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• W1997552994 abstract "Dr Skrobik's1Skrobik Y Counterpoint: Should benzodiazepines be avoided in mechanically ventilated patients? No.Chest. 2012; 142: 284-287Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar counterpoint editorial does an excellent job of describing many of the characteristics that make benzodiazepines such a poor choice for sedation in the ICU, including delayed clearance and prolonged awakening, especially in patients with kidney injury, liver dysfunction, or advanced age (all common among patients in the ICU); tremendous variability in response; and alterations in metabolism when coadministered with many medications used in the ICU. We agree with her that benzodiazepines lack the characteristics of an ideal ICU sedative. As we respond to the matters in dispute, we are reminded of our initial reluctance to write an editorial against the use of benzodiazepines for sedation in the ICU. We had reservations about being a “bully” against such a commonly used class of sedatives or against well-intentioned ICU practitioners. But Dr Skrobik's claim that “no study has convincingly made the point that the type of drug makes a difference [when sedating ICU patients]”1Skrobik Y Counterpoint: Should benzodiazepines be avoided in mechanically ventilated patients? No.Chest. 2012; 142: 284-287Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar prompted us to summarize the literature in Table 1,2Grounds RM Lalor JM Lumley J et al.Propofol infusion for sedation in the intensive care unit: preliminary report.Br Med J (Clin Res Ed). 1987; 294: 397-400Crossref PubMed Scopus (130) Google Scholar, 3Aitkenhead AR Pepperman ML Willatts SM et al.Comparison of propofol and midazolam for sedation in critically ill patients.Lancet. 1989; 2: 704-709Abstract PubMed Scopus (204) Google Scholar, 4McMurray TJ Collier PS Carson IW et al.Propofol sedation after open heart surgery. A clinical and pharmacokinetic study.Anaesthesia. 1990; 45: 322-326Crossref PubMed Scopus (98) Google Scholar, 5Carrasco G Molina R Costa J et al.Propofol vs midazolam in short-, medium-, and long-term sedation of critically ill patients. A cost-benefit analysis.Chest. 1993; 103: 557-564Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 6Roekaerts PM Huygen FJ de Lange S Infusion of propofol versus midazolam for sedation in the intensive care unit following coronary artery surgery.J Cardiothorac Vasc Anesth. 1993; 7: 142-147Abstract Full Text PDF PubMed Scopus (80) Google Scholar, 7Ronan KP Gallagher TJ George B et al.Comparison of propofol and midazolam for sedation in intensive care unit patients.Crit Care Med. 1995; 23: 286-293Crossref PubMed Scopus (133) Google Scholar, 8Sherry KM McNamara J Brown JS et al.An economic evaluation of propofol/fentanyl compared with midazolam/fentanyl on recovery in the ICU following cardiac surgery.Anaesthesia. 1996; 51: 312-317Crossref PubMed Scopus (40) Google Scholar, 9Chamorro C de Latorre FJ Montero A et al.Comparative study of propofol versus midazolam in the sedation of critically ill patients: results of a prospective, randomized, multicenter trial.Crit Care Med. 1996; 24: 932-939Crossref PubMed Scopus (155) Google Scholar, 10Barrientos-Vega R Mar Sanchez-Soria M Morales-Garcia C et al.Prolonged sedation of critically ill patients with midazolam or propofol: impact on weaning and costs.Crit Care Med. 1997; 25: 33-40Crossref PubMed Scopus (268) Google Scholar, 11Weinbroum AA Halpern P Rudick V et al.Midazolam versus propofol for long-term sedation in the ICU: a randomized prospective comparison.Intensive Care Med. 1997; 23: 1258-1263Crossref PubMed Scopus (122) Google Scholar, 12Sanchez-Izquierdo-Riera JA Caballero-Cubedo RE Perez-Vela JL et al.Propofol versus midazolam: safety and efficacy for sedating the severe trauma patient.Anesth Analg. 1998; 86: 1219-1224PubMed Google Scholar, 13McCollam JS O'Neil MG Norcross ED et al.Continuous infusions of lorazepam, midazolam, and propofol for sedation of the critically ill surgery trauma patient: a prospective, randomized comparison.Crit Care Med. 1999; 27: 2454-2458Crossref PubMed Scopus (70) Google Scholar, 14Hall RI Sandham D Cardinal P et al.Propofol vs midazolam for ICU sedation: a Canadian multicenter randomized trial.Chest. 