The incidence of sub-optimal sedation in the ICU: a systematic review

cc8212CCJ Research The incidence of sub-optimal sedation in the ICU: a systematic review JacksonLDanielDaniel.Jackson@ge.com ProudfootWClareClare.Proudfoot@heronhealth.com CannFKimberleykimkfc@hotmail.co.uk WalshSTimTimothy.Walsh@ed.ac.uk

GE Healthcare, Pollards Wood, Nightingales Lane, Chalfont St. Giles, Bucks, HP8 4SP, UK

Heron Evidence Development Ltd, Building 210A, Butterfield Technology and Business Park, Luton, LU2 8DL, UK

Royal Infirmary of Edinburgh, 51 Little France Crescent, Old Dalkeith Road, Edinburgh, EH16 2SA, UK

Critical Care 1364-8535 2009 13 6 R204 http://ccforum.com/content/13/6/R204 2001535710.1186/cc8212 20720092992009121020091612200916122009 2009Jackson et al.; licensee BioMed Central Ltd.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Introduction

Patients in intensive care units (ICUs) are generally sedated for prolonged periods. Over-sedation and under-sedation both have negative effects on patient safety and resource use. We conducted a systematic review of the literature in order to establish the incidence of sub-optimal sedation (both over- and under-sedation) in ICUs.

Methods

We searched Medline, Embase and CINAHL (Cumulative Index to Nursing and Allied Health Literature) online literature databases from 1988 to 15 May 2008 and hand-searched conferences. English-language studies set in the ICU, in sedated adult humans on mechanical ventilation, which reported the incidence of sub-optimal sedation, were included. All abstracts were reviewed twice by two independent reviewers, with all conflicts resolved by a third reviewer, to check that they met the review inclusion criteria. Full papers of all included studies were retrieved and were again reviewed twice against inclusion criteria. Data were doubly extracted. Study aims, design, population, comparisons made, and data on the incidence of sub-optimal, optimal, over-sedation or under-sedation were extracted.

Results

There was considerable variation between included studies in the definition of optimal sedation and in the scale or method used to assess sedation. Across all included studies, a substantial incidence of sub-optimal sedation was reported, with a greater tendency toward over-sedation.

Conclusions

Our review suggests that improvements in the consistent definition and measurement of sedation may improve the quality of care of patients within the ICU.

Introduction

The majority of mechanically ventilated patients within the intensive care unit (ICU) receive sedative drugs. Sedation is administered to ensure patient comfort, reduce anxiety, and facilitate treatments. Optimising sedation management is recognised as important in improving patient outcomes 1 . Under-sedated patients may become agitated and distressed and are at risk of adverse events such as extubation 2 3 4 , whereas over-sedation can prolong time to recovery 1 5 .

Assessment of sedation level is carried out mainly by nurses or critical care physicians by assessing patient responses to simple stimuli. Sedation scales such as the Ramsay scale or the Richmond Agitation-Sedation Scale (RASS) are widely used 6 7 8 . However, there is no universally accepted standard, and this can make comparison between different studies or ICUs difficult 2 . Furthermore, some of these scales have not been fully validated in ICU patients 4 . Recently, devices such as the bispectral index monitor (BIS), which aim to assess sedation levels more objectively, have been introduced. However, most studies of BIS have been performed in surgical settings, and to date its effectiveness is not fully proven 8 9 10 .

Available guidelines on sedation typically provide limited guidance on optimal sedation monitoring and levels. This is at least partly because optimal sedation levels differ between patients according to their clinical circumstances, and therefore sedation practice is ideally individually tailored to each patient, as recommended by several guidelines 2 11 12 . However, among guidelines that do recommend an optimal level of sedation, there are discrepancies, indicating a lack of consensus on this issue. For example, of a survey of available guidelines, one 13 recommended a sedation level of 2 or 3 on the Ramsay scale, whereas one recommended a goal of RASS -3 for an intubated patient 14 and a second recommended a goal of RASS 0 to -2 15 . A number of guidelines stress the importance of establishing a set protocol for the sedation of ICU patients 16 17 but do not set out such a protocol in detail, leaving it to individual institutions, and more recent guidelines recognise the benefit of regular (daily) interruption of sedation for eligible patients 11 14 18 19 within sedation protocols.

It is recognised that optimising sedation practice is a recognised quality marker for intensive care treatment, and procedures designed to optimise patient sedation state, such as daily sedation breaks and more frequent monitoring, are key elements of recent quality improvement initiatives. However, despite these recent efforts to improve the quality of sedation practice in the ICU, the epidemiology of sedation, and specifically the prevalence of over- or under-sedation, is unclear. To investigate this further, we carried out a systematic review of the publicly available literature to identify the reported incidence of sub-optimal sedation.

Materials and methods

Searching

Medline, Embase and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were searched from 1988 to 15 May 2008 using terms for sedation, ICU, sedation quality management, and sub-optimal sedation. The standard Scottish Intercollegiate Guidance Network (SIGN) filters for randomised controlled trials (RCTs), economic studies and observational studies 20 were combined to capture all study designs relevant to the study question. Full details of the search strategy used are available from the authors on request. Conference proceedings from 2005 through 2008 were hand-searched for relevant studies. All results were uploaded into a bespoke internet SQL (structured query language)-based database.

