Enteral versus intravenous approach for the sedation of critically ill patients: a randomized and controlled trial

Giovanni Mistraletti, Michele Umbrello, Silvia Salini, Paolo Cadringher, Paolo Formenti, Davide Chiumello, Cristina Villa, Riccarda Russo, Silvia Francesconi, Federico Valdambrini, Giacomo Bellani, Alessandra Palo, Francesca Riccardi, Enrica Ferretti, Maurilio Festa, Anna Maria Gado, Martina Taverna, Cristina Pinna, Alessandro Barbiero, Pier Alda Ferrari, Gaetano Iapichino, SedaEN investigators, Gaetano Iapichino, Alberto Morabito, Martin Langer, Franco Valenza, Roberto Malacrida, Marco Rambaldi, Giovanni Mistraletti, Davide Chiumello, Michele Umbrello, Paolo Formenti, Paolo Spanu, Stefania Anania, Elisa Andrighi, Alessandra Di Carlo, Federica Martinetti, Serena Barello, Andrea Noto, Gianfranco Capello, Bruno Sabatelli, Giovanni Brenna, Morena Astori, Pietro Placido, Luciano Gattinoni, Alessandro Protti, Paolo Cadringher, Riccarda Russo, Francesca Pagan, Virna Berto, Paola Roselli, Giulio Ronzoni, Eduardo Beck, Silvia Francesconi, Maurizio Gaiotto, Danilo Radrizzani, Luca Ferla, Federico Valdambrini, Riccardo Giudici, Laura Merlini, Antonio Pesenti, Giacomo Bellani, Alessia La Bruna, Emanuele Rezoagli, Alberto Lucchini, Antonio Braschi, Alessandra Palo, Thekla Niebel, Marina Selvini, Sergio Cortesi, Attilio Quaini, Giorgio Iotti, Francesca Riccardi, Enrico Contri, Antonella Sacchi, Sergio Livigni, Giuseppe Naretto, Enrica Ferretti, Alessandro Deprado, Virna Venturi Degli Esposti, Pietro Caironi, Giulio Radeschi, Maurilio Festa, Lorenzo Odetto, Daniele Ferrero, Stefano Cognolato, Roberto Penso, Roberta Vacchelli, Silvano Cardellino, Edda Bosco, Anna Maria Gado, Anna Bresciani, Ivana Pozzo, Annachiara Alessio, Vanessa Clarindo Rodrigues, Edna Biase, Nicoletta Vivaldi, Martina Taverna, Antonella Nava, Cristina Pinna, Francesco Ponzetta, Lucilla Bavutti, Paola Martina, Beatriz Palacios, Giancarla Bergonzini, Giovanni Mistraletti, Michele Umbrello, Silvia Salini, Paolo Cadringher, Paolo Formenti, Davide Chiumello, Cristina Villa, Riccarda Russo, Silvia Francesconi, Federico Valdambrini, Giacomo Bellani, Alessandra Palo, Francesca Riccardi, Enrica Ferretti, Maurilio Festa, Anna Maria Gado, Martina Taverna, Cristina Pinna, Alessandro Barbiero, Pier Alda Ferrari, Gaetano Iapichino, SedaEN investigators, Gaetano Iapichino, Alberto Morabito, Martin Langer, Franco Valenza, Roberto Malacrida, Marco Rambaldi, Giovanni Mistraletti, Davide Chiumello, Michele Umbrello, Paolo Formenti, Paolo Spanu, Stefania Anania, Elisa Andrighi, Alessandra Di Carlo, Federica Martinetti, Serena Barello, Andrea Noto, Gianfranco Capello, Bruno Sabatelli, Giovanni Brenna, Morena Astori, Pietro Placido, Luciano Gattinoni, Alessandro Protti, Paolo Cadringher, Riccarda Russo, Francesca Pagan, Virna Berto, Paola Roselli, Giulio Ronzoni, Eduardo Beck, Silvia Francesconi, Maurizio Gaiotto, Danilo Radrizzani, Luca Ferla, Federico Valdambrini, Riccardo Giudici, Laura Merlini, Antonio Pesenti, Giacomo Bellani, Alessia La Bruna, Emanuele Rezoagli, Alberto Lucchini, Antonio Braschi, Alessandra Palo, Thekla Niebel, Marina Selvini, Sergio Cortesi, Attilio Quaini, Giorgio Iotti, Francesca Riccardi, Enrico Contri, Antonella Sacchi, Sergio Livigni, Giuseppe Naretto, Enrica Ferretti, Alessandro Deprado, Virna Venturi Degli Esposti, Pietro Caironi, Giulio Radeschi, Maurilio Festa, Lorenzo Odetto, Daniele Ferrero, Stefano Cognolato, Roberto Penso, Roberta Vacchelli, Silvano Cardellino, Edda Bosco, Anna Maria Gado, Anna Bresciani, Ivana Pozzo, Annachiara Alessio, Vanessa Clarindo Rodrigues, Edna Biase, Nicoletta Vivaldi, Martina Taverna, Antonella Nava, Cristina Pinna, Francesco Ponzetta, Lucilla Bavutti, Paola Martina, Beatriz Palacios, Giancarla Bergonzini

Abstract

Background: ICU patients must be kept conscious, calm, and cooperative even during the critical phases of illness. Enteral administration of sedative drugs might avoid over sedation, and would be as adequate as intravenous administration in patients who are awake, with fewer side effects and lower costs. This study compares two sedation strategies, for early achievement and maintenance of the target light sedation.

