Caregiver Education for Paralysis Management

(ED-AWARENES II Trial)

Recruiting at 3 trial locations

Overseen By Brian Fuller, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Washington University School of Medicine

Must be taking: Neuromuscular blockers

Disqualifiers: Neurologic injury, Death, Transfer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

3090 Participants Needed

Trial Summary

What is the purpose of this trial?

The investigators will screen all mechanically ventilated ED patients for study eligibility and will enroll all consecutive patients satisfying inclusion and exclusion criteria. The study design is a pragmatic, multicenter, stepped wedge cluster randomized trial, enrolling at five sites over a 3-year period, divided into six time periods of six months. Prior to the study, each site will be randomized to their position within the design. One site will cross to the intervention period (i.e. succinylcholine as default neuromuscular blocker) every six months from the 2nd to 6th time period. Cluster order will be determined by computer-based randomization. To begin, each site will be exposed to control conditions; by the end of the study, each site will be exposed to intervention conditions. Patients in the control phase will receive usual care, and this phase will be entirely observational. After six months, a site will enter a 2-month transition phase. In this phase, the investigators will implement the intervention, similar to how they have implemented other ED-based interventions for mechanically ventilated patients. The investigators will engage and educate ED clinicians on the importance of AWP prevention and the study objectives. The intervention framework relies on the use of "nudges", without restricting choice. The use of neuromuscular blockers (i.e. "paralytic" medications) is already part of routine care in the ED in order to facilitate endotracheal intubation and initiation of mechanical ventilation for patients with acute respiratory failure. The two most common neuromuscular blockers used in the ED are succinylcholine and rocuronium. The preliminary data show a strong association between rocuronium (a longer-acting neuromuscular blocker) use and AWP. Therefore, this study aims to improve care by educating caregivers on AWP and the use of the neuromuscular blockers, which are already routinely used, and studying that process in a rigorous fashion. The default neuromuscular blocker in the intervention phase will be succinylcholine. Succinylcholine will be the default over rocuronium because: 1) it has safely been the default neuromuscular blocker of choice in the ED for \>40 years ; 2) its 5-minute duration of action greatly reduces AWP risk; 3) the preliminary data regarding an increased risk of AWP with rocuronium and 4) ED rocuronium use has increased despite no patient-centered studies showing benefit over succinylcholine. Passive alerts (i.e. graphics, pocket cards) will also be strategically placed in the ED, and active alerts will be used as reminders before every nursing shift (i.e. "the huddle"). After this transition phase, the site will begin the intervention phase, and patients will again receive clinician-directed care, just after the intervention.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, since the study involves the use of neuromuscular blockers, it's best to discuss your current medications with the trial team to ensure there are no interactions.

What data supports the effectiveness of the treatment Education, Educational Intervention, Coping Education, Mental Health Education, Standard neuromuscular blocker practices, Neuromuscular blockers, Paralytic medications, Succinylcholine, Rocuronium?

Research shows that sugammadex can quickly and safely reverse the effects of neuromuscular blockers like rocuronium, which helps in managing muscle relaxation during surgeries. This suggests that using sugammadex in combination with neuromuscular blockers can improve patient outcomes by ensuring rapid recovery from muscle paralysis. ^{1 2 3 4 5}

Is the use of rocuronium and its reversal with sugammadex safe for humans?

Rocuronium, used for muscle relaxation during surgery, is generally safe and well-tolerated in humans, especially when its effects are reversed with sugammadex. Studies show that it does not cause significant adverse effects, even in high-risk patients, and sugammadex effectively reverses its effects without safety concerns. ^{6 7 8 9 10}

How is the drug used in the Caregiver Education for Paralysis Management trial different from other drugs for paralysis?

This treatment uses neuromuscular blockers like rocuronium, which can be rapidly reversed by sugammadex, allowing for quick recovery from paralysis. This is different from older drugs like succinylcholine, which have a longer duration and more side effects. ^{1 3 4 11 12}

Research Team

Brian Fuller, MD

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

The ED-AWARENESS-2 Trial is for adults over 18 who are receiving mechanical ventilation via an endotracheal tube in the emergency department (ED) and have been treated with neuromuscular blockers. It excludes those with neurological injuries that prevent assessment of awareness during paralysis, patients transferred out, or those who die before extubation.

Inclusion Criteria

I am on a breathing machine through a tube in my windpipe.

I have been treated with a muscle relaxant for intubation.

Exclusion Criteria

Transfer to another hospital from the ED

I have a brain condition that makes it hard to assess my pain.

The participant has passed away before being removed from a breathing tube.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

Not specified

Control Phase

Patients receive usual care with standard neuromuscular blockers; this phase is entirely observational.

6 months

Transition Phase

Implementation of the intervention with education of ED clinicians on AWP prevention and study objectives.

2 months

Intervention Phase

Patients receive succinylcholine as the default neuromuscular blocker, with passive and active alerts to support the intervention.

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments for PTSD symptoms, depression, anxiety, and quality of life.

