Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Shehabi Y

PROVIDER: S-EPMC7939103 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Shehabi Yahya Y Serpa Neto Ary A Howe Belinda D BD Bellomo Rinaldo R Arabi Yaseen M YM Bailey Michael M Bass Frances E FE Kadiman Suhaini Bin SB McArthur Colin J CJ Reade Michael C MC Seppelt Ian M IM Takala Jukka J Wise Matt P MP Webb Steve A SA

Intensive care medicine 20210308 4

<h4>Purpose</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 33686482

Similar Datasets

Project description:IntroductionSleep deprivation, which is a common complication in the intensive care unit (ICU), is associated with delirium and increased mortality. Sedation with gamma-aminobutyric acid agonists (propofol, benzodiazepine) results in significant disturbance of the sleep architecture. Dexmedetomidine is a lipophilic imidazole with an affinity for α2-adrenoceptors and it has sedative and analgesic properties. It has been reported to enhance sleep efficiency, thus sedate while preserving sleep architecture.Methods and analysisThirty consecutive patients are planned to be included, at the Department of Anesthesia and Intensive Care at the Hospital of Southwest Jutland, Denmark. The study is a double-blinded, randomised, controlled trial with two parallel groups (2:1 allocation ratio). Screening and inclusion will be done on day 1 from 8:00 to 16:00. Two 16 hours PSG (polysomnography) recording will be done starting at 16:00 on day 1 and day 2. Randomisation is performed if the first recording is of acceptable quality, otherwise the patient is excluded before randomisation. Dexmedetomidine/placebo will be administered during the second recording from 18:00 on day 2 to 6:00 on day 3.Primary endpointImprovement of total sleep time and sleep quality of clinical significance determined by PSG.Secondary endpointsSleep phases determined by PSG. Daytime function and delirium determined by Confusion Assessment Method-ICU. Alertness and wakefulness determined by Richmonde Agitation Sedation Scale. The objective is to compare the effect of dexmedetomidine versus placebo on sleep quality in critical ill mechanically ventilated patients.Ethics and disseminationThe trial investigate the potential benefit of dexmedetomidine on clinically relevant endpoints. If a beneficial effect is shown, this would have a large impact on future treatment of mechanically ventilated critically ill patients. Publication in peer-reviewed journal are plannedand the study has been approved by the National Committee on Health Research Ethics (ID:S-20180214).Trial registration numberEudraCT (2017-001612-11DK) and Danish National Committee on Health Research Ethics (ID:S-20180214). The study related to pre-results.

Project description:BackgroundLong-term complications of critical illness include intensive care unit (ICU)-acquired weakness and neuropsychiatric disease. Immobilisation secondary to sedation might potentiate these problems. We assessed the efficacy of combining daily interruption of sedation with physical and occupational therapy on functional outcomes in patients receiving mechanical ventilation in intensive care.MethodsSedated adults (>/=18 years of age) in the ICU who had been on mechanical ventilation for less than 72 h, were expected to continue for at least 24 h, and who met criteria for baseline functional independence were eligible for enrolment in this randomised controlled trial at two university hospitals. We randomly assigned 104 patients by computer-generated, permuted block randomisation to early exercise and mobilisation (physical and occupational therapy) during periods of daily interruption of sedation (intervention; n=49) or to daily interruption of sedation with therapy as ordered by the primary care team (control; n=55). The primary endpoint-the number of patients returning to independent functional status at hospital discharge-was defined as the ability to perform six activities of daily living and the ability to walk independently. Therapists who undertook patient assessments were blinded to treatment assignment. Secondary endpoints included duration of delirium and ventilator-free days during the first 28 days of hospital stay. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00322010.FindingsAll 104 patients were included in the analysis. Return to independent functional status at hospital discharge occurred in 29 (59%) patients in the intervention group compared with 19 (35%) patients in the control group (p=0.02; odds ratio 2.7 [95% CI 1.2-6.1]). Patients in the intervention group had shorter duration of delirium (median 2.0 days, IQR 0.0-6.0 vs 4.0 days, 2.0-8.0; p=0.02), and more ventilator-free days (23.5 days, 7.4-25.6 vs 21.1 days, 0.0-23.8; p=0.05) during the 28-day follow-up period than did controls. There was one serious adverse event in 498 therapy sessions (desaturation less than 80%). Discontinuation of therapy as a result of patient instability occurred in 19 (4%) of all sessions, most commonly for perceived patient-ventilator asynchrony.InterpretationA strategy for whole-body rehabilitation-consisting of interruption of sedation and physical and occupational therapy in the earliest days of critical illness-was safe and well tolerated, and resulted in better functional outcomes at hospital discharge, a shorter duration of delirium, and more ventilator-free days compared with standard care.FundingNone.

