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Intensive care sedation, trends and habits.

The traditional link between anaesthesia and intensive care has led to an extended, albeit modified use of hypnotics and analgesics such as benzodiazepines, propofol, etomidate and different opiates as sedatives in intensive care units (ICU) over a prolonged period of time. It is surprising, however, that proper safety and efficacy assessment of these agents for long-term use in the context of critical illness is limited. The last decade witnessed three chapters that shaped sedation practice today. First, recognition of better outcomes with avoidance of prolonged sedation and iatrogenic coma using sedation interruption and protocolised sedation (1,2). Second, a move away from long-acting benzodiazepines, in particular lorazepam, in North America (3,4). Third, the trials comparing dexmedetomidine with midazolam and with propofol (5,6).

In this issue of Anaesthesia Intensive Care (7), the group from the Austin Hospital in Melbourne described changes in ICU sedative usage (excluding additional opiates and antipsychotic medications) for critically ill patients over the last few years. In this study, using multiple datasets including pharmacy supply, Jarman and colleagues retrospectively analysed data of more than 5700 ICU admissions between 2002 and 2010, over one-third of which involved mechanical ventilation. They found a significant increase in the average propofol infusion dose (13.3-101.8 mg per ventilation hour), and a decrease in the use of midazolam, with the average estimated infusion dose of midazolam reduced from 2-0.7 mg per ventilation hour over the study period. The authors assumed that all propofol and midazolam supply was given to ventilated patients, which may not have been correct. Moreover, averaging the total drug supply over ventilation hours should be cautiously interpreted. Whether this means that over time, ventilated patients needed less midazolam and more propofol to be sedated, or fewer patients received midazolam and more received propofol cannot be ascertained from the data presented.

The authors suggested that an observed reduction in ventilation time and ICU and hospital length-of-stay, over the same period, was a result of the above change in sedative usage. One speculative explanation is that the use of propofol led to a decrease in over-sedation and iatrogenic coma allowing more lightly sedated patients to have a shorter ventilation time and thus earlier discharge. In any event, retrospective analysis has inherent limitations; one ought to be cautious, therefore, making any causal links with clinical outcomes. The Jarman and colleagues data are essentially a description of usage trends. One might ask, what was the cause of these trends?

Landmark studies (1,2,8,9), albeit with small number of patients and with many limitations, suggested benefits of avoiding over-sedation using different strategies, including benzodiazepine minimisation, sedation algorithms, nurse-directed protocols, analgesia first sedation and daily sedation interruption. In simple terms, deep sedation mediates the harm, not the actual sedative agent used. The above strategies were independent of the choice of sedative agents. Many of these strategies, however, depend on the intensity of bedside nursing care (10).

There are good reasons to use propofol. However, there is no good evidence to avoid appropriate use of midazolam. Despite the acceptance and the apparent congruence of strategies to reduce over-sedation, the choice of sedative and analgesic agents in critically ill patients is often dictated by local habits rather than evidence-based choices. Whether a patient receives midazolam, propofol or other agents is determined by personal preferences and familiarity, availability, local regulatory approval, institutional policies, healthcare systems and apparent cost. There is also uncertainty of the desired goals of sedative choice. Is it to produce adequate sedation (poorly defined)? Is it to reduce ventilation time? Is it to reduce delirium and emergent agitation? Is it to decrease the risk of death? Coupled with limited high-level evidence in favour of propofol over midazolam, the increased uptake of propofol is likely the result of a perception that over-sedation is less likely with propofol than with midazolam. The sedation depth achieved with propofol, however, is dose-dependent and therefore, highly dependent on bedside nurses' behaviour and attitudes.

The 2013 updated American College of Critical Care Medicine guidelines (11) on pain, agitation and delirium management in critically ill adults made two important recommendations: delivering analgesia before sedation and the provision of light sedation whenever clinically appropriate. The guidelines consist of a comprehensive review of over 18,000 published articles and did not find strong evidence to promote one sedative agent over another. However, it made a suggestion that using non-benzodiazepine sedatives such as propofol and dexmedetomidine may promote light sedation and improve clinical outcomes such as ventilation time.

Jarman and colleagues concur with other ICU trends and is consistent with international data (12). In particular, reduced mortality (13) over the last decade increased ICU admissions and reduced proportion of ventilated patients (14). Increased propofol prescription in the United States and Europe was also reported over the same period (15). It is, however, important to acknowledge the limitations and confounders associated with the above analysis. First, deliberate, although pragmatic, exclusion of opiates and antipsychotics prescription from the analysis may have affected the outcomes of study. Patients receiving less midazolam may have received high-dose opiates causing prolonged ventilation. Second, the calculated dose of midazolam is an estimated average over ventilated hours; it does not relate to individual patient usage. Third, introduction of sedation scale and sedative interruption during the study period may have led to a reduction in total midazolam usage to produce light sedation and hence reduced ventilation time. Fourth, there is no adjustment for the proportion of surgical versus medical patients admitted over the study period. Fifth, death was not accommodated for in the analysis. The trend of midazolam and propofol prescription, over the study period, between survivors and non-survivors would have added important insight into the drivers and outcomes associated with these trends. It is therefore crucial not to misinterpret or over-interpret the findings of Jarman and colleagues. More importantly, their data do not imply that the observed changes in the use of different sedative agents contributed to better patient outcome.

