Multicentre pilot randomised clinical trial of early in-bed cycle ergometry with ventilated patients.

Introduction: Acute rehabilitation in critically ill patients can improve post-intensive care unit (post-ICU) physical function. In-bed cycling early in a patient\u27s ICU stay is a promising intervention. The objective of this study was to determine the feasibility of recruitment, intervention delivery and retention in a multi centre randomised clinical trial (RCT) of early in-bed cycling with mechanically ventilated (MV) patients. Methods: We conducted a pilot RCT conducted in seven Canadian medical-surgical ICUs. We enrolled adults who could ambulate independently before ICU admission, within the first 4 days of invasive MV and first 7 days of ICU admission. Following informed consent, patients underwent concealed randomisation to either 30 min/day of in-bed cycling and routine physiotherapy (Cycling) or routine physiotherapy alone (Routine) for 5 days/week, until ICU discharge. Our feasibility outcome targets included: accrual of 1-2 patients/month/site; \u3e80% cycling protocol delivery; \u3e80% outcomes measured and \u3e80% blinded outcome measures at hospital discharge. We report ascertainment rates for our primary outcome for the main trial (Physical Function ICU Test-scored (PFIT-s) at hospital discharge). Results: Between 3/2015 and 6/2016, we randomised 66 patients (36 Cycling, 30 Routine). Our consent rate was 84.6 % (66/78). Patient accrual was (mean (SD)) 1.1 (0.3) patients/month/site. Cycling occurred in 79.3% (146/184) of eligible sessions, with a median (IQR) session duration of 30.5 (30.0, 30.7) min. We recorded 43 (97.7%) PFIT-s scores at hospital discharge and 37 (86.0%) of these assessments were blinded. Discussion: Our pilot RCT suggests that a future multicentre RCT of early in-bed cycling for MV patients in the ICU is feasible. Trial registration number: NCT02377830

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Imagined gait modulates neuronal network dynamics in the human pedunculopontine nucleus

The pedunculopontine nucleus (PPN) is a part of the mesencephalic locomotor region and is thought to be important for the initiation and maintenance of gait. Lesions of the PPN induce gait deficits, and the PPN has therefore emerged as a target for deep brain stimulation for the control of gait and postural disability. However, the role of the PPN in gait control is not understood. Using extracellular single-unit recordings in awake patients, we found that neurons in the PPN discharged as synchronous functional networks whose activity was phase locked to alpha oscillations. Neurons in the PPN responded to limb movement and imagined gait by dynamically changing network activity and decreasing alpha phase locking. Our results indicate that different synchronous networks are activated during initial motor planning and actual motion, and suggest that changes in gait initiation in Parkinson's disease may result from disrupted network activity in the PPN

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Clonidine for sedation in the critically ill: a systematic review and meta-analysis

Abstract Background This systematic review and meta-analysis investigates the efficacy and safety of clonidine as a sedative in critically ill patients requiring invasive mechanical ventilation. Methods We performed a comprehensive search of MEDLINE, EMBASE, CINAHL and the Cochrane trial registry. We identified RCTs that compared clonidine to any non-clonidine regimen in critically ill patients, excluding neonates, requiring mechanical ventilation. The GRADE method was used to assess certainty of evidence. Results We included eight RCTs (n = 642 patients). In seven of the trials clonidine was used for adjunctive rather than stand-alone sedation. There was no difference in the duration of mechanical ventilation (mean difference (MD) 0.05 days, 95% confidence interval (CI) = -0.65 to 0.75, I 2  = 86%, moderate certainty), ICU mortality (relative risk (RR) 0.98, 95% CI = 0.51 to 1.90, I 2  = 0%, low certainty), or ICU length of stay (MD 0.04 days, 95% CI = -0.46 to 0.53, I 2  = 16%, moderate certainty), with clonidine. There was a significant reduction in the total dose of narcotics (standard mean difference (SMD) -0.26, 95% CI = -0.50 to -0.02, I 2  = 0%, moderate certainty) with clonidine use. Clonidine was associated with increased incidence of clinically significant hypotension (RR 3.11, 95% CI = 1.64 to 5.87, I 2  = 0%, moderate certainty). Conclusions Until further RCTs are performed, data remains insufficient to support the routine use of clonidine as a sedative in the mechanically ventilated population. Clonidine may act as a narcotic-sparing agent, albeit with an increased risk of clinically significant hypotension

Clonidine for sedation in the critically ill: a systematic review and meta-analysis (protocol)

Abstract Background Management and choice of sedation is important during critical illness in order to reduce patient suffering and to facilitate the delivery of care. Unfortunately, medications traditionally used for sedation in the intensive care unit (ICU) such as benzodiazepines and propofol are associated with significant unwanted effects. Clonidine is an alpha-2 selective adrenergic agonist that may have a role in optimizing current sedation practices in the pediatric and adult critically ill populations by potentially minimizing exposure to other sedative agents. Methods/design We will search MEDLINE, EMBASE, CINAHL, ACPJC, the Cochrane trial registry, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and clinicaltrials.gov for eligible observational studies and randomized controlled trials investigating the use of clonidine as an adjunctive or stand-alone sedative agent in patients requiring invasive mechanical ventilation. Our primary outcome is the duration of mechanical ventilation. Secondary outcomes include the following, listed by priority: duration of sedation infusions, dose of sedation used, level of sedation, incidence of withdrawal from other sedatives, delirium incidence, ICU and hospital length of stay, use and duration of non-invasive ventilation, and all-cause ICU and hospital mortality. We will also capture unwanted effects potentially associated with clonidine administration such as clinically significant hypotension or bradycardia, clonidine withdrawal, self-extubation, and the accidental removal of central intravenous lines and arterial lines. We will not apply any publication date, language, or journal restrictions. Two reviewers will independently screen and identify eligible studies using predefined eligibility criteria and then review full reports of all potentially relevant citations. A third reviewer will resolve disagreements if consensus cannot be achieved. We will use Review Manager (RevMan) to pool effect estimates from included studies across outcomes. We will present the results as relative risk (RR) with 95 % confidence intervals (CI) for dichotomous outcomes and as mean difference (MD) or standardized mean difference (SMD) for continuous outcomes with 95 % CI. We will assess the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Discussion The aim of this systematic review is to summarize the evidence on the efficacy and safety of clonidine as a sedative agent in the critically ill population. Systematic review registration PROSPERO CRD42015019365

Additional file 2: of Clonidine for sedation in the critically ill: a systematic review and meta-analysis (protocol)

Observational studies data abstraction form. (DOCX 75 kb