The Efficacy of P0.1-guided Sedation Protocol in Critically Ill Patients Receiving Invasive Mechanical Ventilation: A Randomized Controlled Trial

Overview

This clinical trial aims to assess the efficacy of sedation protocol targeting optimal respiratory drive using P0.1 and arousal level compared with conventional sedation strategy (targeting arousal level alone) in patients requiring mechanical ventilation in the medical intensive care unit.

Detailed description

Objective: to assess the efficacy of sedation protocol targeting optimal respiratory drive using P0.1 and RASS score compared with conventional sedation strategy (targeting RASS score alone) in patients requiring mechanical ventilation in the medical intensive care unit

The main questions it aims to answer are:

• Will titration of sedation targeting optimal respiratory drive assessed by P0.1 and arousal level improve outcomes in patients requiring mechanical ventilation in the medical ICU?

Study protocol Mechanically ventilated patients admitted to the medical ICU will be screened daily by the investigators. If the patients meet the eligibility criteria, they will be informed about the study protocol and potential risks and undergo informed consent. Then patients will be randomized in a 1:1 ratio and allocated to each study group (intervention and control group).

* After allocation, patients will be monitored for arousal level using RASS score and respiratory drive by P0.1 measured automatically from mechanical ventilators during the study period. * Sedation and neuromuscular blocking agents used will be adjusted according to the group to which patients are allocated. * Intervention group: Adjustment of sedation and neuromuscular blocking agents to achieve the target of light sedation (RASS 0 to -2) and optimal P0.1 (1.5 to 3.5 cmH2O) for 48 hours * Control group: Adjustment of sedation to achieve the target of light sedation (RASS 0 to -2) alone for 48 hours

Researchers will compare the outcomes (rate of successful extubation, ICU and hospital mortality, ICU and hospital length of stay, duration of mechanical ventilation, amount and duration of sedation used during the study period) between the above sedation protocol (interventional group) and conventional sedation strategy (control group)

Interventions

• Procedure Titrating sedation targeting both optimal P0.1 and appropriate arousal level
  * Sedation will be adjusted initially to target light sedation (RASS 0 to -2). * Sedative drugs include IV fentanyl (25-75 mcg/h), midazolam (0.02- 0.1 mg/kg/h), propofol (5-50 mcg/kg/min), dexmedetomidine (0.2-0.7 mcg/kg/h). * Deep sedation and neuromuscular blocking agents are allowed to facilitate mechanical ventilation adjustment in patients with refractory hypoxemia. * Dose of cisatracurium is 0.15-0.2 mg/kg intravenous bolus, then continuous infusion at 5 -20 mg/h. * Then sedation adjustme
• Drug Fentanyl
  Continuous intravenous infusion of fentanyl 25-75 micrograms/hour
• Drug Midazolam
  Continuous intravenous infusion of midazolam 0.02 - 0.1 milligrams/kilogram/hour
• Drug Propofol
  Continuous intravenous infusion of propofol 5 - 50 micrograms/kilogram/minute
• Drug Dexmedetomidine
  Continuous intravenous infusion of dexmedetomidine 0.2 - 0.7 micrograms/kilogram/hour
• Drug Cisatracurium
  Continuous intravenous infusion of cisatracurium 5 - 20 milligrams/hour

Primary outcome measures

• Successful extubation within 14 days after randomization [Time frame: 14 days after randomization]

Secondary outcome measures (12)

• Successful extubation within 7 days after randomization [Time frame: 7 days after randomization]
• Successful extubation within 28 days after randomization [Time frame: 28 days after randomization]
• Duration of mechanical ventilation [Time frame: From date of intubation until the date of last successful extubation or date of death from any cause, whichever came first, assessed up to 28 days]
• Ventilator-free days to day 28 after randomization [Time frame: 28 days after randomization]
• Reintubation rate at 7 days after randomization [Time frame: 7 days after randomization]
• Self extubation rate at 7 days after extubation [Time frame: 7 days after randomization]
• Post-extubation respiratory failure [Time frame: From date of randomization until the date of the first event of post-extubation respiratory failure or date of death from any cause or ICU discharge, whichever came first, assessed up to 28 days]
• Tracheostomy [Time frame: From date of randomization until the date of tracheostomy or date of death from any cause or ICU discharge, whichever came first, assessed up to 28 days]
• Lung injury score on day 3 after randomization [Time frame: 3 days after randomization]
• Lung injury score on day 7 after randomization [Time frame: 7 days after randomization]
• PaO2/FiO2 ratio on day 3 after randomization [Time frame: 3 days after randomization]
• PaO2/FiO2 ratio on day 7 after randomization [Time frame: 7 days after randomization]

