Inhaled Sedation for Delirium in Critically Ill Children

(ABOVE Trial)

Recruiting at 2 trial locations

Overseen By Sunnybrook Research Institute, Program Manager - Centre for Clinical Trials Services

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Sunnybrook Health Sciences Centre

Must not be taking: Inhaled prostacyclin

Disqualifiers: Malignant hyperthermia, Myopathy, High ICP, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether inhaled sedatives can reduce extreme confusion (delirium) in children requiring a breathing machine, compared to the usual IV sedatives. Researchers aim to determine if children will participate and complete the study and if healthcare teams will accept the procedures. Participants will receive either inhaled sedation (such as Isoflurane or Sevoflurane) or IV sedation and undergo daily monitoring for up to 28 days, with follow-up tests on memory and behavior after 9-12 months. Children who have been on a breathing machine for at least 24 hours and need sedation qualify as good candidates for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that participants will be receiving either inhaled or IV sedation, so it's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that inhaled sedation treatments like Isoflurane and Sevoflurane are generally well-tolerated in seriously ill children. Studies found that Isoflurane does not cause treatment-related deaths and effectively sedates these patients.

For Sevoflurane, safety data indicates it has few side effects. Among millions of reports, only a small number identified Sevoflurane as the main cause of problems. Some children experienced low blood pressure, but it was manageable.

Both treatments appear promising in terms of safety, with Isoflurane and Sevoflurane showing few serious side effects in studies. This suggests they could be safe options for children needing sedation while on a ventilator. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about inhaled sedation using Isoflurane and Sevoflurane for delirium in critically ill children because these inhalants offer a different delivery method compared to the typical intravenous (IV) sedation. Inhaled sedatives can be adjusted more quickly and precisely, potentially leading to faster stabilization of the patient. Additionally, they might reduce the risk of prolonged sedation and associated complications often seen with traditional IV drugs. This approach could enhance safety and effectiveness in managing delirium in the pediatric ICU setting.

What evidence suggests that inhaled sedation might be an effective treatment for delirium in critically ill children?

This trial will compare inhaled sedation using volatile anesthetics with standard IV sedation in critically ill children. Research has shown that inhaled sedatives like isoflurane and sevoflurane can help calm critically ill children on ventilators. Studies have found that isoflurane works as well as intravenous (IV) sedatives, like midazolam, to keep children calm and comfortable. Another study found that sevoflurane is also effective for sedation in similar situations, meeting the child's needs. These inhaled treatments offer alternatives to traditional IV methods and may reduce some side effects. Overall, these inhaled options show promise for helping children who need sedation in critical care. ^{1 2 5 6 7}

Who Is on the Research Team?

Angela Jerath, MD

Principal Investigator

Sunnybrook Health Sciences Centre

Are You a Good Fit for This Trial?

This trial is for children aged 1 month to less than 18 years who need sedation for mechanical ventilation. They should be on IV sedation for no more than 72 hours and expected to remain ventilated for at least a day. It's not suitable for kids with certain metabolic diseases, high brain pressure, or allergies to inhaled anesthetics.

Inclusion Criteria

I am on IV sedation to help with mechanical breathing for less than 72 hours.

I am under 18, need sedation for ventilation, and will be ventilated for over 24 hours.

Exclusion Criteria

I or someone in my family has had malignant hyperthermia.

I am currently using inhaled prostacyclin medication.

I have a condition like muscular dystrophy that could react badly to certain anesthesia.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either inhaled sedation or standard IV sedation and are monitored daily

28 days

Daily monitoring

Follow-up

Participants complete memory, thinking, and behavior tasks to assess neurocognitive outcomes

1 year

Long-term follow-up

Participants are monitored for safety and effectiveness, including adverse events and survival status

13 months

What Are the Treatments Tested in This Trial?

Interventions

• Isoflurane Inhalant Product
• Sevoflurane inhalant product

Trial Overview The study tests if inhaled sedatives like Isoflurane or Sevoflurane can better prevent confusion (delirium) compared to standard IV sedatives in critically ill children needing ventilators. The trial will randomly assign participants to either the new approach or standard care and monitor them up to one year.

How Is the Trial Designed?