Selection criteria

Inclusion of studies was according to a predetermined set of criteria. To be included, studies had to be in adult humans who were sedated and undergoing mechanical ventilation within the ICU and furthermore had to report the incidence of sub-optimal sedation, over- or under-sedation, or of optimal sedation, as defined by the study. Studies that reported the impact of sedation practice on outcomes were also included; these data are reported separately. In addition, short-term studies (including only patients sedated less than 24 hours) were excluded. Only English-language studies were included. To check that they met the review inclusion criteria, all abstracts were reviewed twice by two independent reviewers, with all conflicts resolved by a third reviewer. Full papers of all included studies were retrieved and were again reviewed twice to ensure that they met inclusion criteria. Studies included at this stage were classified as to which aspect of the review question they met, and appropriate data were extracted, summarised and analysed.

Data extraction

Data were extracted by two reviewers and checked by a third reviewer against the original studies. For all studies, the following data were extracted: country, sponsor, study design, patient population, objective, number of patients in the study, details of comparisons made (such as between different treatment arms or between different sedation monitoring systems), and the proportion of measurements, patients, or time in which patients were judged to be optimally sedated, sub-optimally sedated, over-sedated, or under-sedated.

Quantitative data synthesis

Due to the wide range of included study types, no studies were suitable for quantitative data synthesis.

Results

Systematic review study flow

The flow of studies through the systematic review is documented in the QUOROM (Quality of Reporting of Meta-Analyses) diagram in Figure 1. Seventy-five primary and seven secondary studies met the inclusion criteria. Of these, 18 did not provide any data; either they did not contain data on the outcomes extracted in this review or they did not provide these data in quantitative form. Thirty-six studies reported data on the incidence of sub-optimal sedation. The remainder reported the impact of sedation practice on outcomes; these data are reported separately. Of the included studies, three were cohort studies that specifically investigated the epidemiology of sedation, 23 were studies investigating anaesthetic drugs (of which 19 were RCTs and four were observational studies), six studies compared sedation monitoring devices or scales (of which one was an RCT and the remainder were observational studies), three studies investigated the introduction of sedation guidelines, and one did not fit any of these categories. The majority of studies (20) were published after 2002, indicating the increasing interest in the practice of sedation quality in recent years, in particular following the publication of updated sedation guidelines from the American College of Critical Care Medicine 2 6 .

Figure 1

The QUOROM (Quality of Reporting of Meta-Analyses) diagram illustrates the flow of studies through the systematic review

The QUOROM (Quality of Reporting of Meta-Analyses) diagram illustrates the flow of studies through the systematic review.

Definitions of adequate sedation

To assess the incidence of sub-optimal sedation, it is necessary to consider the definition of what constitutes optimal sedation. We used the definition of optimal sedation (and consequently of what constituted sub-optimal sedation) provided by individual studies due to the fact that optimal sedation levels will vary according to study setting (for example, between neurological ICU and medical ICU).

Across all of the studies, 13 different sedation scales were used to assess sedation quality; additionally, nurse assessment of sedation quality simply as over-sedated, under-sedated, or adequate was used three times (Table 1). The Ramsay scale was the most commonly used scale, in 14 studies, with a variant used in a further 7 studies. This is illustrated in Figure 2.

Figure 2

The frequency with which each sedation scale was used in the studies included in our systematic review

The frequency with which each sedation scale was used in the studies included in our systematic review. ICU, intensive care unit; MAAS, Motor Activity Assessment Scale; OAAS, Observer's Assessment of Alertness/Sedation Scale; RASS, Richmond Agitation Sedation Scale; SAS, Riker Sedation-Agitation Scale.

Table 1

Incidence of optimal and sub-optimal sedation in included studies

Study

Study design and comparisons made

Number

Treatment arms (if relevant)

Incidence of sub-optimal sedation

Incidence of over-sedation

Incidence of under-sedation

Incidence of optimal sedation

Sedation scale/monitoring system used

Definition of optimal sedation

Weinert, et al., 2007 44

Cohort study

274

326 (2.6%) of 12,414 assessments.

111 patients (40%) had ≥ 1 rating of over-sedation. Patients were unarousable/minimally arousable 32% of the time.

1,731 (13.9%) of 12,414 assessments.

211 (76.2%) had ≥ 1 rating of under-sedation.

10,357 (83%) of 12,414

Minnesota Sedation Assessment Tool -- nurse assessment

Arousal level 3-5 (of 6-point scale)

Martin, et al., 2006 30

Cohort study

305 (from 220 ICUs)

42.6% of 49 patients sedated 24-72 hours, 39.5% of 157 patients sedated >72 hours, and 43.9% of 57 patients under weaning had significantly deeper sedation than desired level

5.2% of 157 patients sedated >72 hours and 3.5% of 57 patients under weaning had significantly lower sedation than desired level

In patients sedated >72 hours, the desired Ramsay score was 0-4 in 44% of cases -- this was achieved in 28%; in 55% of patients, the desired value was 4-5, which was achieved in 68%; in 1% of patients, the desired score was 6, which was achieved in 6%.

