Figure 2 shows the differences in medication use for continuous sedative and analgesic infusions used in the ICU. Fewer patients were managed with continuous propofol infusions in 2013 than 2011 (92.3% vs 13.9%, P < 0.0001), and more patients were managed with continuous fentanyl infusions in 2013 than 2011 (20.0% vs 65.8%, P < 0.0001). Although 92.3% of patients in the preimplementation group were exposed to continuous infusions of sedatives (ie, propofol, dexmedetomidine, midazolam, lorazepam, or ketamine), only 38.0% of patients postimplementation required these medications (P < 0.001). The percentage of patients exposed to both sedative and analgesic infusions did not differ between groups (92.3% preimplementation compared with 83.5% postimplementation, P = 0.13). Use of the analgosedation protocol resulted in an average per patient medication cost of $293.98 ± $641.37 compared with $519.05 ± $880.53 with the 2011 sedation protocol (difference, 225.07; P = 0.0786; 95% CI, −476.18 to 26.04).
Analgosedation and targeting light levels of sedation are new paradigms in ICU management of patients on mechanical ventilation and form the basis for our current sedation practice.4 Our study demonstrated that an analgosedation protocol was associated with a lighter overall level of sedation than a previous sedative-based strategy. In addition, we found a shorter duration of mechanical ventilation time and ICU LOS. The study also demonstrated a significant decrease in the use of continuous infusion sedative agents, a significant increase in analgesics, and a potential reduction in associated medication costs.
Because blinding caregivers to specific sedation regimens is difficult, studies of analgosedation are challenging to perform. A 2012 review and critique of analgosedation studies found that analgosedation appears to be well tolerated and may improve patient outcomes.4 However, analgosedation studies have also been criticized for study design, analgesic selection, or feasibility. A 2010 trial5 assessing the impact of a “no sedation” scheme randomized patients to either continuous infusions of propofol or midazolam or to an analgesia-first method of morphine boluses only. Although the study demonstrated that patients in the “no sedation” arm experienced a shorter duration of mechanical ventilation and shorter ICU LOS, this study had several limitations. The choice of morphine for analgosedation has been associated with more frequent incidences of delirium, hypotension, anticholinergic effects, and renal impairment,12 which may have contributed to the higher incidence of delirium in the “no sedation” arm (20% vs 7%). This increase in delirium may also have been because of difficulty in detecting hypoactive delirium in more sedated patients. Finally, the use of 1:1 nursing during this study raises the question of whether such a strategy is feasible in other critical care settings.
A more recent 2014 retrospective study evaluated patients who required either continuous infusion fentanyl or continuous infusion propofol for management of agitation and sedation while on mechanical ventilation.8 Fentanyl infusion use reduced the need for rescue analgesia compared with propofol. Both duration of mechanical ventilation and frequency of gastrointestinal side effects were similar between groups. Our study differs from this one in several ways. We did not mandate patients be managed with continuous infusions. With implementation of our analgesia-first protocol, we successfully managed 16.5% of patients with only intermittent, IV boluses of fentanyl and midazolam.
In contrast to our study, many other analgosedation studies have used remifentanil, a short-acting opioid agonist.4,6,13,14 Trials comparing remifentanil with a sedative-hypnotic have demonstrated acceptable safety and a shortened duration of mechanical ventilation.4,6 However, remifentanil must be administered through continuous infusion, is associated with rebound hyperalgesia, and is more costly than other agents.13 A single study has compared remifentanil with fentanyl and found comparable outcomes between the agents.14
Another criticism of analgosedation studies has been the inconsistent use of daily sedation interruption. Although early studies found benefit to this strategy,15 a 2012 multicenter trial of 430 mechanically ventilated adults demonstrated that when compared with light levels of sedation, daily sedative interruption did not affect the time to successful extubation, duration of ICU or hospital LOS, or rates of delirium.16 Sedation interruption was an element of our sedation strategy in both 2011 and 2013 groups, possibly explaining why we did not observe reductions in LOS or duration of mechanical ventilation. With our protocol, we achieved a significantly lighter level of sedation and a significant reduction in oversedation during the first day of ICU care, which has been associated with improved outcomes in mechanically ventilated patients.17,18
Our study has several strengths. To maximize generalizability, our retrospective study was conducted in the MICU of a community, teaching hospital and did not interfere with clinical care. Our protocol was a multidisciplinary product of collaboration between clinical pharmacy, intensive care physicians, and ICU nursing staff. We did not employ specific “sedation” nurses or research staff. Before new protocol implementation, nurses, physicians, and other critical care providers were reeducated on the utility of RASS levels, titration of continuous infusion medications, and appropriate documentation. The study was conducted 6 months after implementation to ensure uniformity of practices among different health care providers. The institution used both RASS and CPOT, 2 of the validated, recommended tools for assessing pain and agitation in the ICU.1 We did not change the management of ventilator patients between time periods, including spontaneous awakening and spontaneous breathing trials. In addition, multiple baseline characteristics were similar between the 2 groups, limiting the potential effect of confounding factors such as severity of illness, underlying pulmonary diseases, and previous exposure to opioids and benzodiazepines.
