Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Trials
Published in: Trials 1/2018

Open Access 01-12-2018 | Methodology

Methods in the design and implementation of the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial

Authors: Martha A. Q. Curley, Rainer G. Gedeit, Brenda L Dodson, June K. Amling, Deborah J. Soetenga, Christiane O. Corriveau, Lisa A. Asaro, David Wypij, For the RESTORE Investigative Team

Published in: Trials | Issue 1/2018

Login to get access

Abstract

Background

Few papers discuss the pragmatics of conducting large, cluster randomized clinical trials. Here we describe the sequential steps taken to develop methods to implement the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) trial that tested the effect of a nurse-implemented, goal-directed, comfort algorithm on clinical outcomes in pediatric patients with acute respiratory failure.

Methods

After development in a single institution, the RESTORE intervention was pilot-tested in two pediatric intensive care units (PICUs) to evaluate safety and feasibility. After the pilot, the RESTORE intervention was simplified to enhance reproducibility across multiple PICUs. The final RESTORE trial was developed as a cluster randomized clinical trial where the unit of randomization was the PICU, stratified by PICU size, and the unit of inference was the patient. Study execution was revised based on our Data and Safety Monitoring Board’s recommendation to consult with the Department of Health and Human Services’ Office of Human Research Protection (OHRP) on how best to consent eligible subjects. OHRP deemed that the RESTORE intervention posed greater than minimal risk and that all enrolled subjects provide consent reflecting their level of participation.

Results

Thirty-one PICUs of varying size, organization and academic affiliation participated and over 2800 critically ill infants and children supported on mechanical ventilation for acute pulmonary disease were enrolled. The primary outcome for the trial was the duration of mechanical ventilation; secondary outcomes included time awake and comfortable, total sedative exposure and iatrogenic withdrawal symptoms. Throughout the clinical trial the investigative team worked to maintain treatment fidelity, enrollment milestones and co-investigator enthusiasm. We considered the potential impact of competing clinical trials through a decision-making framework.

Conclusions

The RESTORE clinical trial was a large and complex multicenter study that has provided the necessary evidence to guide sedation practices in the field of pediatric critical care. Specific issues that were unique to this trial included level of consent, adding clinical sites to augment enrollment and evaluating the potential impact of competing clinical trials.