Ramsay scale

Individual to each patient

Payen, et al., 2007 43

Cohort study

1,381

258 (57%) of 451 patients on sedation day 2; 169 (48%) of 355 patients on day 4; 109 (41%) of 266 patients on day 6

Multiple: most commonly Ramsay, RASS, Sedation-Agitation scale

Over-sedation defined as Ramsay 5-6, RASS -5 or --4, Sedation-Agitation scale 1-2

Sandiumenge, et al., 2000 36

RCT/observational study of sedative drugs

Midazolam

19 (7%) of 266 hours

247 (93%) of 266 hours

Modified Ramsay scale

Equivalent of Ramsay 5-6 (for deep sedation)

2% propofol

14 (9%) of 156 hours

142 (91%) of 156 hours

Carrasco, et al., 1993 26

RCT (with economic study) of sedative drugs

Midazolam

18% of time (hours)

82% of time (hours)

Ramsay scale; Glasgow coma scale (modified by Cook and Palma)

Ramsay scale 2-5, Glasgow coma scale 8-13

Propofol

7% of time (hours)

93% of time (hours)

McCollam, et al., 1999 23

RCT of sedative drugs

Lorazepam

32% of assessments

14% of assessments

18% of assessments

68% of assessments

Ramsay scale

Ramsay scale 2-4

Midazolam

21% of assessments

6% of assessments

16% of assessments

79% of assessments

Propofol

38% of assessments

7% of assessments

31% of assessments

62% of assessments

Chinachoti, et al., 2002 40

RCT of sedative drugs

152

Remifentanil

28% of patients; 17.3% of time (hours)

13% of time (hours)

4% of time (hours)

78% of patients (without midazolam), 83% of time (hours) (maintenance phase)

SAS

SAS 4 with no or mild pain

Morphine

27% of patients; 16% of time (hours)

13% of time (hours)

3% of time (hours)

73% of patients (without midazolam), 84% of time (hours) (maintenance phase)

Harper, et al., 1991 25

RCT of sedative drugs

Alfentanil low, moderate and high doses -- results reported together

4 patients had >10% of time at sedation level 6

3 patients had >10% of time at sedation level 1

Ramsay (assessed hourly)

2-5

Manley, et al., 1997 46

RCT (and economic study) of sedative drugs

Morphine + midazolam

56.8% of time

43.2% of time

North Staffordshire ICU (modification of Ramsay/Addenbrooke's scores)

3-4

Alfentanil + propofol

57.8% of time

42.2% of time

Millane, 1992 21

RCT of sedative drugs

Isoflurane for 24 hours followed by propofol

3.4%

Ramsay plus subjective nurse assessment

2-3 (plus subjective nurse assessment)

Propofol for 24 hours followed by isoflurane

3.6%

Muellejans, et al., 2004 41

RCT of sedative drugs

152

Remifentanil

11.7% of time (hours)

88.3% of time (hours)

SAS

Fentanyl

10.7% of time (hours)

89.3% of time (hours)

Muellejans, et al., 2006 47

RCT of sedative drugs

Remifentanil -- propofol

41% of time

28% of time

13% of time

59% of time

3 level sedation score specific to study

Level 2

Midazolam -- fentanyl

30% of time

19% of time

11% of time

70% of time

Chamorro, et al., 1996 45

RCT of sedative drugs

Propofol

332 assessments -- 3% (after first hour)

332 assessments -- 76.5% effective, 20.5% acceptable

Study-specific (modified Glasgow coma scale). Patients monitored at 1 and 6 hours and then every 12 hours.

4 = effective, 3 = acceptable

less than 3 = ineffective

Midazolam

355 assessments -- 7.6%

355 assessments -- 66.2% effective, 26.2% acceptable

Barr, et al., 2001 34

RCT of sedative drugs

Lorazepam

51% of time

47% of time

49% of time

Modified Ramsay

3-4 (5-6 = over-sedation)

Midazolam

31% of time

22% of time

69% of time

Finfer, et al., 1999 33

RCT of sedative drugs

Diazepam (intermittent)

9 (64.3%) of 14 patients; 15.0% of time (hours)

2.8% of time (hours)

21.1% of time (hours)

5 (35.7%) of 14 patients;

85.0% of time (hours)

Modified Ramsay

1-4

Midazolam (continuous)

6 (35.3%) of 17 patients; 40.8% of time (hours)

14.8% of time (hours)

0% of time (hours)

11 (64.7%) of 17 patients;

59.2% of time (hours)

Richman, et al., 2006 37

RCT of sedative drugs

Midazolam

Mean 9.1 hours/day (SD 4.9)

Modified Ramsay

Individual to each patient

Midazolam and fentanyl

Mean 4.2 hours/day (SD 2.4)

Karabinis, et al., 2004 39

RCT of sedative drugs

161

Remifentanil

4.4% of time

95.6% of time (median)

SAS

1-3

Fentanyl

1.9% of time

98.1% of time (median)

Morphine

1.0% of time

99.0% of time (median)

Pandharipande, et al., 2007 48, Pandharipande, et al., 2006 59

RCT of sedative drugs

106

Dexmedetomidine

20% of patients according to nurse goals; 33% according to physician goals

15% of patients

80% of patients within 1 point of nurse goal; 67% within 1 point of physician goal

RASS, confusion-assessment method for the ICU (CAM-ICU)

Individual to each patient

Lorazepam

33% of patients according to nurse goals; 45% according to physician goals

33% of patients

67% within 1 point of nurse goal; 55% within 1 point of physician goal

Swart, et al., 1999 50

RCT of sedative drugs

Lorazepam

13% of time

87.0% of time (SD 10.5)

Addenbrooke's Hospital's ICU sedation scale

Individual to each patient

Midazolam

34% of time

66.2% of time (SD 23.1)

Carson, et al., 2006 22

RCT of sedative drugs

132

Intermittent lorazepam

42.8% (ventilator hours)

37.9% (ventilator hours)

15.1% (ventilator hours)

Ramsay

2-3

Continuous propofol

49.9% (ventilator hours)