Group I: Inhaled sedation - volatile anesthetic Experimental Treatment 2 Interventions

The ICU patient will receive either Isoflurane or Sevoflurane, whichever is available at the hospital. Dosage will be modified as per health care team guidance for the best treatment of the participant.

Group II: IV sedation - standard of care Active Control 1 Intervention

The ICU patient will receive standard of care, which is IV sedation supplied by the hospital. Dosage will be modified as per health care team guidance for the best treatment of the participant.

Isoflurane Inhalant Product is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Forane for:

• General anesthesia
• Maintenance of anesthesia

Approved in European Union as Isoflurane for:

• Induction and maintenance of general anesthesia

Approved in Canada as Isoflurane for:

• General anesthesia

Approved in Japan as Isoflurane for:

• General anesthesia

Who Is Running the Clinical Trial?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Published Research Related to This Trial

Inhaled sedation using agents like isoflurane and sevoflurane is now possible in ICU settings, offering a well-tolerated and adjustable sedation option for patients, provided that proper equipment and training are available.

These inhaled agents not only serve as effective sedatives but may also offer additional clinical benefits for ICU patients, suggesting a promising alternative to traditional intravenous sedation methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled sedation in the intensive care unit. Jabaudon, M., Zhai, R., Blondonnet, R., et al.[2022]

Sevoflurane is preferred over halothane for pediatric anesthesia due to its rapid induction and recovery, nonpungent odor, and reduced airway irritation, which lowers the risk of bronchospasm and laryngospasm.

However, sevoflurane can cause side effects such as seizures, increased plasma inorganic fluoride levels, and a higher incidence of emergence delirium compared to halothane, highlighting the need for awareness among perianesthesia nurses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sevoflurane and emergence behavioral changes in pediatrics. Moos, DD.[2019]

In a study involving 143 adult patients, sevoflurane was found to allow for a quicker recovery from general anesthesia compared to isoflurane, with shorter times for extubation, eye opening, and command response.

Both sevoflurane and isoflurane demonstrated similar safety profiles, as there were no significant differences in renal and hepatic function before and after surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maintenance and recovery characteristics of sevoflurane anaesthesia in adult patients. A multicenter, randomized comparison with isoflurane. Ranieri, R., Martinelli, G., Pagani, I., et al.[2018]

Sevoflurane is considered a safe and effective inhalational anesthetic for both adults and children, suitable for various surgical procedures due to its rapid induction and recovery properties.

Its ideal characteristics, such as low flammability, non-irritating odor, minimal cardiovascular and respiratory side effects, and compatibility with standard delivery techniques, make it one of the most widely used anesthetics available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sevoflurance: approaching the ideal inhalational anesthetic. a pharmacologic, pharmacoeconomic, and clinical review. Delgado-Herrera, L., Ostroff, RD., Rogers, SA.[2023]

The proposed maximum admissible concentrations (MAC) for sevoflurane and isoflurane are 55 mg/m3 (7 ppm) and 32 mg/m3 (4 ppm), respectively, which aim to protect surgical staff from potential health risks associated with these anesthetics.

Establishing these MAC values is crucial as it provides a guideline for employers to assess and manage exposure to these inhalant anesthetics in the workplace, ensuring the safety of healthcare workers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Assessment of health risk of sevoflurane and isoflurane exposure among surgical staff: a problem for employers]. Kupczewska-Dobecka, M., Soćko, R.[2018]

Children recovering from anesthesia with sevoflurane experienced faster recovery times compared to those who received halothane, with spontaneous eye opening occurring in a median of 25 minutes for sevoflurane versus 48 minutes for halothane (P < 0.01).

While sevoflurane led to quicker recovery, it was associated with a higher incidence of agitation, particularly in younger children, indicating that while sevoflurane may be effective for rapid recovery, it may also require careful monitoring for agitation post-anesthesia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sevoflurane causes more postoperative agitation in children than does halothane. Beskow, A., Westrin, P.[2022]

Sevoflurane was successfully used for sedation in two critically ill pediatric patients undergoing ECMO, demonstrating its effectiveness in achieving deep sedation while still allowing for patient-initiated breathing.