2001; 119: 1151-1159Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar, 15Carson SS Kress JP Rodgers JE et al.A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients.Crit Care Med. 2006; 34: 1326-1332Crossref PubMed Scopus (234) Google Scholar, 16Searle NR Cote S Taillefer J et al.Propofol or midazolam for sedation and early extubation following cardiac surgery.Can J Anaesth. 1997; 44: 629-635Crossref PubMed Scopus (55) Google Scholar, 17Kress JP Pohlman AS O'Connor MF et al.Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation.N Engl J Med. 2000; 342: 1471-1477Crossref PubMed Scopus (2218) Google Scholar, 18Huey-Ling L Chun-Che S Jen-Jen T et al.Comparison of the effect of protocol-directed sedation with propofol vs. midazolam by nurses in intensive care: efficacy, haemodynamic stability and patient satisfaction.J Clin Nurs. 2008; 17: 1510-1517Crossref PubMed Scopus (22) Google Scholar, 19Breen D Karabinis A Malbrain M et al.Decreased duration of mechanical ventilation when comparing analgesia-based sedation using remifentanil with standard hypnotic-based sedation for up to 10 days in intensive care unit patients: a randomised trial [ISRCTN47583497].Crit Care. 2005; 9: R200-R210Crossref PubMed Google Scholar, 20Muellejans B Matthey T Scholpp J et al.Sedation in the intensive care unit with remifentanil/propofol versus midazolam/fentanyl: a randomised, open-label, pharmacoeconomic trial.Crit Care. 2006; 10: R91Crossref PubMed Scopus (120) Google Scholar, 21Rozendaal FW Spronk PE Snellen FF et al.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: 291-298Crossref PubMed Scopus (98) Google Scholar, 22Pandharipande PP Pun BT Herr DL et al.Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial.JAMA. 2007; 298: 2644-2653Crossref PubMed Scopus (1028) Google Scholar, 23Riker RR Shehabi Y Bokesch PM et al.Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial.JAMA. 2009; 301: 489-499Crossref PubMed Scopus (1181) Google Scholar, 24Ruokonen E Parviainen I Jakob SM et al.Dexmedetomidine versus propofol/midazolam for long-term sedation during mechanical ventilation.Intensive Care Med. 2009; 35: 282-290Crossref PubMed Scopus (176) Google Scholar, 25Maldonado JR Wysong A van der Starre PJ et al.Dexmedetomidine and the reduction of postoperative delirium after cardiac surgery.Psychosomatics. 2009; 50: 206-217Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar, 26Esmaoglu A Ulgey A Akin A et al.Comparison between dexmedetomidine and midazolam for sedation of eclampsia patients in the intensive care unit.J Crit Care. 2009; 24: 551-555Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 27Dasta JF Kane-Gill SL Pencina M et al.A cost-minimization analysis of dexmedetomidine compared with midazolam for long-term sedation in the intensive care unit.Crit Care Med. 2010; 38: 497-503Crossref PubMed Scopus (89) Google Scholar, 28Jakob SM Ruokonen E Grounds RM et al.Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials.JAMA. 2012; 307: 1151-1160Crossref PubMed Scopus (604) Google Scholar where numerous studies remind us of the urgency of our position: The routine use of benzodiazepines for sedation in patients in the ICU should be a thing of the past. Of 27 available randomized trials totaling 3,056 patients, 24 trials involving 2,757 patients showed that alternatives to benzodiazepines yielded better results. In contrast, only three trials (involving 299 participants) found no difference in outcomes, and not a single trial favored benzodiazepines. Even if trials whose participants were heavily sedated early during their ICU stay—a practice that should be, but is not often, avoided—are considered obsolete (as implied by Dr Skrobik), one must acknowledge that recent trials wherein iatrogenic coma was avoided in both treatment groups continue to show that benzodiazepines yield worse outcomes than alternative sedatives.15Carson SS Kress JP Rodgers JE et al.A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients.Crit Care Med. 2006; 34: 1326-1332Crossref PubMed Scopus (234) Google Scholar, 23Riker RR Shehabi Y Bokesch PM et al.Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial.JAMA. 2009; 301: 489-499Crossref PubMed Scopus (1181) Google Scholar, 28Jakob SM Ruokonen E Grounds RM et al.Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials.JAMA. 2012; 307: 1151-1160Crossref PubMed Scopus (604) Google Scholar Benzodiazepines may be needed in special circumstances, but they should not be the standard sedative used in any ICU population.Table 1Randomized Trials Comparing Benzodiazepines With Alternative Sedatives in the ICUStudy/YearPopulationOutcome(s) ImprovedBenzodiazepines vs propofol Trials finding better outcomes with propofol Grounds et al2Grounds RM Lalor JM Lumley J et al.Propofol infusion for sedation in the intensive care unit: preliminary report.Br Med J (Clin Res Ed). 1987; 294: 397-400Crossref PubMed Scopus (130) Google Scholar/1987Cardiac surgeryFaster awakening Aitkenhead et al3Aitkenhead AR Pepperman ML Willatts SM et al.Comparison of propofol and midazolam for sedation in critically ill patients.Lancet. 1989; 2: 704-709Abstract PubMed Scopus (204) Google Scholar/1989General ICUMore consistent awakening, faster weaning McMurray et al4McMurray TJ Collier PS Carson IW et al.Propofol sedation after open heart surgery. A clinical and pharmacokinetic study.Anaesthesia. 1990; 45: 322-326Crossref PubMed Scopus (98) Google Scholar/1990Cardiac surgeryFaster awakening Carrasco et al5Carrasco G Molina R Costa J et al.Propofol vs midazolam in short-, medium-, and long-term sedation of critically ill patients. A cost-benefit analysis.Chest. 1993; 103: 557-564Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar/1993General ICUMore accurate sedation, faster awakening, lower costs Roekaerts et al6Roekaerts PM Huygen FJ de Lange S Infusion of propofol versus midazolam for sedation in the intensive care unit following coronary artery surgery.J Cardiothorac Vasc Anesth. 1993; 7: 142-147Abstract Full Text PDF PubMed Scopus (80) Google Scholar/1993Cardiac surgeryFaster awakening, earlier extubation Ronan et al7Ronan KP Gallagher TJ George B et al.Comparison of propofol and midazolam for sedation in intensive care unit patients.Crit Care Med. 1995; 23: 286-293Crossref PubMed Scopus (133) Google Scholar/1995Surgical ICUFaster awakening Sherry et al8Sherry KM McNamara J Brown JS et al.An economic evaluation of propofol/fentanyl compared with midazolam/fentanyl on recovery in the ICU following cardiac surgery.Anaesthesia. 1996; 51: 312-317Crossref PubMed Scopus (40) Google Scholar/1996Cardiac surgeryLower costs Chamorro et al9Chamorro C de Latorre FJ Montero A et al.Comparative study of propofol versus midazolam in the sedation of critically ill patients: results of a prospective, randomized, multicenter trial.Crit Care Med. 1996; 24: 932-939Crossref PubMed Scopus (155) Google Scholar/1996General ICUBetter ventilator synchrony, faster awakening Barrientos-Vega et al10Barrientos-Vega R Mar Sanchez-Soria M Morales-Garcia C et al.Prolonged sedation of critically ill patients with midazolam or propofol: impact on weaning and costs.Crit Care Med. 1997; 25: 33-40Crossref PubMed Scopus (268) Google Scholar/1997General ICUEarlier extubation Weinbroum et al11Weinbroum AA Halpern P Rudick V et al.Midazolam versus propofol for long-term sedation in the ICU: a randomized prospective comparison.Intensive Care Med. 1997; 23: 1258-1263Crossref PubMed Scopus (122) Google Scholar/1997General ICUFaster awakening Sanchez-Izquierdo-Riera et al12Sanchez-Izquierdo-Riera JA Caballero-Cubedo RE Perez-Vela JL et al.Propofol versus midazolam: safety and efficacy for sedating the severe trauma patient.Anesth Analg. 1998; 86: 1219-1224PubMed Google Scholar/1998Trauma ICUFaster awakening McCollam et al13McCollam JS O'Neil MG Norcross ED et al.Continuous infusions of lorazepam, midazolam, and propofol for sedation of the critically ill surgery trauma patient: a prospective, randomized comparison.Crit Care Med. 1999; 27: 2454-2458Crossref PubMed Scopus (70) Google Scholar/1999Trauma ICULess oversedation Hall et al14Hall RI Sandham D Cardinal P et al.Propofol vs midazolam for ICU sedation: a Canadian multicenter randomized trial.Chest. 