There is a striking absence of high-level evidence to guide the choice of sedative agents in critically ill patients. It is extraordinary that despite the universal prescription of sedative agents to over a million ICU patients every year, there is very limited data on patient-centred outcomes such as mortality, cognitive function and quality of life after ICU discharge and whether sedative agents can improve these outcomes.

While the shift to propofol is real, the justification is cloudy. A systematic review (16) collected fewer than 1000 patients in clinical trials of propofol versus alternative agents. Prolonged use of propofol is associated with saturation of peripheral tissues and prolonged emergence. Significant side-effects are also associated with propofol infusions such as hypertriglyceridaemia, acute pancreatitis, myoclonus, hypotension, respiratory depression and the more serious, albeit rare, propofol-infusion-syndrome.

The Australian and New Zealand Sedation Practice in Intensive Care Evaluation (SPICE) (17) study group showed a comparable split in the prescription of midazolam and propofol to critically ill patients, with a higher proportion of those patients staying in the ICU longer than four days receiving midazolam and antipsychotic agents. It also revealed that deep sedation up to 48 hours after commencing mechanical ventilation was very common and its occurrence is independent of sedative choice. In a pilot study conducted by the SPICE study group (18), the use of propofol or traditional sedatives was not associated with reduced early sedation depth.

The above suggests that future clinical trials should focus on addressing limitations of previous sedation trials and investigate long-term outcomes in carefully designed adequately powered randomised trials. Until then, let us maintain equipoise on sedation choice in the ICU.


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(2.) Brook AD, Ahrens TS, Schaiff R, Prentice D, Sherman G, Shannon Wet al. Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med 1999; 27:2609-2615.

(3.) Carson SS, Kress JP, Rodgers JE, Vinayak A, Campbell-Bright S, Levitt J et al. A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients. Crit Care Med 2006; 34:1326-1332.

(4.) Pandharipande PE Pun BT, Herr DL, Maze M, Girard TD, Miller RR et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007; 298:2644-2653.

(5.) Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009; 301:489-499.

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(8.) 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; 111:451-463.

(9.) Treggiari MM, Romand JA, Yanez ND, Deem SA, Goldberg J, Hudson Let al. Randomized trial of light versus deep sedation on mental health after critical illness. Crit Care Med 2009; 37:2527-2534.

(10.) Bucknall TK, Manias E, Presneill JJ. A randomized trial of protocol-directed sedation management for mechanical ventilation in an Australian intensive care unit. Crit Care Med 2008; 36:1444-1450.

(11.) Barr J, Fraser GL, Puntillo K, Ely EW, Gelinas C, Dasta JF et al. 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.

(12.) Goligher E, Ferguson ND. Mechanical ventilation: epidemiological insights into current practices. Curr Opin Crit Care 2009; 15:44-51.

(13.) Moran JL, Bristow P, Solomon PJ, George C, Hart GK. Mortality and length-of-stay outcomes, 1993-2003, in the binational Australian and New Zealand intensive care adult patient database. Crit Care Med 2008; 36:46-61.

(14.) Australian and New Zealand Intensive Care Society. CCR Resources and Activity 2009/2010. 2010 Annual Report. From Accessed April 2013.

(15.) Wunsch H, Linde-Zwirble WT, Angus DC, Hartman ME, Milbrandt EB, Kahn JM. The epidemiology of mechanical ventilation use in the United States. Crit Care Med 2010; 38:1947-1953.

(16.) Ho KM, Ng JY. The use of propofol for medium and long-term sedation in critically ill adult patients: a meta-analysis. Intensive Care Med 2008; 34:1969-1979.

(17.) Shehabi Y, Bellomo R, Reade MC, Bailey M, Bass F, Howe B et al. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med 2012; 186:724-731.

(18.) Shehabi Y, Bellomo R, Reade MC, Bailey M, Bass E Howe B et al. Early goal directed sedation vs standard care sedation in mechanically ventilated critically ill patients, randomized controlled trial. Crit Care Med 2013; 41:In press.

Y. Shehabi

Clinical School of Medicine, University of New South Wales, Acute Care Services Program, Intensive Care Research, Prince of Wales Hospital, Sydney, New South Wales
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Author:Shehabi, Y.
Publication:Anaesthesia and Intensive Care
Article Type:Editorial
Geographic Code:8AUST
Date:May 1, 2013
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