Enteral Versus Intravenous Sedation in Critically Ill High-risk ICU Patients

Critical Illness Clinical Trial

Official title:

Multicentric, Single Blind, Randomized Controlled Trial on Enteral Sedation Versus Intravenous Sedation in Critically Ill High-risk ICU Patients

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01360346
• Other study ID #: SedaENvsIV
• Status: Recruiting
• Phase: Phase 3
• First received: May 20, 2011
• Last updated: April 23, 2012
• Start date: January 2012
• Est. completion date: December 2012

Study information

• Verified date: April 2012
• Source: University of Milan
• Contact: Giovanni Mistraletti, MD
• Phone: +39.339.8245014
• Email: giovanni.mistraletti[@]unimi.it
• Is FDA regulated: No
• Health authority: Italy: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

Recent studies suggest the employment of 'conscious' sedation (1) for critically high - risk patients (2), showing more efficacy then deep sedation (3). The investigators want to compare intravenous injection versus enteral sedative drugs administration, purposing to maintain a 'conscious' sedation level compatibly with the needed cares, invasive procedures, and medical and nursing surveillance.

Description:

Recent studies suggest the employment of 'conscious' sedation for critically high - risk patients (2), showing more efficacy then deep sedation (3). From this point of view it's important to consider both the choice of sedative drugs and the way to administer them to maintain the constant 'conscious' sedation level that the investigators wanted.

This research compares two different procedures for sedation therapy: through a randomized and blind controlled trial the interventional group will collect patients receiving sedatives from enteral way (4, 5, 6). In the control arm, sedation administration forecasts intravenous injection (7), recognised like the best practice in the most of intensive care units of the world.

To consider two different clinical approach for administration the investigators have to use different molecules: in the control arm propofol and midazolam will be continuously administered through intravenous injection with daily suspension (7); in the intervention arm the investigators will administer melatonin like a physiological hypnotic inductor (6), the continuous 'conscious' sedation will be maintained through hydroxyzine and eventually lorazepam (4), and all the active principles will be given by enteral administration.

The goal of the study is to compare intravenous injection versus enteral sedative drugs administration, analysing their efficacy and the feasibility to maintain constant the appropriate sedation level (RASS measured = RASS wished ±1) (8) in high - risk patients admitted in Intensive Care Unit (2), purposing to conserve a 'conscious' sedation level compatibly with the needed cares, invasive procedures, and medical and nursing surveillance.

MATERIALS AND METHODS Prospective, randomized and controlled multicentric, single blind trial. Participant ICU centres: San Paolo MI (Iapichino), Policlinico MI (Gattinoni) , Fatebenefratelli MI (Cigada), Niguarda MI (De Gasperi), Desio (Ronzoni), Legnano (Radrizzani), Monza (Pesenti), Belluno (Mazzon), Lugano (Malacrida), Modena (Rambaldi), Torino (Livigni), Asti (Cardellino).

PROCEDURE Bare minimum sedation drug titration will be done to maintain and to achieve prematurely a 'conscious' sedation level (RASS=0). During every shift it will be discussed the appropriate sedation therapy: if physicians choose a deep sedation goal (RASS <-3) this decision has to be explained and registered; then enteral sedation has to be maximized in randomized enteral patients group. If necessary intravenous sedation has to be added , and this procedure dose not represent a violation of research protocol.

If there is pain (VNR>3 or BPS>6) it will be administrated analgesic therapy according to hospital guidelines bare minimum duration. The treatment of procedural pain will be applied both groups trough Fentanest/Morphine + propofol/midazolam bolus intravenous, this procedure dose not represent a violation of research protocol.

If acute cerebral malfunction appears (CAM-ICU positive), it will be administrated haloperidol (1mg per os, max 10 mg/die) or other antipsychotic therapy according to hospital guidelines.