Project description:BACKGROUND:Daily sedative interruption and intermittent sedation are effective in abbreviating the time on mechanical ventilation. Whether one is superior to the other has not yet been determined. Our aim was to compare daily interruption and intermittent sedation during the mechanical ventilation period in a low nurse staffing ICU. METHODS:Adult patients expected to need mechanical ventilation for more than 24 hours were randomly assigned, in a single center, either to daily interruption of continuous sedative and opioid infusion or to intermittent sedation. In both cases, our goal was to maintain a Sedation Agitation Scale (SAS) level of 3 or 4; that is patients should be calm, easily arousable or awakened with verbal stimuli or gentle shaking. Primary outcome was ventilator-free days in 28 days. Secondary outcomes were ICU and hospital mortality, incidence of delirium, nurse workload, self-extubation and psychological distress six months after ICU discharge. RESULTS:A total of 60 patients were included. There were no differences in the ventilator-free days in 28 days between daily interruption and intermittent sedation (median: 24 versus 25 days, P?=?0.160). There were also no differences in ICU mortality (40 versus 23.3%, P?=?0.165), hospital mortality (43.3 versus 30%, P?=?0.284), incidence of delirium (30 versus 40%, P?=?0.472), self-extubation (3.3 versus 6.7%, P?=?0.514), and psychological stress six months after ICU discharge. Also, the nurse workload was not different between groups, but it was reduced on day 5 compared to day 1 in both groups (Nurse Activity Score (NAS) in the intermittent sedation group was 54 on day 1 versus 39 on day 5, P?<?0.001; NAS in daily interruption group was 53 on day 1 versus 38 on day 5, P?<?0.001). Fentanyl and midazolam total dosages per patient were higher in the daily interruption group. The tidal volume was higher in the intermittent sedation group during the first five days of ICU stay. CONCLUSIONS:There was no difference in the number of ventilator-free days in 28 days between both groups. Intermittent sedation was associated with lower sedative and opioid doses. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT00824239.