30 days

Treatment Details

Interventions

• Education
• Standard neuromuscular blocker practices

Trial Overview This trial tests whether educating ED clinicians on the use of succinylcholine—a short-acting neuromuscular blocker—over rocuronium can reduce risks associated with prolonged paralysis. The study uses a stepped wedge design across five sites to compare standard practices against this educational intervention.

Participant Groups

Group I: After group Experimental Treatment 1 Intervention

Mechanically ventilated emergency department patients receiving neuromuscular blockers after an educational initiative aimed at improving use of shorter acting neuromuscular blocker practices in the ED.

Group II: Before group Active Control 1 Intervention

Mechanically ventilated emergency department patients receiving standard neuromuscular blockers prior to an educational initiative on the importance of ED-based targeted shorter acting neuromuscular blocker.

Standard neuromuscular blocker practices is already approved in United States, European Union for the following indications:

Approved in United States as Succinylcholine for:

• Facilitation of endotracheal intubation
• Initiation of mechanical ventilation for acute respiratory failure

Approved in United States as Rocuronium for:

• Facilitation of endotracheal intubation
• Initiation of mechanical ventilation for acute respiratory failure

Approved in European Union as Succinylcholine for:

• Facilitation of endotracheal intubation
• Initiation of mechanical ventilation for acute respiratory failure

Approved in European Union as Rocuronium for:

• Facilitation of endotracheal intubation
• Initiation of mechanical ventilation for acute respiratory failure

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

Sugammadex has been shown to safely and rapidly reverse profound neuromuscular block caused by rocuronium and vecuronium, which is crucial for maintaining safe anesthesia practices.

The use of sugammadex allows for better control over neuromuscular block during surgery, potentially changing clinical practices by enabling quick recovery of muscle power after surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical implications of new neuromuscular concepts and agents: so long, neostigmine! So long, sux! Lee, C., Katz, RL.[2022]

A survey of 1296 Brazilian anesthesiologists revealed that rocuronium, atracurium, and cisatracurium are the most commonly used neuromuscular blockers, but less than 15% frequently use neuromuscular function monitors to assess recovery from muscle relaxants.

The study highlighted significant safety concerns, as many anesthesiologists rely on clinical criteria alone to determine recovery, leading to complications like residual curarization and prolonged blockade, with some cases even resulting in reported deaths.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of neuromuscular blockers in Brazil. Locks, Gde F., Cavalcanti, IL., Duarte, NM., et al.[2022]

Elderly patients (average age 76.9 years) experience a significantly slower recovery from rocuronium-induced muscle paralysis when treated with low-dose sugammadex compared to nonelderly patients (average age 53.7 years), with recovery rates of 1.89%/min versus 3.45%/min, respectively.

The incidence of recurarization (return of muscle paralysis) is notably higher in elderly patients at 35%, compared to just 5% in nonelderly patients, indicating a greater risk of complications when using low-dose sugammadex in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differences of Recovery from Rocuronium-induced Deep Paralysis in Response to Small Doses of Sugammadex between Elderly and Nonelderly Patients. Muramatsu, T., Isono, S., Ishikawa, T., et al.[2019]

In a study of 55 patients (27 with liver cirrhosis and 28 controls), sugammadex was found to significantly reduce recovery time from rocuronium-induced neuromuscular block compared to neostigmine, with recovery times of 3.1 minutes for cirrhosis patients and 2.6 minutes for controls after sugammadex administration.

Sugammadex provided an 80% reduction in recovery time compared to neostigmine, and there were no incidents of postoperative re-curarization with either antagonist, indicating its safety and efficacy in patients with liver cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sugammadex antagonism of rocuronium-induced neuromuscular blockade in patients with liver cirrhosis undergoing liver resection: a randomized controlled study. Abdulatif, M., Lotfy, M., Mousa, M., et al.[2019]

Sugammadex reverses profound neuromuscular block caused by vecuronium significantly faster than neostigmine, with recovery times of 4.5 minutes compared to 66.2 minutes, based on a study of 83 patients.

The study found no serious drug-related adverse events in either treatment group, indicating that sugammadex is a safe option for reversing neuromuscular block during surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reversal of profound vecuronium-induced neuromuscular block under sevoflurane anesthesia: sugammadex versus neostigmine. Lemmens, HJ., El-Orbany, MI., Berry, J., et al.[2021]

Rocuronium is a nondepolarizing neuromuscular blocking agent that acts quickly, making it ideal for situations requiring rapid intubation, and it does not produce active metabolites, enhancing its safety profile.

It has been successfully used in various high-risk surgical settings, including emergency surgeries and cesarean deliveries, due to its hemodynamic stability and predictable reversibility of effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Rocuronium]. Alvarez-Gómez, JA.[2018]

In a study of 150 adults undergoing outpatient surgery, using rocuronium for neuromuscular blockade followed by sugammadex for reversal resulted in a significantly faster recovery time (1.8 minutes) compared to succinylcholine, which took about 10.8 minutes to recover.