Enteral artificial nutrition with prokinetics will be started as soon as possible both group, while parenteral nutrition will be administered only if strictly necessary. If gastric stagnation > 200 ml/4 hours exceeds 2 days duration, it could be positioned nasogastric tube or digiunostomy.

All patients will be sit in a semiortopnoic position (bed back rest inclination between 30 and 45°).

STUDY POWER AND STATISTICAL ANALYSIS The investigators suppose to obtain a difference of 15% per cent between two arms for patients' sedation adequacy benefit (RASS = desired RASS + 1). Knowing that the enteral approach reached 83% adequacy from a observational monocentric research (5), it should be necessary to enrol 141 patients for each arm (power 80%). In consideration of the missing data, the investigators expect to enroll 300 patients. An "ad interim" statistical analysis is planned after the enrollment of 70 patients in each group.

To provide a statistical analysis as "Intention To Treat" for possible arms change risk.

It's planned to obtain a selective analysis involving each hospital included in the study.

It's planned to obtain a selective analysis about septic patients (greater delirium prevalence) (9).

It's planned to obtain a selective analysis divided for age (greater delirium prevalence if age >70) (10).

The randomization will be achieved trough out a particular Internet Website with a specific program expressly built. It will be used minimization technique to maintain groups balanced in the patients' sample of each centre.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: December 2012
• Est. primary completion date: October 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• High Risk Patients (Ventilation days assessment >3, SAPS II >32).

• Until 24 h after ICU admission

• Age > 18 years

Exclusion Criteria:

• Neurosurgical patients

• Allergy to medications used in the study

• CNS diseases (epilepsy, ictus, dementia, anoxic coma…)

• Liver encephalopathy (Child C)

• Previous psychiatric or cognitive pathology

• Absolute contraindications to use enteral route (acceptable NGT, digiunostomy, ileostomy)

• Pregnant patients or in breast-feeding

• DNR patients

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Critical Illness
• Mechanical Ventilation Complication

Intervention

Procedure:
• Enteral Sedation (EN)
Intravenous propofol or midazolam administration at the ICU admission and stopped within 48h. Melatonin by enteral route (3mg x 2/die) from admission to discharge. Hydroxyzine by enteral route from ICU admission (600mg/die), decreased and stopped as soon as possible. Lorazepam supplementation (maximum 16mg/die) if hydroxyzine is inadequate.
• Control group: Intravenous Sedation (IV)
Propofol or midazolam from ICU admission to discharge at the compatible lowest level with harsh ICU environment.

Locations

Country	Name	City	State
Italy	AO San Paolo - Polo Universitario	Milano

Sponsors (12)

Lead Sponsor

Collaborator

University of Milan

Azienda Ospedaliera Fatebenefratelli e Oftalmico, Azienda Ospedaliera Niguarda Cà Granda, Azienda Ospedaliera San Gerardo di Monza, Azienda Ospedaliera, Ospedale Civile di Legnano, IRCCS Policlinico S. Matteo, Nuovo Ospedale Civile S.Agostino Estense, Ospedale Cardinal Massaia, Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Ospedale S. Giovanni Bosco, Ospedale San Paolo, San Luigi Gonzaga Hospital

Country where clinical trial is conducted

Italy, 

References & Publications (13)

Cigada M, Corbella D, Mistraletti G, Forster CR, Tommasino C, Morabito A, Iapichino G. Conscious sedation in the critically ill ventilated patient. J Crit Care. 2008 Sep;23(3):349-53. doi: 10.1016/j.jcrc.2007.04.003. Epub 2007 Jul 5. — View Citation

Cigada M, Pezzi A, Di Mauro P, Marzorati S, Noto A, Valdambrini F, Zaniboni M, Astori M, Iapichino G. Sedation in the critically ill ventilated patient: possible role of enteral drugs. Intensive Care Med. 2005 Mar;31(3):482-6. Epub 2005 Feb 16. — View Citation

