Totally Transdermal Sedation in the Weaning From Remifentanil Infusion

NCT04204967 | Completed Phase 2

• 2 other identifiers: 26872019-002509-22
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

The choice of the sedation protocol has a massive impact on the duration of mechanical ventilation and the timing of extubation. Many sedation protocols are described in the literature. The investigators aim to assess if a transdermal fentanyl-based sedation protocol can have an impact on the global Work of Breathing (WOB)

Conditions

Respiratory Insufficiency; Ventilator Weaning; Analgesics, Opioid

Outcome Measures

Primary Outcomes (10)

• Comparison of the work of breathing (WOB) of the patients randomized to receive transdermal fentanyl vs. remifentanil alone.

  To demonstrate that the area under the curve (AUC) of the work of breathing per minute (cmH20\*sec/min) (assessed at 1, 6, 12, 24 hours for the first day after randomization, and every 24 hours for the following days) in the intervention group is not higher than the control group.

  starts with the randomization and ends 72 hours after randomization

• Comparison of the work of breathing per breath of the patients randomized to receive transdermal fentanyl vs. remifentanil alone.

  cmH20\*sec/min

  starts with the randomization and ends 72 hours after randomization

• Comparison of the inspiratory effort of the patients randomized to receive transdermal fentanyl vs. remifentanil alone.

  cmH20

  starts with the randomization and ends 72 hours after randomization

• Comparison of the delta electrical activity of the diaphragm (EAdi) of the patients randomized to receive transdermal fentanyl vs. remifentanil alone.

  microvolt (mcv)

  starts with the randomization and ends 72 hours after randomization

• Comparison of the plateau pressures of the patients randomized to receive transdermal fentanyl vs. remifentanil alone.

  cmH20

  starts with the randomization and ends 72 hours after randomization

• Comparison of driving pressures of the patients randomized to receive transdermal fentanyl vs. remifentanil alone.

  cmH20

  starts with the randomization and ends 72 hours after randomization

• Comparison of transpulmonary driving pressures of the patients randomized to receive transdermal fentanyl vs. remifentanil alone.

  cmH20

  starts with the randomization and ends 72 hours after randomization

• Comparison of the pulmonary compliance of the patients randomized to receive transdermal fentanyl vs. remifentanil alone.

  ml/cmH20

  starts with the randomization and ends 72 hours after randomization

• Comparison of P0.1 of the patients randomized to receive transdermal fentanyl vs. remifentanil alone.

  cmH20

  starts with the randomization and ends 72 hours after randomization

• Comparison of P/F ratios of the patients randomized to receive transdermal fentanyl vs. remifentanil alone.

  The P/F ratio equals the arterial PaO2 (Arterial Oxygen Partial Pressure) (mmHg) divided by the FIO2 (the fraction of inspired oxygen expressed as a decimal)

  starts with the randomization and ends 72 hours after randomization

Secondary Outcomes (8)

• Comparison of respiratory rates of the patients randomized to receive transdermal fentanyl vs. remifentanil alone.

  starts with the randomization and ends 72 hours after randomization

• Comparison of tidal volumes of the patients randomized to receive transdermal fentanyl vs. remifentanil alone.

  starts with the randomization and ends 72 hours after randomization

• Comparison of arterial blood pressure of the patients randomized to receive transdermal fentanyl vs. remifentanil alone.

  starts with the randomization and ends 72 hours after randomization

• Comparison of heart rates of the patients randomized to receive transdermal fentanyl vs. remifentanil alone.

  starts with the randomization and ends 72 hours after randomization

• Global duration of mechanical ventilation among the two groups.

  starts with the randomization and ends with the discharge from the intensive care unit.