Project description:IntroductionDeep sedation is associated with adverse patient outcomes. We recently described a novel sedation-monitoring technology, the Responsiveness Index (RI), which quantifies patient arousal using processed frontal facial EMG data. We explored the potential effectiveness and safety of continuous RI monitoring during early intensive care unit (ICU) care as a nurse decision-support tool.MethodsIn a parallel-group controlled single centre proof of concept trial, patients requiring mechanical ventilation and sedation were randomized via sequential sealed envelopes following ICU admission. Control group patients received hourly clinical sedation assessment and daily sedation holds; the RI monitor was connected but data were concealed from clinical staff. The intervention group received control group care, but RI monitoring was visible and nurses were asked to adjust sedation to maintain patients with an RI>20 whenever possible. Traffic-light colour coding (RI<20, Red; 20-40, Amber; >40, Green) simplified decision-making. The intervention lasted up to 48 hours. Sixteen nurses were interviewed to explore their views of the novel technology.ResultsWe analysed 74 patients treated per protocol (36 intervention; 38 control). The proportion of patients with RI<20 was identical at the start of monitoring (54% both groups). Overall, the proportion of time with RI<20 trended to lower values for the intervention group (median 16% (1-3rd quartile 8-30%) versus 33% (10-54%); P = 0.08); sedation and analgesic use was similar. A post hoc analysis restricted to patients with RI<20 when monitoring started, found intervention patients spent less time with low RI value (16% (11-45%) versus 51% (33-72%); P = 0.02), cumulative propofol use trended to lower values (median 1090 mg versus 2390 mg; P = 0.14), and cumulative alfentanil use was lower (21.2 mg versus 32.3 mg; P = 0.01). RASS scores were similar for both groups. Sedation related adverse event rates were similar (7/36 versus 5/38). Similar proportions of patients had sedation holds (83% versus 87 %) and were extubated (47% versus 44%) during the intervention period. Nurses valued the objective visible data trends and simple colour prompts, and found RI monitoring a useful adjunct to existing practice.ConclusionsRI monitoring was safe and acceptable. Data suggested potential to modify sedation decision-making. Larger trials are justified to explore effects on patient-centred outcomes.Trial registrationNCT01361230 (registered April 19, 2010).

Project description:IntroductionNeuromuscular weakness resulting in severe functional impairment is common in critical care survivors. This study aimed to evaluate effects of an early progressive rehabilitation intervention in mechanically ventilated adults at risk.MethodsThis was a parallel, two-arm, assessor-blinded, randomised controlled trial with 6-months follow-up that was conducted in a mixed ICU of an academic centre in Switzerland. Previously independent, mechanically ventilated, critically ill adults with expected critical care stay ≥72 hours (n = 115) were randomised to a control group receiving standard physiotherapy including early mobilisation or to an experimental group with early endurance and resistance training combined with mobilisation. Primary endpoints were functional capacity (6-Minute Walk Distance) and functional independence (Functional Independence Measure) at hospital discharge. Secondary endpoints including muscle strength were assessed at critical care discharge. Safety was monitored closely by standard monitoring and predefined adverse events.ResultsPhysiotherapy started within 48 hours of critical care admission while 97% of participants were still ventilated and 68% on inotropes. Compared to the control group (n = 57), the experimental group (n = 58) received significantly more physiotherapy (sessions: 407 vs 377, p<0.001; time/session: 25min vs 18min, p<0.001) and had less days with sedation (p<0.001). Adverse events were rare (0.6%) and without consequences. There were no significant between-group differences in 6-Minute Walk Distance (experimental 123m (IQR 25-280) vs control 100m (IQR 0-300); p = 0.542) or functional independence (98 (IQR 66-119) vs 98 (IQR 18-115); p = 0.308). Likewise, no differences were found for the secondary outcomes, except a trend towards improved mental health in the experimental group after 6 months (84 (IQR 68-88) vs 70 (IQR 64-76); p = 0.023).ConclusionsEarly endurance and resistance training in mechanically ventilated, intensive care patients does not improve functional capacity or independence at hospital discharge compared to early standard physiotherapy but may improve mental health 6-months after critical care discharge.Trial registrationGerman Clinical Trials Register (DRKS): DRKS00004347, registered on 10 September 2012.