Girard TD, Kress JP, Fuchs BD, Thomason JW, Schweickert WD, Pun BT, Taichman DB, Dunn JG, Pohlman AS, Kinniry PA, Jackson JC, Canonico AE, Light RW, Shintani AK, Thompson JL, Gordon SM, Hall JB, Dittus RS, Bernard GR, Ely EW. 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 Jan 12;371(9607):126-34. doi: 10.1016/S0140-6736(08)60105-1. — View Citation

Iapichino G, Mistraletti G, Corbella D, Bassi G, Borotto E, Miranda DR, Morabito A. Scoring system for the selection of high-risk patients in the intensive care unit. Crit Care Med. 2006 Apr;34(4):1039-43. — View Citation

Inouye SK. Delirium in older persons. N Engl J Med. 2006 Mar 16;354(11):1157-65. Review. Erratum in: N Engl J Med. 2006 Apr 13;354(15):1655. — View Citation

Mistraletti G, Sabbatini G, Taverna M, Figini MA, Umbrello M, Magni P, Ruscica M, Dozio E, Esposti R, DeMartini G, Fraschini F, Rezzani R, Reiter RJ, Iapichino G. Pharmacokinetics of orally administered melatonin in critically ill patients. J Pineal Res. 2010 Mar;48(2):142-7. doi: 10.1111/j.1600-079X.2009.00737.x. Epub 2010 Jan 8. — View Citation

Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, Shintani AK, Thompson JL, Jackson JC, Deppen SA, Stiles RA, Dittus RS, Bernard GR, Ely EW. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007 Dec 12;298(22):2644-53. — View Citation

Pandharipande PP, Sanders RD, Girard TD, McGrane S, Thompson JL, Shintani AK, Herr DL, Maze M, Ely EW; MENDS investigators. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial. Crit Care. 2010;14(2):R38. doi: 10.1186/cc8916. Epub 2010 Mar 16. Erratum in: Crit Care. 2011;15(1):402. — View Citation

Payen JF, Chanques G, Mantz J, Hercule C, Auriant I, Leguillou JL, Binhas M, Genty C, Rolland C, Bosson JL. Current practices in sedation and analgesia for mechanically ventilated critically ill patients: a prospective multicenter patient-based study. Anesthesiology. 2007 Apr;106(4):687-95; quiz 891-2. — View Citation

Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, Whitten P, Margolis BD, Byrne DW, Ely EW, Rocha MG; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009 Feb 4;301(5):489-99. doi: 10.1001/jama.2009.56. Epub 2009 Feb 2. — View Citation

Schoenfeld DA, Bernard GR; ARDS Network. Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome. Crit Care Med. 2002 Aug;30(8):1772-7. — View Citation

Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O'Neal PV, Keane KA, Tesoro EP, Elswick RK. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002 Nov 15;166(10):1338-44. — View Citation

Strøm 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. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent of efficacy, measured by observed RASS = desired RASS ± 1.		One year	Yes
Secondary	Sedation protocol effectiveness: percentage of "protocol violation days" on the total of ICU days.		One year	Yes
Secondary	Delirium and coma free days (respectively negative CAM-ICU and RASS > - 3 in all daily observations until 28° ICU day) (11)		One year	Yes
Secondary	Ventilation free days (12)		One year	Yes
Secondary	Nursing evaluation of sedation adequacy (communication skills, cooperation, environment tolerance) (13)		One year	Yes
Secondary	Overall ICU and hospital mortality, absolute mortality after 1 year from ICU discharge.		24 months	No
Secondary	Sedative drugs costs.		One year	No
Secondary	Indirect inefficacy markers	Prevalence of 'dangerous episodes': self - extubation, removal of other invasive clinical instruments; Length of ICU and hospital stay; Use of anti-psychotic drugs (indirect delirium marker); Other indicators of sedation failure: use of restraining therapies, antagonist administrations (fluamzenil - naloxone).	One year	Yes