Study Arms (2)

transdermal fentanyl

EXPERIMENTAL

transdermal fentanyl will be administered with a starting dose of 50 mcg/hr simultaneously with the preexistent remifentanil continue infusion. Remifentanil infusion rate will be increased or decreased based on PaCO2 value resulting from the Arterial Blood Gases sample (ABG) collected at each visit. After randomization, the transdermal fentanyl dose can be modified every 24 hours according to the study protocol to achieve the desired effect in terms of PaCO2 value resulting from the Arterial Blood Gases sample (ABG) collected

Drug: Fentanyl Transdermal System; Drug: Remifentanil

IV Remifentanil alone

ACTIVE COMPARATOR

remifentanil infusion is administered alone, the infusion rate will be increased or decreased according to the study protocol based on PaCO2 value resulting from the Arterial Blood Gases sample (ABG) collected at each visit

Drug: Remifentanil

Interventions

Fentanyl Transdermal System DRUG

in the experimental arm transdermal fentanyl will be administered with a starting dose of 50 mcg/hr simultaneously with the preexistent remifentanil continue infusion. Remifentanil infusion rate will be increased or decreased based on PaCO2 value resulting from the Arterial Blood Gases sample (ABG) collected at each visit. After randomization, the transdermal fentanyl dose can be modified every 24 hours according to the study protocol to achieve the desired effect in terms of PaCO2 value resulting from the Arterial Blood Gases sample (ABG) collected

Also known as: Alghedon

transdermal fentanyl

Remifentanil DRUG

In the active comparator arm remifentanil infusion is administered alone, the infusion rate will be increased or decreased according to the study protocol based on PaCO2 value resulting from the Arterial Blood Gases sample (ABG) collected at each visit. In the experimental arm remifentanil is use together with transdermal fentanyl

Also known as: Ultiva

IV Remifentanil alone; transdermal fentanyl

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \> 18 yo;
• The informed consent form needs to be signed and dated by the patient or a relative/legal guardian before of any procedure related to the study; if the patient is initially unable to sign the informed consent form, but later regains the ability to sign it, a new informed consent form will be given to the patient and must be signed and dated;
• Mechanically ventilated in Pressure Support Ventilation, according to the decision to the attending physician;
• A patient with prolonged weaning from the mechanical ventilator will be considered eligible. Prolonged weaning is defined as weaning that is still not terminated 7 days after the first separation attempt from the ventilator (by success or death).
• Analgesia provided by continuous infusion of remifentanil lasting five days or more and an intolerance to a dose reduction of 0.025 mcg/kg/min defined as the presence of at least one of the following criteria: RASS ≥ 2, a respiratory rate ≥ 35 breaths/minute, a PaCO2 \< 30 mmHg, a heart rate \> 120 bpm, a systolic blood pressure value \> 160 mmHg or an increase of Visual Analogue Scale for pain assessment of ≥ 2 points.

You may not qualify if:

• Hypersensitivity to the active substance or any of the excipients;
• Hepatic or renal impairment;
• Fever (body temperature ≥ 38 °C) or septic shock, hypothermia (body temperature \< 35 °C) or presence of active surface cooling systems;
• Hypercapnic patients with a PaCO2 \> 45 mmHg;
• Current enrollment or plan to enroll in any interventional clinical study in which an investigational treatment or approved therapy for investigational use is administered within 30 days or 5 half-lives of the agent, prior to the baseline visit;
• Hypoxemic respiratory failure (P/F \< 200 mmHg);
• Delirium state defined as RASS ≥ 3 and CAM-ICU positive;
• Hemodynamic instability requiring high doses of inotropes or vasopressors;
• Any condition that may contraindicate the use of remifentanil or transdermal fentanyl;
• Patients with a BMI ≥ 35;
• Patient admitted for postoperative monitoring after elective surgery;
• EAdi catheter contraindicated.

Sponsors & Collaborators

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: lead

Study Sites (1)

Fondazione Policlinico Universitario A. Gemelli IRCCS

Roma, 00168, Italy

Location

Related Publications (21)

• Jeong BH, Ko MG, Nam J, Yoo H, Chung CR, Suh GY, Jeon K. Differences in clinical outcomes according to weaning classifications in medical intensive care units. PLoS One. 2015 Apr 15;10(4):e0122810. doi: 10.1371/journal.pone.0122810. eCollection 2015.

  PMID: 25876004 BACKGROUND

• Beduneau G, Pham T, Schortgen F, Piquilloud L, Zogheib E, Jonas M, Grelon F, Runge I, Nicolas Terzi, Grange S, Barberet G, Guitard PG, Frat JP, Constan A, Chretien JM, Mancebo J, Mercat A, Richard JM, Brochard L; WIND (Weaning according to a New Definition) Study Group and the REVA (Reseau Europeen de Recherche en Ventilation Artificielle) Network double dagger. Epidemiology of Weaning Outcome according to a New Definition. The WIND Study. Am J Respir Crit Care Med. 2017 Mar 15;195(6):772-783. doi: 10.1164/rccm.201602-0320OC.