No side effects were observed during or after the use of sevoflurane, indicating a favorable safety profile for its use in this challenging clinical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled sedation with sevoflurane in critically ill children during extracorporeal membrane oxygenation. Butragueño Laiseca, L., Murciano, M., López-Herce, J., et al.[2021]

In a study of 29 children aged 6 months to 10 years requiring intensive care, prolonged sedation with isoflurane for more than 24 hours was associated with reversible neurologic dysfunction, including symptoms like ataxia and confusion.

All neurologic symptoms resolved within 72 hours post-extubation, and follow-up examinations showed normal neurologic function, indicating that while isoflurane can lead to temporary side effects, these effects are reversible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reversible neurologic dysfunction following isoflurane sedation in pediatric intensive care. Kelsall, AW., Ross-Russell, R., Herrick, MJ.[2019]

Inhaled sevoflurane was found to be an effective sedative for critically ill children, allowing for the reduction or removal of other sedative medications in 78% of patients after 48 hours of treatment.

While sevoflurane can be easily administered in PICUs using standard ventilators, prolonged use (over 6 days) may lead to withdrawal syndrome in some patients, and moderate hypotension was observed in 30% of cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Exploratory Study of Sevoflurane as an Alternative for Difficult Sedation in Critically Ill Children. Mencía, S., Palacios, A., García, M., et al.[2019]

In a study of 90 preschool children undergoing surgery, low-dose caudal clonidine (1 μg kg⁻¹) significantly reduced the incidence of sevoflurane-induced emergence agitation compared to a control group, with only 6.6% experiencing agitation versus 40% in the control group.

The use of low-dose clonidine did not result in any significant adverse effects, such as bradycardia or respiratory impairment, indicating it is a safe option for managing post-operative agitation in young children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of low-dose caudal clonidine in reduction of sevoflurane-induced agitation in children undergoing urogenital and lower limb surgery: a prospective randomised double-blind study. Ghosh, SM., Agarwala, RB., Pandey, M., et al.[2018]

Sevoflurane is commonly used for starting anesthesia in children due to its pleasant smell and fast action, but its use for maintaining anesthesia raises concerns about emergence delirium.

Emergence delirium can affect 10 to 80% of children after anesthesia, leading to disorientation and hyperactivity, which may result in injuries and longer recovery times, highlighting the need for careful monitoring and management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Should sevoflurane be used for maintenance of anaesthesia in children? Duffen, A., Williams, A.[2019]

Citations

1. thelancet.com thelancet.com/journals/lanres/article/PIIS2213-2600(25)00203-6/fulltext

Inhaled isoflurane for sedation of mechanically ventilated ... Among critically ill children, the effectiveness of sedation with inhaled isoflurane was non-inferior to that of intravenous midazolam ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40680761/

Inhaled isoflurane for sedation of mechanically ventilated ... Interpretation: Among critically ill children, the effectiveness of sedation with inhaled isoflurane was non-inferior to that of intravenous ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06809218

A Pooled Analysis of Long-Term Outcomes After Inhaled ... This pooled analysis will assess Cognitive, Mental Health, Functioning, and Quality of Life Assessments data from the Phase 3 registration studies ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12429693/

Sedation in Critically Ill Children - PMC Our choice of sedative agents has a significant impact on the physiological and psychological outcomes of our patients. Oversedation and ...

5. thelancet.com thelancet.com/pdfs/journals/lanres/PIIS2213-2600(25)00203-6.pdf

Inhaled isoflurane for sedation of mechanically ventilated Interpretation Among critically ill children, the effectiveness of sedation with inhaled isoflurane was non-inferior to that of intravenous ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05867472

Advancing Brain Outcomes in Pediatric Critically Ill Patients ... This study plan is looking at whether the use of inhaled sedatives (medications that help people be calm and sleep) can reduce delirium (extreme confusion) in ...

7. withpower.com withpower.com/trial/phase-3-respiratory-aspiration-5-2023-75d5a

Inhaled Sedation for Delirium in Critically Ill Children (ABOVE Trial) Trial Overview The study tests if inhaled sedatives like Isoflurane or Sevoflurane can better prevent confusion (delirium) compared to standard IV sedatives in ...