was moderately high. CONCLUSIONS: A substantial proportion of ICU NOK report using the internet as a source of health information. Internet use is associated with lower reported understanding, trust and influence of the ICU doctor.

Considerations for co-enrolment in randomised controlled effectiveness trials in critical care: the SPICE-8 co-enrolment guidelines.

The Australian and New Zealand Intensive Care Society Clinical Trials Group and other investigator-led trials groups in critical care publish policies and guidelines outlining the rationale for considering co-enrolment in large, randomised controlled trials in intensive care medicine. However, none present a checklist of criteria by which a request for permission to co-enrol in an existing trial can be assessed. Consequently, such requests tend to be made and assessed on an ad hoc basis. Based on our experience in the SPICE III randomised controlled trial, we propose eight broadly applicable criteria (the SPICE-8 criteria) to be satisfied before co-enrolment should be approved. Reporting co-enrolment in trials, for regulatory purposes and in publications, is uncommon, partly because of the complexity involved in explaining a lack of a plausible coenrolment effect. We suggest that noting compliance with these criteria would simplify such reporting and enhance transparency.

The SPICE III study protocol and analysis plan: a randomised trial of early goaldirected sedation compared with standard care in mechanically ventilated patients.

BACKGROUND: Sedation strategy in critically ill patients who are mechanically ventilated is influenced by patient-related factors, choice of sedative agent and the intensity or depth of sedation prescribed. The impact of sedation strategy on outcome, in particular when delivered early after initiation of mechanical ventilation, is uncertain. OBJECTIVES: To present the protocol and analysis plan of a large randomised clinical trial investigating the effect of a sedation strategy, in critically ill patients who are mechanically ventilated, based on a protocol targeting light sedation using dexmedetomidine as the primary sedative, termed "early goal-directed sedation", compared with usual practice. METHODS: This is a multinational randomised clinical trial in adult intensive care patients expected to require mechanical ventilation for longer than 24 hours. The main exclusion criteria include suspected or proven primary brain pathology or having already been intubated or sedated in an intensive care unit for longer than 12 hours. Randomisation occurs via a secured website with baseline stratification by site and suspected or proven sepsis. The primary outcome is 90-day all-cause mortality. Secondary outcomes include death, institutional dependency, cognitive function and health-related quality of life 180 days after randomisation, as well as deliriumfree, coma-free and ventilation-free days at 28 days after randomisation. A predefined subgroup analysis will also be conducted. Analyses will be on an intention-to-treat basis and in accordance with this pre-specified analysis plan. CONCLUSION: SPICE III is an ongoing large scale clinical trial. Once completed, it will inform sedation practice in critically ill patients who are ventilated.