38.6% (ventilator hours)

11.5% (ventilator hours)

Anis, et al., 2002 31, Hall, et al., 2001 60

RCT of sedative drugs

156

Propofol

39.8% of time

12.0% of time

11.2% of time

60.2% of time

Ramsay

Individual to each patient

Midazolam

56.0% of time

18.4% of time

8.1% of time

44.0% of time

Park, et al., 2007 49

RCT of sedative drugs

134 (111 analysed)

Analgesia-based sedation

50% of time

50% of time on SIMV (median)

Assessor judgement

Adequate judged as awake or easily rousable

Hypnotic-based sedation

81% of time

19% of time on SIMV (median)

Cigada, et al., 2005 32

Observational study of sedative drugs

Propofol or midazolam with enteral hydroxyzine with or without supplemental lorazepam. IV drugs were tapered after 48 hours.

36.9% of assessments as judged by Ramsay score; 17% by nurse assessment

421 (24.6%) of 1,711 assessments (Ramsay score)

42 (7.3%) of 577 assessments (nurse judgement)

211 (12.3%) of 1,711 assessments (Ramsay score)

56 (9.8%) of 577 assessments (nurse judgement)

1,079 (63.1%) of 1,711 assessments (Ramsay score)

479 (83%) of 577 assessments (nurse judgement)

Ramsay score plus nurse assessment

Adequate sedation defined as the achievement of the planned Ramsay score or nurse judgement as adequate

Barrientos-Vega, et al., 2001 29

Observational study of sedative drugs

2% propofol (compared with historical cohort on 1% propofol -- not reported here)

8 (15.6%) of 51 patients judged therapeutic failure on 2% propofol (inadequate level of sedation)

Ramsay score

4-5

MacLaren, et al., 2007 42

Observational study of sedative drugs

Dexmedetomidine as adjunct to lorazepam/midazolam/propofol

35% of patients with dexmedetomidine; 52% without

12 (30%) patients with dexmedetomidine; 9 (23%) without

4 (10%) patients with dexmedetomidine; 12 (30%) without

65% of patients with dexmedetomidine; 48% without

SAS

3-4

Shehabi, et al., 2004 24

Observational study of sedative drugs

Dexmedetomidine with supplemental midazolam if required

455 (33%) of 1,381 assessments

97 (7%) of 1,381 assessments were Ramsay level 6

137 (10%) of 1,381 assessments were Ramsay level 1

926 (67%) of 1,381

Ramsay

2-4

Sackey, et al., 2004 51

RCT of sedation devices

Isoflurane using AnaConDa

46% of time; nursing staff estimate 11% of time

44% of time

2% of time

54% of time;

nursing staff estimate 89% of time

Bloomsbury scale

- 1 to +1

IV midazolam

41%; nursing staff estimate 13% of time

37% of time

4% of time

59% of time; nursing staff estimate 87% of time

Walsh, et al., 2008 52

Observational study of sedation devices

All sedated patients

137 (32.9%) of 416 assessments (Ramsay score 5-6)

5 (1.2%) of 416 assessments (Ramsay score 1)

Entropy Module/Modified Ramsay scale

None stated. Refers to guidelines suggesting 2-3 is adequate and heavy/over-sedated is 5-6.

Hernández-Gancedo, et al., 2006 28

Observational study of sedation scales

44% (66 cases) -- Ramsay level 6

25% (38 cases)

Ramsay, Observer's Assessment of Alertness and Sedation

Ramsay 3-4

Roustan, et al., 2005 27

Observational study of sedation scales

All sedated patients -- treated with midazolam and morphine

93 (61.6%) of 151 records

19 (12.6%) of 151 records

Ramsay, Comfort score, EEG

Ramsay 3-4

McMurray, et al., 2004 38

Observational study of sedation scales

122

Propofol-containing regimens

15.6% of time

Mean 5.0% of time (SD 12.7)

Mean 10.6% of time (SD 14.5)

Mean 84.4% of time (SD 18.0)

Modified Ramsay

Individual to each patient

Detriche, et al., 1999 53

Before-after study of introduction of sedation protocol

Before

20 (30%) of 67 assessment days

Brussels sedation scale

3-4

After protocol introduction

9 (12%) of 77 assessment days

Costa, et al., 1994 54

RCT of controlled and empirical sedation

Controlled

17% of time

83% of time

Ramsay, and Glasgow coma scale modified by Cook and Palma

Empirical

65% of time

35% of time

MacLaren, et al., 2000 35

Before-after comparison of sedation protocol

158

Before

22.4% (experience of anxiety or pain)

Modified Ramsay

After

11.0% (P < 0.001)

Tallgren, et al., 2006 3

Before-after comparison of sedation protocol

Before reinforcement

Median Ramsay level was 4 during the day and 5 at night, in contrast to the study's stated aim of Ramsay level 2-3 during the day and 3-4 at night

Ramsay

After reinforcement

Median Ramsay level was 4 during the day and 5 at night, in contrast to the study's stated aim of Ramsay level 2-3 during the day and 3-4 at night

Samuelson, et al., 2007 61, Samuelson, et al., 2006 62

Observational study

250

50% of patients had MAAS 0-2 (although 2 was target for study, 0-1 could be viewed as over-sedated)

39% of patients achieved MAAS 3 in ventilated period

MAAS

Stated 2-3 but results reported for patients achieving 3

EEG, electroencephalogram; ICU, intensive care unit; IV, intravenous; MAAS, Motor Activity Assessment Scale; RASS, Richmond Agitation-Sedation Scale; RCT, randomised controlled trial; SAS, Riker Sedation-Agitation Scale; SD, standard deviation; SIMV, synchronised intermittent mandatory ventilation.