Trial registration

ClinicalTrials.​gov, Identifiers: Pilot trial: NCT00142766; Retrospectively registerd on 2 September 2005.
Cluster randomized trial: NCT00814099. Registered on 23 December 2008.
Literature
1.
Rhoney DH, Murry KR. National survey on the use of sedatives and neuromuscular blocking agents in the pediatric intensive care unit. Pediatr Crit Care Med. 2002;3:129–33.CrossRef
2.
3.
Marx CM, Rosenberg DI, Ambuel B, Hamlett KW, Blumer JL. Pediatric intensive care sedation: survey of fellowship training programs. Pediatrics. 1993;91:369–78.PubMed
4.
Durbin CG. Sedation in the critically ill patient. New Horiz. 1994;2:64–74.PubMed
5.
Barrientos-Vega R, Mar Sanchez-Soria M, Morales-Garcia C, Robas-Gomez A, Cuena-Boy R, Ayensa-Rincon A. Prolonged sedation of critically ill patients with midazolam or propofol: impact on weaning and costs. Crit Care Med. 1997;25:33–40.CrossRef
6.
Brook AD, Ahrens TS, Schaiff R, et al. Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med. 1999;27:2609–15.CrossRef
7.
Kollef MH, Shapiro SD, Silver P, et al. A randomized, controlled trial of protocol-directed versus physician-directed weaning from mechanical ventilation. Crit Care Med. 1997;25:567–74.CrossRef
8.
Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;342:1471–7.CrossRef
9.
Randolph AG, Wypij D, Venkataraman ST, et al. Effect of mechanical ventilator weaning protocols on respiratory outcomes in infants and children: a randomized controlled trial. JAMA 2002;288:2561–1568.
10.
11.
Cook DJ, Walter SD, Cook RJ, et al. Incidence of and risk factors for ventilator-associated pneumonia in critically ill patients. Ann Intern Med. 1998;129:433–40.CrossRef
12.
Elward AM, Warren DK, Fraser VJ. Ventilator-associated pneumonia in pediatric intensive care unit patients: risk factors and outcomes. Pediatrics. 2002;109:758–64.CrossRef
13.
Schweickert WD, Gelbach BK, Pohlman AS, Hall JB, Kress JP. Daily interruption of sedative infusions and complications of critical illness in mechanically ventilated patients. Crit Care Med. 2004;32:1272–6.CrossRef
14.
Arnold JH, Truog RD, Orav EJ, Scavone JM, Hershenson MB. Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation. Anesthesiology. 1990;73:1136–40.CrossRef
15.
Arnold JH, Truog RD, Scavone JM, Fenton T. Changes in the pharmacodynamic response to fentanyl in neonates during continuous infusion. J Pediatr. 1991;119:639–43.CrossRef
16.
Fonsmark L, Rasmussen YH, Carl P. Occurrence of withdrawal in critically ill sedated children. Crit Care Med. 1999;27:196–9.CrossRef
17.
Anand KJ, Ingraham J. Pediatric tolerance, dependence, and strategies for compassionate withdrawal of analgesics and anxiolytics in the pediatric ICU. Crit Care Nurse. 1996;16:87–93.PubMed
18.
Franck LS, Vilardi J, Durand D, Powers R. Opioid withdrawal in neonates after continuous infusions of morphine or fentanyl during extracorporeal membrane oxygenation. Am J Crit Care. 1998;7:364–9.PubMed
19.
Tobias JD. Tolerance, withdrawal, and physical dependency after long-term sedation and analgesia of children in the pediatric intensive care unit. Crit Care Med. 2000;28:2122–32.CrossRef
20.
Schweickert W, Hall JB. Agitation in the critically ill patient: a marker of health or a plea for treatment? Crit Care Med. 2005;33:263–5.CrossRef
21.
Riker RR, Picard JT, Fraser GL. Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients. Crit Care Med. 1999;27:1325–9.CrossRef
22.
Bair N, Bobek MB, Hoffman-Hogg L, Mion LC, Slomka J, Arroliga AC. Introduction of sedative, analgesic, and neuromuscular blocking agent guidelines in a medical intensive care unit: physician and nurse adherence. Crit Care Med. 2000;28:707–13.CrossRef
23.
Kress JP, Gehlbach B, Lacy M, Pliskin N, Pohlman AS, Hall JB. The long-term psychological effects of daily sedative interruption on critically ill patients. American Respir Criti Care Med. 2003;168:1457–61.CrossRef
24.
Girard TD, Kress JP, Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet. 2008. https://​doi.​org/​10.​1016/​S0140-6736(08)60105-1.
25.
26.
Curley MAQ, Dodson BL, Arnold JH. Designing a nurse-implemented sedation algorithm for use in a pediatric intensive care unit. Pediatr Crit Care Med. 2003;4:A158.
27.
Lugo W, Lee E, Cash J, Vernon DD, Ward RM. Opioid abstinence syndrome in the PICU: frequency of signs. J Pediatr Pharmacol Ther. 2003;8:232–3.
28.
Fiser DH. Assessing the outcome of pediatric intensive care. J Pediatr. 1992;121:68–74.CrossRef
29.
Pollack MM, Patel KM, Ruttimann UE. The pediatric risk of mortality III—Acute physiology score (PRISM III-APS): a method of assessing physiologic instability for pediatric intensive care unit patients. J Pediatr. 1997;131:575–81.CrossRef
30.