2001; 119: 1151-1159Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar/2001Mixed ICUMore accurate sedation, earlier extubation Carson et al15Carson SS Kress JP Rodgers JE et al.A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients.Crit Care Med. 2006; 34: 1326-1332Crossref PubMed Scopus (234) Google Scholar/2006Medical ICUFewer ventilator days Trials finding no differences in outcomes Searle et al16Searle NR Cote S Taillefer J et al.Propofol or midazolam for sedation and early extubation following cardiac surgery.Can J Anaesth. 1997; 44: 629-635Crossref PubMed Scopus (55) Google Scholar/1997Cardiac surgeryNone Kress et al17Kress JP Pohlman AS O'Connor MF et al.Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation.N Engl J Med. 2000; 342: 1471-1477Crossref PubMed Scopus (2218) Google Scholar/2000Medical ICUNone Huey-Ling et al18Huey-Ling L Chun-Che S Jen-Jen T et al.Comparison of the effect of protocol-directed sedation with propofol vs. midazolam by nurses in intensive care: efficacy, haemodynamic stability and patient satisfaction.J Clin Nurs. 2008; 17: 1510-1517Crossref PubMed Scopus (22) Google Scholar/2008Cardiac surgeryNone Trials finding better outcomes with the benzodiazepine None……Benzodiazepines vs remifentanil Trials finding better outcomes with remifentanil Breen et al19Breen D Karabinis A Malbrain M et al.Decreased duration of mechanical ventilation when comparing analgesia-based sedation using remifentanil with standard hypnotic-based sedation for up to 10 days in intensive care unit patients: a randomised trial [ISRCTN47583497].Crit Care. 2005; 9: R200-R210Crossref PubMed Google Scholar/2005Mixed ICUShorter duration of mechanical ventilation Muellejans et al20Muellejans B Matthey T Scholpp J et al.Sedation in the intensive care unit with remifentanil/propofol versus midazolam/fentanyl: a randomised, open-label, pharmacoeconomic trial.Crit Care. 2006; 10: R91Crossref PubMed Scopus (120) Google Scholar/2006Cardiac surgeryEarlier extubation and ICU discharge Rozendaal et al21Rozendaal FW Spronk PE Snellen FF et al.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: 291-298Crossref PubMed Scopus (98) Google Scholar/2009Mixed ICULighter sedation, shorter weaning time Trials finding no differences in outcomes None…… Trials finding better outcomes with the benzodiazepine None……Benzodiazepines vs dexmedetomidine Trials finding better outcomes with dexmedetomidine Pandharipande et al22Pandharipande PP Pun BT Herr DL et al.Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial.JAMA. 2007; 298: 2644-2653Crossref PubMed Scopus (1028) Google Scholar/2007Mixed ICUMore accurate sedation, more delirium/coma-free days Riker et al23Riker RR Shehabi Y Bokesch PM et al.Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial.JAMA. 2009; 301: 489-499Crossref PubMed Scopus (1181) Google Scholar/2009Mixed ICULower prevalence of delirium, earlier extubation Ruokonen et al24Ruokonen E Parviainen I Jakob SM et al.Dexmedetomidine versus propofol/midazolam for long-term sedation during mechanical ventilation.Intensive Care Med. 2009; 35: 282-290Crossref PubMed Scopus (176) Google Scholar/2009Mixed ICUShorter duration of mechanical ventilationaAccording to post hoc analysis adjusting for study center, sedative agent before randomization, and target sedation level. Maldonado et al25Maldonado JR Wysong A van der Starre PJ et al.Dexmedetomidine and the reduction of postoperative delirium after cardiac surgery.Psychosomatics. 2009; 50: 206-217Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar/2009Cardiac surgeryLower incidence and duration of delirium Esmaoglu et al26Esmaoglu A Ulgey A Akin A et al.Comparison between dexmedetomidine and midazolam for sedation of eclampsia patients in the intensive care unit.J Crit Care. 2009; 24: 551-555Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar/2009EclampsiaShorter ICU length of stay Dasta et al27Dasta JF Kane-Gill SL Pencina M et al.A cost-minimization analysis of dexmedetomidine compared with midazolam for long-term sedation in the intensive care unit.Crit Care Med. 2010; 38: 497-503Crossref PubMed Scopus (89) Google Scholar/2010Mixed ICULower ICU costs Jakob et al28Jakob SM Ruokonen E Grounds RM et al.Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials.JAMA. 2012; 307: 1151-1160Crossref PubMed Scopus (604) Google Scholar/2012General ICULighter sedation, fewer ventilation days Trials finding no differences in outcomes None…… Trials finding better outcomes with the benzodiazepine None……a According to post hoc analysis adjusting for study center, sedative agent before randomization, and target sedation level. Open table in a new tab In her editorial, Dr Skrobik uses the word “preoccupation,” which seems to insinuate that the concerns shared by ICU physicians and nurses about pain, agitation, and delirium experienced by patients in the ICU are exaggerated and perhaps distracting. As we know her to be passionate about reducing pain, agitation, and delirium through the use of evidence-based protocols, it seems that we may have misunderstood her use of this word. Nevertheless, we are compelled to point out that these consequences of critical illness must be a primary focus of all ICU health-care providers. The largest quality improvement programs in the United States (such as those sponsored by the Institute for Healthcare Improvement) are focusing on addressing pain, agitation, and delirium in the ICU using the ABCDE approach, which is evidence-based and which promotes the use of analgesics and alternative sedatives rather than benzodiazepines. Even when we consider expense, as Dr Skrobik has done, we find that benzodiazepines (despite their very low drug acquisition costs) are costly. As listed in Table 1, several trials have shown that overall ICU costs were lower when alternative sedatives were used. Also, we must consider expenses that are not monetary but are no less important, such as the loss of priceless interactions between patients and their family members as well as patients' communication with nurses and physicians. Invaluable communication with patients in the ICU is much more likely to occur in the absence of benzodiazepine use.28Jakob SM Ruokonen E Grounds RM et al.Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials.JAMA. 2012; 307: 1151-1160Crossref PubMed Scopus (604) Google Scholar We recently read the book Wrong by David Friedman, in which he cites numerous instances in which we have learned that our former ways of thinking were wrong. The trials in Table 1 have shown that we were wrong to adopt benzodiazepines for such rampant use in our sickest patients. Well, perhaps it was not so much that we were wrong as it was that we had no better strategy at the time. But now we do, and the question we now face is, “Will we adjust our practice accordingly?” The use of benzodiazepines for sedation of mechanically ventilated patients in the ICU should become a thing of the past, as have renal-dose dopamine,29Bellomo R Chapman M Finfer S et al.Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group.Lancet. 2000; 356: 2139-2143Abstract Full Text Full Text PDF PubMed Scopus (804) Google Scholar synchronized intermittent mandatory ventilation weaning,30Esteban A Frutos F Tobin MJ et al.A comparison of four methods of weaning patients from mechanical ventilation. Spanish Lung Failure Collaborative Group.N Engl J Med. 1995; 332: 345-350Crossref PubMed Scopus (1054) Google Scholar intensive glucose control,31Finfer S Chittock DR Su SY et al.Intensive versus conventional glucose control in critically ill patients.N Engl J Med. 2009; 360: 1283-1297Crossref PubMed Scopus (3634) Google Scholar and pulmonary artery catheters in ARDS.32Wheeler AP Bernard GR Thompson BT et al.Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury.N Engl J Med. 2006; 354: 2213-2224Crossref PubMed Scopus (754) Google Scholar" @default.
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