Both methods had similar health outcomes and adverse event rates, indicating that rocuronium-sugammadex is a safe and effective alternative for outpatient procedures without extending recovery times.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Rocuronium With Sugammadex Reversal Versus Succinylcholine in Outpatient Surgery-A Multicenter, Randomized, Safety Assessor-Blinded Trial. Soto, R., Jahr, JS., Pavlin, J., et al.[2018]

Tubocurarine, a key neuromuscular blocking agent derived from curare, was instrumental in understanding acetylcholine's role in muscle contraction, but it has unwanted side effects that led to the development of newer alternatives.

Current nondepolarising neuromuscular blockers, like rocuronium, offer rapid onset for intubation and may have their effects quickly reversed by a novel antagonist, enhancing safety and efficacy during surgical procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuromuscular block. Bowman, WC.[2018]

In a study involving 13 healthy adults, high doses of sugammadex (up to 96 mg/kg) were generally well tolerated, with mild adverse events occurring more frequently at higher doses, but no serious adverse events reported.

Pharmacokinetic analysis showed that sugammadex was eliminated in a dose-linear manner, with 90-93% of the administered dose excreted unchanged in urine within 48 hours, indicating effective renal clearance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, tolerability and pharmacokinetics of sugammadex using single high doses (up to 96 mg/kg) in healthy adult subjects: a randomized, double-blind, crossover, placebo-controlled, single-centre study. Peeters, PA., van den Heuvel, MW., van Heumen, E., et al.[2022]

A patient who received an accidental high dose of sugammadex (40 mg/kg) experienced a rapid and effective reversal of a profound neuromuscular block caused by rocuronium (1.2 mg/kg).

No adverse events or safety concerns were reported, highlighting the safety profile of sugammadex even at higher doses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reversal of rocuronium-induced (1.2 mg kg-1) profound neuromuscular block by accidental high dose of sugammadex (40 mg kg-1). Molina, AL., de Boer, HD., Klimek, M., et al.[2022]

In a study of 105 children undergoing elective day-case tonsillectomy, using a reduced dose of rocuronium (0.45 mg/kg) significantly shortened the recovery time from neuromuscular block to 7.3 minutes, compared to 15.9 minutes for vecuronium and 16.0 minutes for standard rocuronium doses.

The reduced-dose rocuronium maintained acceptable intubating conditions while minimizing operating room time by up to 37%, and it was associated with low rates of postoperative nausea and vomiting, indicating its efficacy and safety for short surgical procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-dose rocuronium for day-case tonsillectomy in children where volatile anaesthetics are not used: operating room time saving. Bartolek, D., Jakobović, J., Bartolek, F., et al.[2018]

Pregabalin 150mg significantly reduces the incidence and severity of myalgia after succinylcholine use in patients undergoing elective spine surgery, compared to a placebo group.

While pregabalin did not significantly reduce the overall incidence of muscle fasciculations, it was associated with fewer patients experiencing moderate to severe fasciculations, indicating a potential benefit in managing side effects of succinylcholine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prophylactic use of pregabalin for prevention of succinylcholine-induced fasciculation and myalgia: a randomized, double-blinded, placebo-controlled study. Srivastava, VK., Agrawal, S., Nimbhorkar, VK., et al.[2017]

References

1. United States pubmed.ncbi.nlm.nih.gov

Clinical implications of new neuromuscular concepts and agents: so long, neostigmine! So long, sux! [2022]

2. Brazil pubmed.ncbi.nlm.nih.gov

Use of neuromuscular blockers in Brazil. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Differences of Recovery from Rocuronium-induced Deep Paralysis in Response to Small Doses of Sugammadex between Elderly and Nonelderly Patients. [2019]

4. Italy pubmed.ncbi.nlm.nih.gov

Sugammadex antagonism of rocuronium-induced neuromuscular blockade in patients with liver cirrhosis undergoing liver resection: a randomized controlled study. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Reversal of profound vecuronium-induced neuromuscular block under sevoflurane anesthesia: sugammadex versus neostigmine. [2021]

6. Spain pubmed.ncbi.nlm.nih.gov

[Rocuronium]. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Rocuronium With Sugammadex Reversal Versus Succinylcholine in Outpatient Surgery-A Multicenter, Randomized, Safety Assessor-Blinded Trial. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Neuromuscular block. [2018]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Safety, tolerability and pharmacokinetics of sugammadex using single high doses (up to 96 mg/kg) in healthy adult subjects: a randomized, double-blind, crossover, placebo-controlled, single-centre study. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Reversal of rocuronium-induced (1.2 mg kg-1) profound neuromuscular block by accidental high dose of sugammadex (40 mg kg-1). [2022]

11. France pubmed.ncbi.nlm.nih.gov

Reduced-dose rocuronium for day-case tonsillectomy in children where volatile anaesthetics are not used: operating room time saving. [2018]

12. Brazil pubmed.ncbi.nlm.nih.gov

Prophylactic use of pregabalin for prevention of succinylcholine-induced fasciculation and myalgia: a randomized, double-blinded, placebo-controlled study. [2017]