Eligibility criteria

Inclusion criteria

• Patients admitted to the medical intensive care unit at Department of Medicine, Siriraj Hospital
• Age ≥18 years old
• Receiving mechanical ventilation due to acute respiratory failure within 72 hours before enrollment (including patients receiving mechanical ventilation before ICU admission)

Exclusion criteria

• Patients receiving mechanical ventilation due to indications other than acute respiratory failure, such as postoperative procedures or airway protection in comatose patients
• Patients receiving mechanical ventilation for >72 hours before enrollment
• Patients receiving neuromuscular blocking agents prior to randomization
• Patients with impaired secretion clearance or upper airway obstruction anticipating a tracheostomy
• Patients with severe metabolic acidosis (arterial pH <7.2) who do not have a plan for renal replacement therapy
• Patients intubated for neurological conditions, including intracranial hypertension, intracranial hemorrhage, large cerebral infarction, status epilepticus, or neuromuscular diseases
• Post-cardiac arrest patients
• Patients with severe liver dysfunction, including acute fulminant liver failure or cirrhosis with the Child-Pugh score B or C
• Patients who have a previous allergy to any of the opioid, sedation, or neuromuscular blocking drugs
• Pregnancy
• Patients with do-not-resuscitate (DNR) orders or decisions to withhold life-sustaining treatments
• Patients who refuse to participate in the study or cannot identify legally authorized representatives (LAR) within 24 hours after enrollment

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Thailand · 1 center

• Siriraj Hospital — Bangkok

Publications

• Brochard L, Slutsky A, Pesenti A. Mechanical Ventilation to Minimize Progression of Lung Injury in Acute Respiratory Failure. Am J Respir Crit Care Med. 2017 Feb 15;195(4):438-442. doi: 10.1164/rccm.201605-1081CP. PMID 27626833
• Sklienka P, Frelich M, Bursa F. Patient Self-Inflicted Lung Injury-A Narrative Review of Pathophysiology, Early Recognition, and Management Options. J Pers Med. 2023 Mar 28;13(4):593. doi: 10.3390/jpm13040593. PMID 37108979
• Carteaux G, Parfait M, Combet M, Haudebourg AF, Tuffet S, Mekontso Dessap A. Patient-Self Inflicted Lung Injury: A Practical Review. J Clin Med. 2021 Jun 21;10(12):2738. doi: 10.3390/jcm10122738. PMID 34205783
• Spinelli E, Mauri T, Beitler JR, Pesenti A, Brodie D. Respiratory drive in the acute respiratory distress syndrome: pathophysiology, monitoring, and therapeutic interventions. Intensive Care Med. 2020 Apr;46(4):606-618. doi: 10.1007/s00134-020-05942-6. Epub 2020 Feb 3. PMID 32016537
• Spinelli E, Pesenti A, Slobod D, Fornari C, Fumagalli R, Grasselli G, Volta CA, Foti G, Navalesi P, Knafelj R, Pelosi P, Mancebo J, Brochard L, Mauri T. Clinical risk factors for increased respiratory drive in intubated hypoxemic patients. Crit Care. 2023 Apr 11;27(1):138. doi: 10.1186/s13054-023-04402-z. PMID 37041553
• Chanques G, Constantin JM, Devlin JW, Ely EW, Fraser GL, Gelinas C, Girard TD, Guerin C, Jabaudon M, Jaber S, Mehta S, Langer T, Murray MJ, Pandharipande P, Patel B, Payen JF, Puntillo K, Rochwerg B, Shehabi Y, Strom T, Olsen HT, Kress JP. Analgesia and sedation in patients with ARDS. Intensive Care Med. 2020 Dec;46(12):2342-2356. doi: 10.1007/s00134-020-06307-9. Epub 2020 Nov 10. PMID 33170331
• Goligher EC, Jonkman AH, Dianti J, Vaporidi K, Beitler JR, Patel BK, Yoshida T, Jaber S, Dres M, Mauri T, Bellani G, Demoule A, Brochard L, Heunks L. Clinical strategies for implementing lung and diaphragm-protective ventilation: avoiding insufficient and excessive effort. Intensive Care Med. 2020 Dec;46(12):2314-2326. doi: 10.1007/s00134-020-06288-9. Epub 2020 Nov 2. PMID 33140181
• Dzierba AL, Khalil AM, Derry KL, Madahar P, Beitler JR. Discordance Between Respiratory Drive and Sedation Depth in Critically Ill Patients Receiving Mechanical Ventilation. Crit Care Med. 2021 Dec 1;49(12):2090-2101. doi: 10.1097/CCM.0000000000005113. PMID 34115638

Identifiers

NCT: NCT06203405 · SI915/2023

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