Methods: This was a multicenter, single-blind, randomized and controlled trial carried out in 12 Italian ICUs, involving patients with expected mechanical ventilation duration > 72 h at ICU admission and predicted mortality > 12% (Simplified Acute Physiology Score II > 32 points) during the first 24 h on ICU. Patients were randomly assigned to receive intravenous (midazolam, propofol) or enteral (hydroxyzine, lorazepam, and melatonin) sedation. The primary outcome was percentage of work shifts with the patient having an observed Richmond Agitation-Sedation Scale (RASS) = target RASS ±1. Secondary outcomes were feasibility, delirium-free and coma-free days, costs of drugs, length of ICU and hospital stay, and ICU, hospital, and one-year mortality.

Results: There were 348 patients enrolled. There were no differences in the primary outcome: enteral 89.8% (74.1-100), intravenous 94.4% (78-100), p = 0.20. Enteral-treated patients had more protocol violations: n = 81 (46.6%) vs 7 (4.2%), p < 0.01; more self-extubations: n = 14 (8.1%) vs 4 (2.4%), p = 0.03; a lighter sedative target (RASS = 0): 93% (71-100) vs 83% (61-100), p < 0.01; and lower total drug costs: 2.39 (0.75-9.78) vs 4.15 (1.20-20.19) €/day with mechanical ventilation (p = 0.01).

Conclusions: Although enteral sedation of critically ill patients is cheaper and permits a lighter sedation target, it is not superior to intravenous sedation for reaching the RASS target.

Trial registration: ClinicalTrials.gov, NCT01360346 . Registered on 25 March 2011.

Keywords: Hydroxyzine; Hypnotics and sedatives; Melatonin; Nursing education research; Patient care planning.

Conflict of interest statement

Ethics approval and consent to participate

All participating centers obtained local ethics committee approvals to conduct the trial.

The coordinating center approval was issued by Comitato Etico of A.O. San Paolo - Polo Universitario, Milano: Prot.34/Reg.delibere 2011/CE on 23 February 2011.

The other ethics committees were:

  1. Comitato Etico Interaziendale for the centers A.O.N. SS. Antonio e Biagio e Cesare Arrigo, Alessandria, and A.O. Ospedale Cardinal Massaia, Asti: Prot. 20848 on 16 September 2011

  2. Comitato Etico of A.O. Ospedale Civile di Desio (MI): Prot. 17235 on 28 July 2011

  3. Comitato Etico of A.O. Ospedale Civile di Legnano (MI): Prot. 15/12 on 18 May 2012

  4. ‘Comitato etico’ of N.O.C. Sant’Agostino Estense, Modena: Prot. 3083/CE of September 13, 2011.

  5. Comitato Etico of A.O. San Gerardo, Monza (MB): Parere on 17 November 2011

  6. Comitato Etico of A.O.U. San Luigi Gonzaga, Orbassano (TO): Prot. 18362 on 23 September 2011

  7. Comitato Etico of I.R.C.C.S Ospedale Maggiore Policlinico, Milano: Parere on 13 December 2011

  8. Comitato Etico of I.R.C.C.S. San Matteo, Pavia: Prot. 48199 on 3 March 2012

  9. Comitato Etico of A.O. San Giovanni Bosco, Torino: Prot. 43718 on 3 August 2011

Written informed consent was mandatory for all able patients. When it could not be given, a written declaration of information received was collected from relatives, according to local ethics committee indications. As soon as patients’ neurological conditions improved, all enrolled patients were duly informed of the study and their written consent was obtained, both for the use of previously collected data, and for all prospective treatments and data collection. Patients or their next of kin could request withdrawal from the study at any time.

Consent for publication

Besides informed consent to participate, specific permission to use anonymized data for scientific purposes was collected from all patients.

Competing interests

All the authors, the Steering Committee members, and the SedaEN investigators declare they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
The Consolidated Standards of Reporting Trials (CONSORT) diagram for screening and randomization in the “Enteral versus intravenous sedation” (SedaEN) trial. The 339 patients were analyzed using an intention-to-treat approach, without considering treatment interruptions. ICU, intensive care unit; MV, mechanical ventilation; SAPS II, Simplified Acute Physiology Score II; CNS, central nervous system; DNR, do not resuscitate orders; IV, intravenous; EN, enteral
Fig. 2
Fig. 2
A Percentage of shifts in total ICU stay. Main outcome means the Richmond Agitation Sedation Scale RASS observed = RASS target ±1. RASS at target means RASS observed = RASS target. Too sedated means RASS observed < RASS target. Too agitated means RASS observed > RASS target. B Absolute number of RASS observations. *P <0.05. ICU, Intensive Care Unit; IV, intravenous; EN, enteral

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