  PMID: 27626706 BACKGROUND

• Girard TD, Alhazzani W, Kress JP, Ouellette DR, Schmidt GA, Truwit JD, Burns SM, Epstein SK, Esteban A, Fan E, Ferrer M, Fraser GL, Gong MN, Hough CL, Mehta S, Nanchal R, Patel S, Pawlik AJ, Schweickert WD, Sessler CN, Strom T, Wilson KC, Morris PE; ATS/CHEST Ad Hoc Committee on Liberation from Mechanical Ventilation in Adults. An Official American Thoracic Society/American College of Chest Physicians Clinical Practice Guideline: Liberation from Mechanical Ventilation in Critically Ill Adults. Rehabilitation Protocols, Ventilator Liberation Protocols, and Cuff Leak Tests. Am J Respir Crit Care Med. 2017 Jan 1;195(1):120-133. doi: 10.1164/rccm.201610-2075ST.

  PMID: 27762595 BACKGROUND

• Penuelas O, Frutos-Vivar F, Fernandez C, Anzueto A, Epstein SK, Apezteguia C, Gonzalez M, Nin N, Raymondos K, Tomicic V, Desmery P, Arabi Y, Pelosi P, Kuiper M, Jibaja M, Matamis D, Ferguson ND, Esteban A; Ventila Group. Characteristics and outcomes of ventilated patients according to time to liberation from mechanical ventilation. Am J Respir Crit Care Med. 2011 Aug 15;184(4):430-7. doi: 10.1164/rccm.201011-1887OC.

  PMID: 21616997 BACKGROUND

• Perkins GD, Mistry D, Gates S, Gao F, Snelson C, Hart N, Camporota L, Varley J, Carle C, Paramasivam E, Hoddell B, McAuley DF, Walsh TS, Blackwood B, Rose L, Lamb SE, Petrou S, Young D, Lall R; Breathe Collaborators. Effect of Protocolized Weaning With Early Extubation to Noninvasive Ventilation vs Invasive Weaning on Time to Liberation From Mechanical Ventilation Among Patients With Respiratory Failure: The Breathe Randomized Clinical Trial. JAMA. 2018 Nov 13;320(18):1881-1888. doi: 10.1001/jama.2018.13763.

  PMID: 30347090 BACKGROUND

• Muellejans B, Lopez A, Cross MH, Bonome C, Morrison L, Kirkham AJ. Remifentanil versus fentanyl for analgesia based sedation to provide patient comfort in the intensive care unit: a randomized, double-blind controlled trial [ISRCTN43755713]. Crit Care. 2004 Feb;8(1):R1-R11. doi: 10.1186/cc2398. Epub 2003 Nov 20.

  PMID: 14975049 BACKGROUND

• Akinci SB, Kanbak M, Guler A, Aypar U. Remifentanil versus fentanyl for short-term analgesia-based sedation in mechanically ventilated postoperative children. Paediatr Anaesth. 2005 Oct;15(10):870-8. doi: 10.1111/j.1460-9592.2005.01574.x.

  PMID: 16176316 BACKGROUND

• Zhu Y, Wang Y, Du B, Xi X. Could remifentanil reduce duration of mechanical ventilation in comparison with other opioids for mechanically ventilated patients? A systematic review and meta-analysis. Crit Care. 2017 Aug 3;21(1):206. doi: 10.1186/s13054-017-1789-8.

  PMID: 28774327 BACKGROUND

• Futier E, Chanques G, Cayot Constantin S, Vernis L, Barres A, Guerin R, Chartier C, Perbet S, Petit A, Jabaudon M, Bazin JE, Constantin JM. Influence of opioid choice on mechanical ventilation duration and ICU length of stay. Minerva Anestesiol. 2012 Jan;78(1):46-53. Epub 2011 Nov 5.

  PMID: 21971434 BACKGROUND

• Natalini G, Di Maio A, Rosano A, Ferretti P, Bertelli M, Bernardini A. Remifentanil improves breathing pattern and reduces inspiratory workload in tachypneic patients. Respir Care. 2011 Jun;56(6):827-33. doi: 10.4187/respcare.01014. Epub 2011 Feb 11.

  PMID: 21333087 BACKGROUND

• Newshan G. Heat-related toxicity with the fentanyl transdermal patch. J Pain Symptom Manage. 1998 Nov;16(5):277-8. doi: 10.1016/s0885-3924(98)00100-6. No abstract available.

  PMID: 9846020 BACKGROUND

• Carter KA. Heat-associated increase in transdermal fentanyl absorption. Am J Health Syst Pharm. 2003 Jan 15;60(2):191-2. doi: 10.1093/ajhp/60.2.191. No abstract available.

  PMID: 12561665 BACKGROUND

• Lotsch J, Walter C, Parnham MJ, Oertel BG, Geisslinger G. Pharmacokinetics of non-intravenous formulations of fentanyl. Clin Pharmacokinet. 2013 Jan;52(1):23-36. doi: 10.1007/s40262-012-0016-7.

  PMID: 23100195 BACKGROUND

• Bulow HH, Linnemann M, Berg H, Lang-Jensen T, LaCour S, Jonsson T. Respiratory changes during treatment of postoperative pain with high dose transdermal fentanyl. Acta Anaesthesiol Scand. 1995 Aug;39(6):835-9. doi: 10.1111/j.1399-6576.1995.tb04180.x.

  PMID: 7484044 BACKGROUND

• Beck J, Gottfried SB, Navalesi P, Skrobik Y, Comtois N, Rossini M, Sinderby C. Electrical activity of the diaphragm during pressure support ventilation in acute respiratory failure. Am J Respir Crit Care Med. 2001 Aug 1;164(3):419-24. doi: 10.1164/ajrccm.164.3.2009018.

  PMID: 11500343 BACKGROUND

• Bellani G, Mauri T, Coppadoro A, Grasselli G, Patroniti N, Spadaro S, Sala V, Foti G, Pesenti A. Estimation of patient's inspiratory effort from the electrical activity of the diaphragm. Crit Care Med. 2013 Jun;41(6):1483-91. doi: 10.1097/CCM.0b013e31827caba0.

  PMID: 23478659 BACKGROUND

• Liu L, Liu H, Yang Y, Huang Y, Liu S, Beck J, Slutsky AS, Sinderby C, Qiu H. Neuroventilatory efficiency and extubation readiness in critically ill patients. Crit Care. 2012 Jul 31;16(4):R143. doi: 10.1186/cc11451.

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• Jansen D, Jonkman AH, Roesthuis L, Gadgil S, van der Hoeven JG, Scheffer GJ, Girbes A, Doorduin J, Sinderby CS, Heunks LMA. Estimation of the diaphragm neuromuscular efficiency index in mechanically ventilated critically ill patients. Crit Care. 2018 Sep 27;22(1):238. doi: 10.1186/s13054-018-2172-0.

  PMID: 30261920 BACKGROUND

• Adachi YU, Sano H, Doi M, Sato S. Central neurogenic hyperventilation treated with intravenous fentanyl followed by transdermal application. J Anesth. 2007;21(3):417-9. doi: 10.1007/s00540-007-0526-x. Epub 2007 Aug 1.

  PMID: 17680198 BACKGROUND

• Delorme M, Bouchard PA, Simon M, Simard S, Lellouche F. Effects of High-Flow Nasal Cannula on the Work of Breathing in Patients Recovering From Acute Respiratory Failure. Crit Care Med. 2017 Dec;45(12):1981-1988. doi: 10.1097/CCM.0000000000002693.

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  PMID: 12415444 BACKGROUND

MeSH Terms

Conditions

Respiratory Insufficiency

Interventions

Remifentanil

Condition Hierarchy (Ancestors)

Respiration Disorders; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Propionates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Prof. A Caricato, MD

  Fondazione Policlinico Universitario A. Gemelli, IRCCS

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 2-arm, single-center, prospective randomized controlled trial.

Study Record Dates

• First Submitted: December 7, 2019
• First Posted: December 19, 2019
• Study Start: February 15, 2021
• Primary Completion: April 6, 2024
• Study Completion: April 6, 2024
• Last Updated: May 17, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)