Our study also had several limitations. Because it was performed in the MICU, our findings may not be generalizable to patients in other settings such as the surgical ICU, trauma ICU, or long-term ventilator care units. The inherent noncontrolled nature of a retrospective study also raises the possibility of confounding variables, which may have influenced study outcomes. It is possible that changes to practice from 2011 to 2013 may have affected our results, although we found that only the analgosedation protocol and type of admission were associated with duration of mechanical ventilation in the linear regression model. Although our protocol allowed for lighter levels of sedation with the use of an analgesia-first strategy, other factors including improved pain control may have affected the duration of mechanical ventilation. Thus, our findings should be considered hypothesis generating only, and randomized, controlled studies are needed to validate our results. We also did not assess the incidence of delirium between 2011 and 2013 because the Confusion Assessment Method for ICU was not fully implemented until after the 2011 study period. However, based on the guidelines and existing literature, managing pain and agitation with an analgosedation protocol is likely to reduce exposure to sedative-hypnotics, increase the rates of early mobilization of mechanically ventilated patients, and thus decrease the incidence of iatrogenic-induced delirium.
This study demonstrated that implementation of an analgesia-based sedation protocol, primarily with fentanyl, was correlated with lighter sedation levels, better pain management, and reduced both average duration of mechanical ventilation and ICU LOS. Further prospective, randomized studies are needed to fully elucidate the potential role of analgosedation in the critical care of ventilated patients.
Name: Andrew C. Faust, PharmD, BCPS.
Contribution: This author helped design the study, conduct the study, analyze the data, and prepare the manuscript, and is the archival author.
Name: Pearl Rajan, PharmD, BCPS.
Contribution: This author helped design the study, conduct the study, analyze the data, and prepare the manuscript.
Name: Lyndsay A. Sheperd, PharmD, BCPS.
Contribution: This author helped design the study, analyze the data, and prepare the manuscript.
Name: Carlos A. Alvarez, PharmD, MSc, MSCS, BCPS.
Contribution: This author helped analyze the data and prepare the manuscript.
Name: Phyllis McCorstin, APRN, CNS.
Contribution: This author helped design the study, conduct the study, and prepare the manuscript.
Name: Rebecca L. Doebele, MD.
Contribution: This author helped design the study and prepare the manuscript.
This manuscript was handled by: Avery Tung, MD.
1. Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, Davidson JE, Devlin JW, Kress JP, Joffe AM, Coursin DB, Herr DL, Tung A, Robinson BR, Fontaine DK, Ramsay MA, Riker RR, Sessler CN, Pun B, Skrobik Y, Jaeschke R; American College of Critical Care Medicine. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013;41:263–306.
2. Skrobik Y, Ahern S, Leblanc M, Marquis F, Awissi DK, Kavanagh BP. Protocolized intensive care unit management of analgesia, sedation, and delirium improves analgesia and subsyndromal delirium rates. Anesth Analg 2010;111:451–63.
3. Reade MC, Finfer S. Sedation and delirium in the intensive care unit. N Engl J Med 2014;370:444–54.
4. Devabhakthuni S, Armahizer MJ, Dasta JF, Kane-Gill SL. Analgosedation: a paradigm shift in intensive care unit sedation practice. Ann Pharmacother 2012;46:530–40.
5. Strøm T, Martinussen T, Toft P. A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial. Lancet 2010;375:475–80.
6. Rozendaal FW, Spronk PE, Snellen FF, Schoen A, van Zanten AR, Foudraine NA, Mulder PG, Bakker J; UltiSAFE Investigators. Remifentanil-propofol analgo-sedation shortens duration of ventilation and length of ICU stay compared to a conventional regimen: a centre randomised, cross-over, open-label study in the Netherlands. Intensive Care Med 2009;35:291–8.
7. Afsharimani B, Cabot P, Parat MO. Morphine and tumor growth and metastasis. Cancer Metastasis Rev 2011;30:225–38.
8. Tedders KM, McNorton KN, Edwin SB. Efficacy and safety of analgosedation with fentanyl compared with traditional sedation with propofol. Pharmacotherapy 2014;34:643–7.
9. 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;166:1338–44.
10. Gélinas C, Fillion L, Puntillo KA, Viens C, Fortier M. Validation of the critical-care pain observation tool in adult patients. Am J Crit Care 2006;15:420–7.
11. Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA 1993;270:2957–63.
12. Patel SB, Kress JP. Sedation and analgesia in the mechanically ventilated patient. Am J Respir Crit Care Med 2012;185:486–97.
13. Joly V, Richebe P, Guignard B, Fletcher D, Maurette P, Sessler DI, Chauvin M. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology 2005;103:147–55.
14. Muellejans B, López 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;8:R1–R11.
15. 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;371:126–34.
16. 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, Hébert 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;308:1985–92.
17. Shehabi Y, Chan L, Kadiman S, Alias A, Ismail WN, Tan MA, Khoo TM, Ali SB, Saman MA, Shaltut A, Tan CC, Yong CY, Bailey M; Sedation Practice in Intensive Care Evaluation (SPICE) Study Group investigators. Sedation depth and long-term mortality in mechanically ventilated critically ill adults: a prospective longitudinal multicentre cohort study. Intensive Care Med 2013;39:910–8.
18. Shehabi Y, Bellomo R, Reade MC, Bailey M, Bass F, Howe B, McArthur C, Seppelt IM, Webb S, Weisbrodt L; Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators; ANZICS Clinical Trials Group. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med 2012;186:724–31.
Supplemental Digital Content
© 2016 International Anesthesia Research Society