Analgesia-First Sedation in Trauma Patients

The study's aim is to ascertain the best approach for providing sedation and pain management for patients who have sustained trauma and are requiring respiratory support from a mechanical ventilator. The common approach to patients who need mechanical ventilation is to provide continuous drips of sedatives and pain medicine and awaken the patient once a day to check the brain functions. Another approach is to provide pain medicine and reserve sedatives for only a short duration when needed. The difference between approaches has not been studied in Trauma patients.

Study Overview

• Status: Recruiting
• Conditions: Respiratory Failure; Mechanical Ventilation
• Intervention / Treatment: Other: Analgesia First Sedation Strategy for Mechanically Ventilated (MV) Trauma Subjects; Other: Protocol Directed Sedation and Daily Sedation Interruption

Detailed Description

A significant proportion of patients admitted to the intensive care unit (ICU) require mechanical ventilation (MV). To facilitate care and maintain comfort for patients requiring MV, the utilization of a large quantity of sedatives and analgesics is required with either continuous infusion or intermittent dosing. However, prolonged continuous administration of sedatives and analgesics can contribute to prolonged MV. Numerous studies have shown that instituting protocol-directed sedation (PDS) by continuous infusion of sedatives and analgesics using a protocol that includes a daily interruption (DI) of the sedative will improve MV outcomes, specifically the duration of MV.

Protocol-directed sedation and daily sedation interruption:

Brook AD et al. performed a randomized, single-center, clinical trial; comparing protocol-directed sedation versus non-protocol-directed sedation in 321 mechanically ventilated patients. They included patients greater than the age of who were admitted to the medical intensive care unit. Based on randomization, 162 patients received protocol-directed sedation and 159 patients received non-protocol-directed sedation. The primary outcome measure was the duration of mechanical ventilation and secondary outcomes included: the length of ICU and hospital stay. The results revealed a reduction in the mean duration of mechanical ventilation for the protocol-directed sedation group (89.1 ± 133.6 hrs vs. 124.0 ± 153.6 hrs; p = .003). In addition, the protocol-directed sedation group had a reduced length of stay in the intensive care unit and hospital {5.7 ± 5.9 days vs. 7.5 ± 6.5 days (p = .013) and 14.0 ± 17.3 days vs. 19.9 ± 24.2 days (p < .001); respectively}. The protocol-directed sedation group (n = 66) had a reduced duration of continuous intravenous sedation (3.5 ± 4.0 days vs. 5.6 ± 6.4 days; p = .003). Brook's study demonstrated the clinical benefits of having protocol-directed or nurse-directed sedation in the medical intensive care unit. Since the study only involved patients in the medical intensive care unit, it is uncertain if the results are applicable to patients in the surgical unit.

Kress JP, et al. performed a randomized, single-center, clinical trial to evaluate daily interruption of continuous infusion of sedation in 128 mechanically ventilated adult patients. Notable exclusion criteria included patients already on sedative agents upon transfer to the ICU and admission due to resuscitation from cardiac arrest. The primary endpoints of the study included: the duration of mechanical ventilation, the length of stay in the intensive care unit, and the length of stay in the hospital. Total doses of sedatives (i.e. midazolam, propofol) and analgesic agents (i.e. morphine) were additional measured outcomes. Results from the study revealed a reduction in the median duration of mechanical ventilation for the daily interrupted group (4.9 vs. 7.3 days, p=.004). In addition, there was a reduction in the median length of stay in the ICU and hospital (6.4 vs. 9.9 days, p=.02 and 13.3 vs. 16.9 days, p=0.19; respectively). The total dose of midazolam was lesser in the daily interruption group (229.8 vs. 425.5 mg; p=.05). The study found no difference in regard to the incidence of self-extubation. Kress' study showed positive clinical outcomes with DI in the medical intensive care unit. However, many clinicians are concerned with the risk-related complications from DI (i.e. posttraumatic stress disorder and enhanced catecholamine response leading to cardiac complications). The study did contain limitations: it was limited to a single center and only included patients that were admitted to the medical intensive care unit. Thus, it is not clear if the results can be reproduced in other centers or applied to critically-ill surgical patients. Additionally, there was no mention of the use of PD-SBTs

Can analgesia first effectively facilitate mechanical ventilation for critically ill patients?

