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).

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.

The cost-effectiveness of early goal-directed therapy: an economic evaluation alongside the ARISE trial.

Objective: To determine the cost-effectiveness of early goal-directed therapy (EGDT) for patients with early septic shock. Design: Within-trial cost-effectiveness evaluation. Setting: Nineteen hospitals in Australia and New Zealand. Participants and interventions: Patients with early septic shock enrolled in the Australasian Resuscitation in Sepsis Evaluation (ARISE) trial were randomly assigned to EGDT versus usual care. A subgroup of patients participated in a nested economic evaluation study in which detailed resource use data were collected until 12 months after randomisation. Outcome measures: Clinical outcomes included lives saved, life-years gained and quality-adjusted life-years (QALYs), with mortality collected until 12 months and health-related quality of life assessed at baseline, 6 and 12 months using the 3-level EuroQol five dimensions questionnaire (EQ-5D-3L). Economic outcomes included health care resource use, costs and cost-effectiveness from the Australian health care payer perspective. Results: A total of 205 patients (100 EGDT, 105 usual care) participated in the nested economic evaluation study, of which 203 had complete resource use data. Unadjusted mean health care costs to 12 months were $67 223 (standard deviation [SD], $72 397) in the EGDT group and $54 179 (SD, $61 980) in the usual care group, with a mean difference of $13 044 (95% CI, -$5791 to $31 878). There was no difference between groups with regards to lives saved (EGDT, 69.4% v usual care, 68.6%; P = 1.0), life-years gained (mean EGDT, 0.746 [SD, 0.406] v usual care, 0.725 [SD, 0.417]; P = 0.72) or QALYs (mean EGDT, 0.318 [SD, 0.291] v usual care, 0.367 [SD, 0.295]; P = 0.24). EGDT was dominated (higher costs, lower effectiveness) by usual care in 80.4% of bootstrap replications. For a willingness-to-pay threshold of $50 000 per QALY, the probability of EGDT being cost-effective was only 6.4%. Conclusions: In patients presenting to the emergency department with early septic shock, EGDT compared with usual care was not cost-effective. Clinical trial registration:ClinicalTrials.gov number NCT00975793.

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.).

Quality of Life and 1-Year Survival in Patients With Early Septic Shock: Long-Term Follow-Up of the Australasian Resuscitation in Sepsis Evaluation Trial.

OBJECTIVES: To examine long-term survival and quality of life of patients with early septic shock. DESIGN: Prospective, randomized, parallel-group trial. SETTING: Fifty-one hospitals in Australia, New Zealand, Finland, Hong Kong, and the Republic of Ireland. PATIENTS: One-thousand five-hundred ninety-one patients who presented to the emergency department with early septic shock between October 2008 and April 2014, and were enrolled in the Australasian Resuscitation in Sepsis Evaluation trial. INTERVENTIONS: Early goal-directed therapy versus usual care. MEASUREMENTS AND MAIN RESULTS: Long-term survival was measured up to 12 months postrandomization. Health-related quality of life was measured using the EuroQoL-5D-3L, Short Form 36 and Assessment of Quality of Life 4D at baseline, and at 6 and 12 months following randomization. Mortality data were available for 1,548 patients (97.3%) and 1,515 patients (95.2%) at 6 and 12 months, respectively. Health-related quality of life data were available for 85.1% of survivors at 12 months. There were no significant differences in mortality between groups at either 6 months (early goal-directed therapy 21.8% vs usual care 22.6%; p = 0.70) or 12 months (early goal-directed therapy 26.4% vs usual care 27.9%; p = 0.50). There were no group differences in health-related quality of life at either 6 or 12 months (EuroQoL-5D-3L utility scores at 12 mo early goal-directed therapy 0.65 ± 0.33 vs usual care 0.64 ± 0.34; p = 0.50), with the health-related quality of life of both groups being significantly lower than population norms. CONCLUSIONS: In patients presenting to the emergency department with early septic shock, early goal-directed therapy compared with usual care did not reduce mortality nor improve health-related quality of life at either 6 or 12 months.

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.

Goal-directed resuscitation for patients with early septic shock.

BACKGROUND: Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock. However, its effectiveness is uncertain. METHODS: In this trial conducted at 51 centers (mostly in Australia or New Zealand), we randomly assigned patients presenting to the emergency department with early septic shock to receive either EGDT or usual care. The primary outcome was all-cause mortality within 90 days after randomization. RESULTS: Of the 1600 enrolled patients, 796 were assigned to the EGDT group and 804 to the usual-care group. Primary outcome data were available for more than 99% of the patients. Patients in the EGDT group received a larger mean (±SD) volume of intravenous fluids in the first 6 hours after randomization than did those in the usual-care group (1964±1415 ml vs. 1713±1401 ml) and were more likely to receive vasopressor infusions (66.6% vs. 57.8%), red-cell transfusions (13.6% vs. 7.0%), and dobutamine (15.4% vs. 2.6%) (P<0.001 for all comparisons). At 90 days after randomization, 147 deaths had occurred in the EGDT group and 150 had occurred in the usual-care group, for rates of death of 18.6% and 18.8%, respectively (absolute risk difference with EGDT vs. usual care, -0.3 percentage points; 95% confidence interval, -4.1 to 3.6; P=0.90). There was no significant difference in survival time, in-hospital mortality, duration of organ support, or length of hospital stay. CONCLUSIONS: In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days. (Funded by the National Health and Medical Research Council of Australia and the Alfred Foundation; ARISE ClinicalTrials.gov number, NCT00975793.).

Pandemic H1N1 in children requiring intensive care in Australia and New Zealand during winter 2009.

OBJECTIVE: To describe in detail the pediatric intensive care experience of influenza A, particularly pandemic H1N1-09, in Australia and New Zealand during the 2009 Southern Hemisphere winter and to compare the pediatric experience with that of adults. METHOD: This was an inception-cohort study of all children who were admitted to intensive care with confirmed influenza A during winter 2009 at all general ICUs and PICUs in Australia and New Zealand. RESULTS: From June 1 through August 31, 2009, 107 children (20.0 per million [95% confidence interval: 16.1-23.8]) with influenza A, including 83 (15.5 per million [95% confidence interval: 12.1-18.9]) with H1N1-09 were admitted to ICUs. Fifty-two percent (39 of 75) of children with H1N1-09 had 1 or more comorbidity, most commonly neurologic (20%). Most (48 of 83 [58%]) presented with pneumonia. Thirteen of 83 (16%) had neurologic presentations. Eighty percent of the children with H1N1-09 required ventilation. Mortality was lower than in adults: 6 of 83 (7%) vs 114 of 668 (17%) (P = .02). The median length of stay for children with H1N1-09 was 5 days. Children with H1N1-09 occupied 773 bed-days (147 per million children) and 5.8% of specialist PICU beds. Presentation with septic shock or after cardiac arrest and the presence of 1 or more comorbidities were risk factors for severe disease. CONCLUSIONS: H1N1-09 caused a substantial burden on pediatric intensive care services in Australia and New Zealand. Compared with adults, children more commonly had nonrespiratory presentations and required ventilation more often but had a lower mortality rate.