In addition to the variation in scales used to assess sedation, there was variation in the recommended range of optimal sedation levels stated. Sedation requirements obviously differ among patients; nevertheless, the variation in recommended ranges in included studies indicates some uncertainty in what constitutes optimal sedation. Of the studies using the Ramsay scale, recommended ranges were 2 to 3 (recommended in two studies 21 22 ), 2 to 4 (two studies 23 24 ), 2 to 5 (two studies 25 26 ), 3 to 4 (two studies 27 28 ) and 4 to 5 (one study 29 ), while three studies did not recommend specific levels but recommended that levels be optimised for each individual patient 30 31 32 . This variation was reflected in the other scales used; for studies recommending a modified Ramsay scale, recommended ranges were 1 to 4 33 , 3 to 4 34 , 4 35 , and 5 to 6 (the last range being specifically for seriously injured patients 36 ) or targets optimised for each patient 37 38 . The stated SAS (Riker Sedation-Agitation Scale) target level was 1 to 3 39 , 4 40 41 , or 3 to 4 42 . Due to the number of studies recommending that optimal sedation state be determined individually for each patient, there was no comparison possible for other scales.

Incidence of sub-optimal sedation

Table 1 lists the study design, sedation assessment scale or tool used, and incidence of sub-optimal sedation reported by studies. As stated above, we used individual study definitions of optimal and sub-optimal sedation because of the fact that optimal sedation levels are likely to vary by study setting.

The three observational studies that investigated the epidemiology of sedation were considered to be the most relevant to the study question as their specific aim was to investigate clinical sedation practice rather than practice within the confines of a trial, where more frequent monitoring and the Hawthorne effect could contribute to improving standards.

A survey of practice across 44 ICUs in France also found a high incidence of deep sedation, in 41% to 57% of readings over a 6-day period 43 . This study highlighted the risks of prolonged deep sedation, which, however, was not specifically defined as over-sedation. Results from these three studies indicate that 30% to 60% of sedation assessments indicate 'deep' or 'over' sedation, although precise description of the prevalence is confounded by imprecise definition or health care worker perceptions. These studies clearly indicate an excess of over-sedation compared with under-sedation.

Martin and colleagues 30 conducted a postal survey of 220 ICUs in Germany. This study found that 42.6% of patients sedated between 24 and 72 hours and 39.5% of patients sedated over 72 hours were over-sedated; the incidence of under-sedation was much lower (<6%).

In the US-based study of Weinert and colleagues 44 , the aim was to compare subjective and objective ratings of sedation. Subjects provided 12,414 sedation assessments and were judged by nurses to be sub-optimally sedated in 17% of assessments, over-sedated in 2.6%, and under-sedated in 13.9%. Critically, however, patients were unrousable or minimally rousable just under one third of the time, indicating a high incidence of deep sedation. This finding illustrates the importance of the perception of the health care worker or assessor or both in describing the prevalence of sub-optimal sedation.

The remaining included studies comprised studies of sedative drugs 21 22 23 24 25 26 29 31 32 33 34 36 37 39 40 41 42 45 46 47 48 49 50 , studies investigating different sedation devices or scales 27 28 38 51 52 , and studies looking at the introduction of a sedation guideline or protocol 3 35 53 54 . Studies varied by design and aim, by sedatives used, by scales and definitions of sub-optimal sedation used, and by the way incidence was reported (as a proportion of measurements, patients, or time). While these studies did not necessarily have the incidence of sub-optimal sedation as their primary focus, the data in such studies were considered to be of interest to the inclusive scope of this review. Although studies of sedative drugs or of the introduction of guidelines or protocols may not give an accurate estimate of the incidence of sub-optimal sedation within routine clinical practice, they nevertheless show that it does occur and can give an impression of the extent to which it may be a problem, even in settings that could be reasonably expected to be more controlled than in routine practice. The incidence of sub-optimal sedation reported in these studies is summarised in Figure 3 (separated by study and treatment arm where relevant). The reported incidence varied from 1% 39 to 75% 28 , with the majority reporting an incidence of over 20%. The incidence of over- and under-sedation was similarly variable, and figures of between 2.8% and 44% for over-sedation 28 33 51 and between 2% and 31% for under-sedation 23 51 were reported. A further study 2 that looked at the introduction of a sedation guideline did not record the incidence of sub-optimal sedation but recorded the median Ramsay scale values. These were 4 during the day and 5 at night, in contrast to the study's stated aim of Ramsay levels of 2 to 3 during the day and 3 to 4 at night; this study again noted a possible tendency toward over-sedation of patients. Importantly, there was no change in this tendency before and after reinforcement of the guideline, suggesting that this was insufficient to improve sedation practice 3 .

Figure 3

Incidence of sub-optimal sedation across included studies

Incidence of sub-optimal sedation across included studies. The plot shows the percentage of measurements, patients, or time in which patients were sub-optimally sedated according to each included study's definition of optimal sedation and measurements reported. Studies are grouped by study design. Where more than one group was reported by a study (for example, a comparison of two different treatment arms), separate points are shown for each group. RCT, randomised controlled trial.