Strøm T et al evaluated the analgesia first in critically ill patients requiring mechanical ventilation. This was a randomized controlled trial involving 140 patients who were assigned in a 1:1 ratio to no sedation with analgesia (analgesia-first) group or sedation with DI group. The analgesia-first group or intervention arm received analgesics for pain control and sedation only if the analgesia-first approach failed. The intervention arm had significantly more days without ventilation (13.8 days ± 11.0 vs. 9.6 ± 10.0; p=0.0191) and shorter ICU days and hospital days. No difference was recorded in the occurrences of accidental extubations, but delirium was significantly higher in the analgesia-first group (20% vs. 7%, p=0.04).

Conclusion:

A literature search did not reveal any published studies demonstrating whether trauma patients should be managed with an AFS approach. This study will evaluate mechanical ventilation and ICU outcomes associated with the AFS approach to facilitate mechanical ventilation in critically ill patients. All patients will be managed with institutional-approved PDS-DSI or AFS protocols in the ICU.

- Rationale for the study

A limited number of randomized controlled trials:

Using the terms sedation and analgesia, mechanical ventilation discontinuation/weaning, critically ill, and trauma adult patients, a literature review was conducted to identify peer-reviewed articles in MEDLINE (1966-November 2021). Articles reviewed included those published in the English language, review articles, and trials with an emphasis on prospective, randomized, double-blind, placebo-controlled clinical trials. Reference citations were reviewed as an additional resource. The literature search revealed no studies that included the implementation of an AFS in trauma patients.

Which approach is preferred? There are no published studies demonstrating whether patients should be on AFS versus PDS-DSI for the management of trauma patients requiring mechanical ventilation beyond 48 hours.

How will this trial help? - Literature review

The above-mentioned literature review and search revealed no studies that included the implementation of an AFS versus PDS-DSI in ICUs. In addition, under these circumstances, it is uncertain if an AFS allowing minimal sedation is as efficacious and safe in comparison to a PDS-DSI.

- Use of trial results

The results of this study are clinically and economically relevant. The clinical data will provide information on what is the preferred sedation practice during mechanical ventilation weaning. In addition, the study will support a multi-disciplinary approach to managing mechanically ventilated patients. The measured outcomes from the study will generate further research to improve patient outcomes, specifically in mechanically ventilated patients. The economic implications can be potentially derived from the length of ICU or hospital stay.

• Study Type: Interventional
• Enrollment (Anticipated): 170
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Long Beach, California, United States, 90806
      • Recruiting
      • Long Beach Memorial Medical Center
      • Contact: Hyunsoon Park, RN; Phone Number: 562-933-7176; Email: hpark@memorialcare.org
      • Principal Investigator: Maged Tanios, MD. MPH

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. ≥ 18 years of age
2. Mechanically ventilated with an expected duration of MV ≥ 48h
3. Initiated continuous sedative/analgesic infusions by the ICU team
4. Patient is a candidate for MV weaning

Exclusion Criteria:

1. Admission after resuscitation from cardiac arrest
2. Significant neurological deficit due to a chronic disorder
3. History of alcohol dependence and/or other illicit drug abuse
4. Prior administration of continuous sedative/analgesic from a transferring institution
5. Patient receiving neuromuscular blocking agents
6. Allergy to midazolam, lorazepam, and/or propofol