Project description:BackgroundsKetamine possesses analgesia, anti-inflammation, anticonvulsant, and neuroprotection properties. However, the evidence that supports its use in mechanically ventilated critically ill patients with COVID-19 is insufficient. The study's goal was to assess ketamine's effectiveness and safety in critically ill, mechanically ventilated (MV) patients with COVID-19.MethodsAdult critically ill patients with COVID-19 were included in a multicenter retrospective-prospective cohort study. Patients admitted between March 1, 2020, and July 31, 2021, to five ICUs in Saudi Arabia were included. Eligible patients who required MV within 24 hours of ICU admission were divided into two sub-cohort groups based on their use of ketamine (Control vs. Ketamine). The primary outcome was the length of stay (LOS) in the hospital. P/F ratio differences, lactic acid normalization, MV duration, and mortality were considered secondary outcomes. Propensity score (PS) matching was used (1:2 ratio) based on the selected criteria.ResultsIn total, 1,130 patients met the eligibility criteria. Among these, 1036 patients (91.7 %) were in the control group, whereas 94 patients (8.3 %) received ketamine. The total number of patients after PS matching, was 264 patients, including 88 patients (33.3 %) who received ketamine. The ketamine group's LOS was significantly lower (beta coefficient (95 % CI): -0.26 (-0.45, -0.07), P = 0.008). Furthermore, the PaO2/FiO2 ratio significantly improved 24 hours after the start of ketamine treatment compared to the pre-treatment period (6 hours) (124.9 (92.1, 184.5) vs. 106 (73.1, 129.3; P = 0.002). Additionally, the ketamine group had a substantially shorter mean time for lactic acid normalization (beta coefficient (95 % CI): -1.55 (-2.42, -0.69), P 0.01). However, there were no significant differences in the duration of MV or mortality.ConclusionsKetamine-based sedation was associated with lower hospital LOS and faster lactic acid normalization but no mortality benefits in critically ill patients with COVID-19. Thus, larger prospective studies are recommended to assess the safety and effectiveness of ketamine as a sedative in critically ill adult patients.

Project description:ObjectiveKetamine has been shown to decrease sedative requirements in intensive care unit (ICU). Randomized trials are limited on patient-centered outcomes. We designed this pilot trial to evaluate the feasibility of a large randomized controlled trial (RCT) testing the effect of ketamine as an adjunct analgosedative compared with standard of care alone as a control group (CG) in critically ill patients with mechanical ventilation (MV). We also provided preliminary evidence on clinically relevant outcomes to plan a larger trial.Material and methodsPilot, active-controlled, open-label RCT was conducted at medical, surgical, and transplant ICUs at a large tertiary and quaternary care medical institution (King Faisal Specialist Hospital and Research Center, Saudi Arabia). The study included adult patients who were intubated within 24 h, expected to require MV for the next calendar day, and had institutional pain and sedation protocol initiated. Patients were randomized in a 1:1 ratio to adjunct ketamine infusion 1-2 μg/kg/min for 48 h or CG alone.ResultsOf 437 patients screened from September 2019 through November 2020, 83 (18.9%) patients were included (43 in CG and 40 in ketamine) and 352 (80.5%) were excluded. Average enrollment rate was 3-4 patients/month. Consent and protocol adherence rates were adequate (89.24% and 76%, respectively). Demographics were balanced between groups. Median MV duration was 7 (interquartile range [IQR] 3-9.25 days) in ketamine and 5 (IQR 2-8 days) in CG. Median VFDs was 19 (IQR 0-24.75 days) in ketamine and 19 (IQR 0-24 days) in the CG (p = 0.70). More patients attained goal Richmond Agitation-Sedation Scale at 24 and 48 h in ketamine (67.5% and 73.5%, respectively) compared with CG (52.4% and 66.7%, respectively). Sedatives and vasopressors cumulative use, and hemodynamic changes were similar. ICU length-of-stay was 12.5 (IQR 6-21.2 days) in ketamine, compared with 12 (IQR 5.5-23 days) in CG. No serious adverse events were observed in either group.ConclusionsKetamine as an adjunct analgosedative agent appeared to be feasible and safe with no negative impact on outcomes, including hemodynamics. This pilot RCT identified areas of improvement in study protocol before conducting a large, adequately powered, multicenter RCT which is likely justified to investigate ketamine association with patient-centered outcomes further. Trial registration ClinicalTrials.gov: NCT04075006. Registered on 30 August 2019. Current controlled trials: ISRCTN14730035. Registered on 3 February 2020.

Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets