Totally Transdermal Sedation in the Weaning From Remifentanil Infusion (TOES)

Impact of Totally Transdermal Sedation in the Weaning From Remifentanil Infusion Among Critically Ill Patients Undergoing Mechanical Ventilation: a Pilot Randomized-controlled Study (The TOES Trial)

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)

Study Overview

• Status: Completed
• Conditions: Respiratory Insufficiency; Ventilator Weaning; Analgesics, Opioid
• Intervention / Treatment: Drug: Fentanyl Transdermal System; Drug: Remifentanil

Detailed Description

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. No data are available about the possibility of using transdermal fentanyl as an alternative to intravenous opioids during the weaning phase from mechanical ventilation and the post-extubation period until the discharge from ICU to the ward. The investigators aim to assess if a transdermal fentanyl-based sedation protocol can have an impact on the global Work of Breathing (WOB). Secondary endpoints of the study are the duration of mechanical ventilation, the duration of continuous infusion of opioids, the length of stay in ICU and in hospital. Eligible patients will be randomized in 2 groups: Group 1 will receive remifentanil; Group 2 will receive transdermal fentanyl and remifentanil. An Edi Catheter for diaphragm electrical activity monitoring will be put in place for each patient.

Statistical Analysis: Distribution normality will be assessed with the Kolmogorov-Smirnov test. Continuous variables will be reported expressed as medians (interquartile ranges). Qualitative variables will be reported as frequencies. Analysis on the primary efficacy criterion and other quantitative variables will be assessed with the Wilcoxon-Mann-Whitney test. Categorical outcomes will be compared with the chi-square test, or Fisher's exact test, as appropriate. Cochran-Mantel-Haenszel statistics will be reported for all these results. Two-way analysis of variance (ANOVA) for repeated measures with Bonferroni correction will be used to determine the differences in secondary endpoints. Comparisons between groups regarding these variables at each study time point were performed with the Student's t-test or Mann-Whitney test, as appropriate. Mean difference and 95% confidence interval [Confidence Interval 95%] are reported for most significant results. Two-tail p values≤0.05 Will be considered significant.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Daniele Natalini, MD; Phone Number: 00393334055668; Email: daniele.natalini88@gmail.com
• Study Contact Backup: Name: Anselmo Caricato, MD; Phone Number: 00393393974355; Email: anselmo.caricato@unicatt.it

Study Locations

• Italy
  • Roma, Italy, 00168
    • Fondazione Policlinico Universitario A. Gemelli IRCCS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age > 18 yo;
• Negative pregnancy test prior to inclusion in the study;
• 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.

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: transdermal fentanyl; 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; 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; Other Names: Alghedon; Drug: Remifentanil; 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; Other Names: Ultiva
Active Comparator: IV Remifentanil alone; 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; 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; Other Names: Ultiva

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of respiratory rates of the patients randomized to receive transdermal fentanyl vs. remifentanil alone.	breaths per minute	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.	milliliters	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.	mmHg	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.	bpm	starts with the randomization and ends 72 hours after randomization
Global duration of mechanical ventilation among the two groups.	Days	starts with the randomization and ends with the discharge from the intensive care unit.
Global duration of intravenous remifentanil infusion among the two groups.	Hours	starts with the randomization and ends with the discharge from the intensive care unit.
Length of stay in hospital among the two groups.	Days	starts with the randomization and ends with the discharge from the Hospital.
Length of stay in ICU among the two groups.	Days	starts with the randomization and ends with the discharge from the intensive care unit.

Collaborators and Investigators

• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Investigators: Principal Investigator: Prof. A Caricato, MD, Fondazione Policlinico Universitario A. Gemelli, IRCCS

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Lellouche F, Maggiore SM, Deye N, Taille S, Pigeot J, Harf A, Brochard L. Effect of the humidification device on the work of breathing during noninvasive ventilation. Intensive Care Med. 2002 Nov;28(11):1582-9. doi: 10.1007/s00134-002-1518-9. Epub 2002 Oct 10.

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2021
• Primary Completion (Actual): March 4, 2024
• Study Completion (Actual): March 4, 2024

Study Registration Dates

• First Submitted: December 7, 2019
• First Submitted That Met QC Criteria: December 17, 2019
• First Posted (Actual): December 19, 2019

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Respiratory Insufficiency; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Remifentanil; Fentanyl
• Other Study ID Numbers: 2687; 2019-002509-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No