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Analgesia First Sedation; Subjects will be randomized to receive analgesia-first sedation by intermittent doses of Fentanyl (25 mcg), instead of continuous IV infusions. If the intermittent IVP x4 fails to achieve the target pain score, an infusion starts at 50 mcg/hr and titration by 25 mcg q15 minutes. If sedation score is not achieved, propofol infusion starts at 5 mcg/kg/min to achieve goal RASS of 0 to -2. Subjects will be assessed for a ventilator weaning trial daily.	Other: Analgesia First Sedation Strategy for Mechanically Ventilated (MV) Trauma Subjects; The Intervention is using a sedation strategy for MV trauma that initially targets pain by intermittent boluses followed by an IV drip only if required. Sedatives are limited to agitation management and for a limited duration as needed. This "analgo-sedation" approach differs from the approach of using IV drips of analgesics and sedatives simultaneously and discontinuing both once daily to assess subjects.
Active Comparator: Protocol Directed Sedation and Daily Sedation Interruption; Subjects will receive Fentanyl for analgesia and midazolam for sedation management. The RASS score is used to guide sedation to a goal of 0 to -2 and daily sedation by IV Midazolam at 1 mg/hr and titrated by 1 mg/hr q60 mins. Midazolam boluses are allowed by 1 mg IVP q5 mins x2 before increasing the infusion rate. Propofol and dexmedetomidine are permitted under existing institutional sedation protocol. Fentanyl IV starts at 50 mcg/hr and is titrated by 25 mcg/hr q15 mins to achieve target pain score. Fentanyl bolus of 25 mcg IVP q5 min x2 doses is given before increasing the infusion rate. Daily sedation interruption (DSI) is performed daily and ventilator weaning trial if they pass.	Other: Protocol Directed Sedation and Daily Sedation Interruption; The active comparator in this study is using a sedation strategy for MV trauma that uses IV drips of analgesics and sedatives simultaneously and discontinues both once daily to assess subjects.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mechanical Ventilation days until successful extubation	Duration of mechanical ventilation	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of MV weaning	Time from initiation of MV weaning to successful extubation	28 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
ICU length of stay	Duration of ICU stay (days)	28 days
Adverse Events related to Mechanical Ventilation	The occurrence of any adverse event that is related to MV (e.g., unplanned extubation, delirium)	28 days

Collaborators and Investigators

• Sponsor: MemorialCare Health System

Publications and helpful links

General Publications

• Devlin JW, Skrobik Y, Gelinas C, Needham DM, Slooter AJC, Pandharipande PP, Watson PL, Weinhouse GL, Nunnally ME, Rochwerg B, Balas MC, van den Boogaard M, Bosma KJ, Brummel NE, Chanques G, Denehy L, Drouot X, Fraser GL, Harris JE, Joffe AM, Kho ME, Kress JP, Lanphere JA, McKinley S, Neufeld KJ, Pisani MA, Payen JF, Pun BT, Puntillo KA, Riker RR, Robinson BRH, Shehabi Y, Szumita PM, Winkelman C, Centofanti JE, Price C, Nikayin S, Misak CJ, Flood PD, Kiedrowski K, Alhazzani W. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018 Sep;46(9):e825-e873. doi: 10.1097/CCM.0000000000003299.
• 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 May 18;342(20):1471-7. doi: 10.1056/NEJM200005183422002.
• Strom T, Martinussen T, Toft P. A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial. Lancet. 2010 Feb 6;375(9713):475-80. doi: 10.1016/S0140-6736(09)62072-9. Epub 2010 Jan 29.
• Mehta S, Burry L, Cook D, Fergusson D, Steinberg M, Granton J, Herridge M, Ferguson N, Devlin J, Tanios M, Dodek P, Fowler R, Burns K, Jacka M, Olafson K, Skrobik Y, Hebert P, Sabri E, Meade M; SLEAP Investigators; Canadian Critical Care Trials Group. Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: a randomized controlled trial. JAMA. 2012 Nov 21;308(19):1985-92. doi: 10.1001/jama.2012.13872. Erratum In: JAMA. 2013 Jan 16;309(3):237.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2023
• Primary Completion (Anticipated): March 1, 2025
• Study Completion (Anticipated): September 1, 2025

Study Registration Dates

• First Submitted: February 17, 2023
• First Submitted That Met QC Criteria: February 28, 2023
• First Posted (Actual): March 2, 2023

Study Record Updates

• Last Update Posted (Actual): May 3, 2023
• Last Update Submitted That Met QC Criteria: May 1, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Analgesia; Sedation; Trauma; Intubation
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Respiratory Insufficiency
• Other Study ID Numbers: 279-22

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