Marcin JP, Rutan E, Rapetti PM, Brown JP, Rahnamayi R, Pretzlaff RK. Nurse staffing and unplanned extubation in the pediatric intensive care unit. Pediatr Crit Care Med. 2005;6:254–7.CrossRef
31.
Kapadia FN, Bajan KB, Raje KV. Airway accidents in intubated intensive care unit patients: an epidemiological study. Crit Care Med. 2000;28:659–64.CrossRef
32.
Rivera R, Tibballs J. Complications of endotracheal intubation and mechanical ventilation in infants and children. Crit Care Med. 1992;20:193–9.CrossRef
33.
Little LA, Koenig JC Jr, Newth CJ. Factors affecting accidental extubations in neonatal and pediatric intensive care patients. Crit Care Med. 1990;18:163–5.CrossRef
34.
Benjamin PK, Thompson JE, O’Rourke PP. Complications of mechanical ventilation in a children’s hospital multidisciplinary intensive care unit. Respir Care. 1990;35:873–8.PubMed
35.
Mann H. Controversial choice of a control intervention in a trial of ventilator therapy in ARDS: standard of care arguments in a randomised trial. J Med Ethics. 2005;31:548–53.CrossRef
36.
Bateman ST, Lacroix J, Boven K, Forbes P, Barton R, Thomas NJ, Jacobs B, Markovitz B, Goldstein B, Hanson JH, Li HA, Randolph AG, for thePediatric Acute Lung Injury and Sepsis Investigators Network. Anemia, blood loss, and blood transfusions in North American children in the intensive care unit. Am J Respir Crit Care Med. 2008. https://​doi.​org/​10.​1164/​rccm.​200711-1637OC.​
37.
Curley MAQ, Hibberd P, Finemean L, Wypj D, Mei-Chung S, Thompson J, et al. Effect of prone positioning on clinical outcomes in children with acute lung injury: a randomized controlled trial. JAMA. 2005;294(2):229–37.CrossRef
38.
Watson RS, Asaro LA, Hertzog JH, Sorce L, Kachmar AG, Dervan LA, Angus DC, Wypij D, Curley MAQ, for the RESTORE Study Investigators* and the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Long-term outcomes after protocolized sedation vs usual care in ventilated pediatric patients. Am J Respir Crit Care Med. 2018. https://​doi.​org/​10.​1164/​rccm.​201708-1768OC.
39.
Schoenfeld DA, Bernard GR, Network A. Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome. Crit Care Med. 2002;30:1772–7.CrossRef
40.
Lin DY, Wei LJ. The robust inference for the Cox proportional hazards model. J American Stat Assoc. 1989;84:1074–8.CrossRef
41.
O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35:549–56.CrossRef
42.
Xie T, Waksman J. Design and sample size estimation in clinical trials with clustered survival times as the primary endpoint. Stat Med. 2003;22:2835–46.CrossRef
43.
44.
45.
46.
47.
48.
Faustino EV, Gedeit R, Schwarz AJ, et al. Accuracy of an extubation readiness test in predicting successful extubation in children with acute respiratory failure from lower respiratory tract disease. Crit Care Med. 2017;45:94–102.CrossRef
49.
50.
51.
Cook DJ, Blythe D, Rischbieth, et al. Enrollment of intensive care unit patients into clinical studies: a trinational survey of researchers' experiences, beliefs, and practices. Crit Care Med. 2008;36:2100–5.CrossRef
52.
Randolph AG. The unique challenges of enrolling patients into multiple clinical trials. Crit Care Med. 2009;37:S107–11.CrossRef
53.
Larntz K, Neaton JD, Wentworth DN, Yurik T. Data analysis issues for protocols with overlapping enrollment. Stat Med. 1996;15:2445–53 discussion 2455-8.CrossRef
54.
Metadata
Title
Methods in the design and implementation of the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial
Authors
Martha A. Q. Curley
Rainer G. Gedeit
Brenda L Dodson
June K. Amling
Deborah J. Soetenga
Christiane O. Corriveau
Lisa A. Asaro
David Wypij
For the RESTORE Investigative Team
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Trials / Issue 1/2018
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-018-3075-8

Other articles of this Issue 1/2018

Trials 1/2018 Go to the issue

Methodology

Identifying trial recruitment uncertainties using a James Lind Alliance Priority Setting Partnership – the PRioRiTy (Prioritising Recruitment in Randomised Trials) study

Study protocol

A novel taping therapy for pain after arthroscopic shoulder surgery: study protocol for a randomised controlled pilot trial

Update

COmmunity-based Rehabilitation after Knee Arthroplasty (CORKA): statistical analysis plan for a randomised controlled trial

Study protocol

Protocol and methods for testing the efficacy of well-being therapy in chronic migraine patients: a randomized controlled trial

Study protocol

Electrically guided versus imaging-guided implant of the left ventricular lead in cardiac resynchronization therapy: a study protocol for a double-blinded randomized controlled clinical trial (ElectroCRT)

Study protocol

An intervention to support stroke survivors and their carers in the longer term (LoTS2Care): study protocol for the process evaluation of a cluster randomised controlled feasibility trial