Discussion

Our systematic review identified few studies that specifically described the epidemiology of sedation during ICU care. Description of the incidence of sub-optimal sedation and over- and under-sedation was difficult due to variation in the use of these terms within individual studies. Overall, available data suggest a high incidence of over-sedation in ICUs, potentially present at 40% to 60% of assessments. A lower reported incidence of sub-optimal sedation across most studies suggests that health care workers consider deep levels of sedation appropriate for many patients.

The quality of published studies was low. There was wide variation in the method used to assess sedation state, the frequency of measurement, and the stated response to evaluations. In addition, the completeness of data in relation to entire ICU populations was usually not stated, introducing the potential for selection bias. Only three cohort studies were found. The importance of selection or inclusion bias was lowest with this study design. All of these indicated a substantial incidence of sub-optimal sedation, with over-sedation being more common (33% to 57%). Notably, one study reported that nurse assessment of sedation found a low incidence of over-sedation, which appeared at odds with the fact that in one third of measurements patients were unrousable or minimally rousable. A difference in perceptions of what constitutes optimal sedation between different health care worker groups and between individual health care workers is also likely to affect the reported incidence of sub-optimal sedation. This finding emphasises the importance of using sedation-assessment methods that have high validity and low inter-rater variability. Many of the scales in current use have not been subjected to formal evaluation. The RASS has been shown to have good construct validity and high levels of consistency among health care workers 55 but was used infrequently in the published literature.

When non-cohort studies were considered, a wide range of incidence of sub-optimal sedation levels was reported (from 1% to 75%). These studies were randomised or non-randomised trials of the efficacy of sedative drugs 21 22 23 24 25 26 29 31 32 33 34 36 37 39 40 41 42 45 46 47 48 49 50 , or were studies that evaluated sedation devices or scales 27 28 38 51 52 to monitor sedation levels, or looked at the introduction of sedation guidelines 3 35 53 54 . Overall, the chance of selection and investigator bias, and of study effects, in these studies was high. Drug trials in particular were considered less relevant to our study question as practice within a clinical trial may differ from standard care and is more likely to be controlled. Despite these factors, the majority of studies found an incidence of sub-optimal sedation, using study-specific definitions, of greater than 20%. These studies confirm the findings of the observational cohort studies and suggest high levels of sub-optimal sedation during routine care.

Improving sedation management through sedation protocols and interventions such as daily interruption of sedation is an increasing focus of quality improvement initiatives in critical care in some health care systems 1 56 57 . Sedation protocols and scales are increasingly, though not universally, used. A review of German hospitals by Martin and colleagues 6 showed increases in the use of sedation protocols (from 21% of hospitals to 46%) and in the use of sedation scales (from 8% to 51%) over the period of 2002 to 2006. In Finland, Tallgren and colleagues 3 reported that reinforcing a sedation guideline increased the percentage of expected Ramsay scale recordings made, but only to 71% of expected recordings that were actually made, indicating that formal sedation assessments were still not carried out as regularly as they should have been. These studies suggest that, despite recent evidence supporting the avoidance of over-sedation 57 58 , the use of systematic approaches to measure sedation state and optimise sedation for individual patients is not universal. The high prevalence of sub-optimal sedation and high incidence of over-sedation in published studies indicate potential for significant quality improvement in this aspect of care. This is likely to translate into substantial patient benefit.

There are several limitations to our review. As with any systematic review, studies may have been missed; this review was confined to English-language publications and therefore may be biased toward the US and UK in focus. Despite the inclusion of conference searching, there may be relevant grey literature that we did not search. As previously discussed, many of the included studies did not investigate the quality of sedation practice as their primary aim, limiting the relevance of the information provided.

Conclusions

Our review indicates the poor quality of epidemiological data concerning current sedation practice and the incidence of sub-optimal sedation. A key issue is the standardisation of methods of assessment and definitions of optimal sedation. Despite this, available data suggest that many patients in ICUs are considered sub-optimally sedated and, specifically, that the incidence of over-sedation remains high. The strong associations between sedation practice, especially over-sedation, and adverse patient outcomes suggest that a more uniform approach to monitoring depth and quality of sedation will improve quality of care.

Key messages

• The literature shows that, within the intensive care unit (ICU), a substantial proportion of patients experience inappropriate levels of sedation (that is, under- or over-sedation).

• There is a greater tendency toward over-sedation in particular.

• There is a lack of consensus in the literature as to what constitutes optimal sedation practice within the ICU, with little standardisation of either assessment methods or definitions.

• Improvements in the definition and measurement of optimal sedation may have a positive impact on patient outcomes.

Abbreviations

BIS: bispectral index monitor; ICU: intensive care unit; RASS: Richmond Agitation-Sedation Scale; RCT: randomised controlled trial.

Competing interests

The systematic review reported in this publication was funded by GE Healthcare (Chalfont St. Giles, UK). DLJ is an employee of GE Healthcare. CWP and KFC are employed by Heron Evidence Development Ltd (Luton, UK), which was commissioned to undertake research by GE Healthcare. The article processing charge was funded by GE Healthcare. GE Healthcare has developed a device for monitoring consciousness levels in sedated patients TW is collaborating with GE Healthcare in developing a sedation monitoring device. His institution has received research funding from GE for collaborative research, but TW has not gained personally and has not received any direct payment from GE Healthcare. TW holds no shares in GE Healthcare and is not an employee of the company.

Authors' contributions

DLJ conceived the study and helped with manuscript revisions. CWP designed and performed searches, extracted data and wrote the manuscript draft. KFC researched and wrote the treatment guidelines section and assisted with data extraction for the main systematic review. TW provided expert clinical input and worked on manuscript revisions. All authors read and approved the final manuscript.

Authors' information

TW is a professor of anaesthetics and critical care at Edinburgh University. DLJ is head of health economics, EMEA (Europe, the Middle East and Africa), at GE Healthcare. CWP is a consultant at Heron Evidence Development Ltd, a health outcomes research consultancy. KFC is a health outcomes analyst at Heron Evidence Development Ltd.

Acknowledgements

This review was funded by GE Healthcare. The work was performed at Heron Evidence Development Ltd, UK.

Comfort without coma: changing sedation practicesFraserGLRikerRRCrit Care Med20073563563710.1097/01.CCM.0000254072.83323.4E17251707Clinical practice guidelines for the sustained use of sedative and analgesics in the critically ill adultJacobiJFraserGLCoursinDBRikerRRFontaineDWittbrodtETChalfinDBMasicaMFBjerkeHSCoplinWMCrippenDWFuchsBDKelleherRMMarikPENasrawaySAJrMurrayMJPeruzziWTLumbPDTask Force of the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM), American Society of Health-System Pharmacists (ASHP), American College of Chest PhysiciansCrit Care Med20023011914110.1097/00003246-200201000-0002011902253Quality assessment of sedation in intensive careTallgrenMPettilaVHynninenMTallgrenMPettilaVHynninenMActa Anaesthesiol Scand20065094294610.1111/j.1399-6576.2006.01094.x16923088Instruments for monitoring intensive care unit sedationCarrascoGCrit Care2000421722510.1186/cc69715003911094504The use of continuous i.v. sedation is associated with prolongation of mechanical ventilationKollefMHLevyNTAhrensTSSchaiffRPrenticeDShermanGChest199811454154810.1378/chest.114.2.5419726743Changes in sedation management in German intensive care units between 2002 and 2006: a national follow-up surveyMartinJFranckMSigelSWeissMSpiesCCrit Care200711R12410.1186/cc6189224622018062820Using and understanding sedation scoring systems: a systematic reviewDe JongheBCookDAppere-De-VecchiCGuyattGMeadeMOutinHIntensive Care Med20002627528510.1007/s00134005115010823383The sedation of critically ill adults: Part 1: Assessment. The first in a two-part series focuses on assessing sedated patients in the ICUPunBTDunnJAm J Nurs2007107404817589228Overestimation of Bispectral Index in sedated intensive care unit patients revealed by administration of muscle relaxantVivienBDiMSOuattaraALangeronOCoriatPRiouBAnesthesiology20039991710.1097/00000542-200307000-0000612826836Anesthesia awareness and the bispectral indexAvidanMSZhangLBurnsideBAFinkelKJSearlemanACSelvidgeJASaagerLTurnerMSRaoSBottrosMHantlerCJacobsohnEEversASN Engl J Med20083581097110810.1056/NEJMoa070736118337600Adult critical care sedation guidelineUniversity of Virginia Health SystemCharlottesville, VA: Rector and Board of Visitors of the University of Virginia2005http://www.healthsystem.virginia.edu/internet/e-learning/sedguide.pdfSIAARTI recommendations for analgo-sedation in intensive care unitMattiaCSavoiaGPaolettiFPiazzaOAlbaneseDAmanteaBAmbrosioFBelfioreBBertiMBertiniLBrunoFCarassitiMCellenoDColuzziFConsalesGCostantiniACuppiniFDe GaudioRAFarniaAFincoGGravinoEGubertiALaurenziLMangioneSMaranoMMaricondaGMartoranoPPMediatiRMercieriMMondelloEMinerva Anestesiol20067276980517006417Guidelines for sedation and/or analgesia by non-anaesthesiology doctorsKnapeJTAdriaensenHvan AkenHBlunnieWPCarlssonCDupontMPaschTBoard of Anaesthesiology of the European Union of Medical SpecialistsEur J Anaesthesiol20072456356710.1017/S026502150600209217568472Clinical practice guideline manual: analgesia and sedation in the ICUUniversity of Pennsylvania Medical Center2003http://www.uphs.upenn.edu/surgery/trauma/scc/protocol/Analgesia.pdfPractice parameters for intravenous analgesia and sedation for adult patients in the intensive care unit: an executive summary. Society of Critical Care MedicineShapiroBAWarrenJEgolABGreenbaumDMJacobiJNasrawaySAScheinRMSpevetzAStoneJRCrit Care Med1995231596160010.1097/00003246-199509000-000217664563Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adultAmerican College of Critical Care Medicine of the Society of Critical Care Medicine, American Society of Health-System Pharmacists, American College of Chest PhysiciansAm J Health Syst Pharm20025915017811826570Sedation and analgesia management for mechanically ventilated adults: literature review, case study and recommendations for practiceFeeleyKGardnerAAust Crit Care200619737710.1016/S1036-7314(06)80012-316764155V. Guidelines for sedation and analgesia during mechanical ventilation general overviewShapiroMBWestMANathensABHarbrechtBGMooreFABankeyPEFreemanBJohnsonJLMcKinleyBAMineiJPMooreEEMaierRVInflammation and the Host Response to Injury Large Scale Collaborative Research ProjectJ Trauma20076394595010.1097/TA.0b013e318142d21b18090028Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008DellingerRPLevyMMCarletJMBionJParkerMMJaeschkeRReinhartKAngusDCBrun-BuissonCBealeRCalandraTDhainautJFGerlachHHarveyMMariniJJMarshallJRanieriMRamsayGSevranskyJThompsonBTTownsendSVenderJSZimmermanJLVincentJLInternational Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious DiseasesCrit Care Med20083629632710.1097/01.CCM.0000298158.12101.4118158437Methodology - search filtersScottish Intercollegiate Guidance Networkhttp://www.sign.ac.uk/methodology/filters.htmlAccessed 2008Isoflurane and propofol for long-term sedation in the intensive care unit: a crossover studyMillaneTABennettEDGroundsRMAnaesthesia19924776877410.1111/j.1365-2044.1992.tb03254.x1415973A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients. [See comment]CarsonSSKressJPRodgersJEVinayakACampbell-BrightSLevittJBourdetSIvanovaAHendersonAGPohlmanAChangLRichPBHallJCrit Care Med2006341326133210.1097/01.CCM.0000215513.63207.7F16540958Continuous infusions of lorazepam, midazolam, and propofol for sedation of the critically ill surgery trauma patient: a prospective, randomized comparison. [See comment]McCollamJSO'NeilMGNorcrossEDByrneTKReevesSTCrit Care Med1999272454245810.1097/00003246-199911000-0002210579264Dexmedetomidine infusion for more than 24 hours in critically ill patients: sedative and cardiovascular effectsShehabiYRuettimannUAdamsonHInnesRIckeringillMIntensive Care Med2004302188219610.1007/s00134-004-2417-z15338124Propofol and alfentanil infusions for sedation in intensive therapyHarperSJBuckleyPMCarrKHarperSJBuckleyPMCarrKEur J Anaesthesiol199181571651874212Propofol vs midazolam in short-, medium-, and long-term sedation of critically ill patients. A cost-benefit analysisCarrascoGMolinaRCostaJSolerJMCabreLChest199310355756410.1378/chest.103.2.5578432154Can electroencephalographic analysis be used to determine sedation level in critically ill patients?RoustanJPValetteSAubasPRondouinGCapdevilaXAnesth Analg200510111411151table of contents10.1213/01.ane.0000167782.47957.e116192535Monitoring sedation in critically ill patients: bispectral index, Ramsay and observer scalesHernández-GancedoCPestañaDPeñaNRoyoCPérez-ChrzanowskaHCriadoAEur J Anaesthesiol20062364965310.1017/S026502150600005616438768Pharmacoeconomic assessment of propofol 2% used for prolonged sedationBarrientos-VegaRSánchez-SoriaMMMorales-GarciaCCuena-BoyRCastellano-HernándezMCrit Care Med20012931732210.1097/00003246-200102000-0001811246312Sedation and analgesia in German intensive care units: how is it done in reality? Results of a patient-based survey of analgesia and sedationMartinJFranckMFischerMSpiesCIntensive Care Med2006321137114210.1007/s00134-006-0214-616741692Economic evaluation of propofol for sedation of patients admitted to intensive care unitsAnisAHWangXHLeonHHallRPropofol Study GroupAnesthesiology20029619620110.1097/00000542-200201000-0003411753021Sedation in the critically ill ventilated patient: possible role of enteral drugsCigadaMPezziADi MauroPMarzoratiSNotoAValdambriniFZaniboniMAstoriMIapichinoGIntensive Care Med20053148248610.1007/s00134-005-2559-715714324A prospective randomised pilot study of sedation regimens in a general ICU population: a reality-based medicine studyFinferSRO'ConnorAMFisherMMCrit Care19993798310.1186/cc3442901811056728A double-blind, randomized comparison of i.v. lorazepam versus midazolam for sedation of ICU patients via a pharmacologic model. [See comment]BarrJZomorodiKBertacciniEJShaferSLGellerEAnesthesiology20019528629810.1097/00000542-200108000-0000711506097A prospective evaluation of empiric versus protocol-based sedation and analgesiaMacLarenRPlamondonJMRamsayKBRockerGMPatrickWDHallRIPharmacotherapy20002066267210.1592/phco.20.7.662.3517210853622Midazolam and 2% propofol in long-term sedation of traumatized critically ill patients: efficacy and safety comparisonSandiumenge CampsASanchez-Izquierdo RieraJAToral VazquezDSa BorgesMPeinado RodriguezJAlted LopezECrit Care Med2000283612361910.1097/00003246-200011000-0000911098962Sedation during mechanical ventilation: a trial of benzodiazepine and opiate in combinationRichmanPSBaramDVarelaMGlassPSCrit Care Med2006341395140110.1097/01.CCM.0000215454.50964.F816540957Propofol sedation using Diprifusor target-controlled infusion in adult intensive care unit patientsMcMurrayTJJohnstonJRMilliganKRGrantISMackenzieSJServinFJanvierGGlenJBAnaesthesia20045963664110.1111/j.1365-2044.2004.03745.x15200536Safety and efficacy of analgesia-based sedation with remifentanil versus standard hypnotic-based regimens in intensive care unit patients with brain injuries: a randomised, controlled trialKarabinisAMandragosKStergiopoulosSKomnosASoukupJSpeelbergBKirkhamAJCrit Care20048R268R28010.1186/cc289652285415312228Remifentanil vs morphine for patients in intensive care unit who need short-term mechanical ventilationChinachotiTKesslerPKirkhamAWerawatganonTJ Med Assoc Thai200285Suppl 3S848S85712452221Remifentanil versus fentanyl for analgesia based sedation to provide patient comfort in the intensive care unit: a randomized, double-blind controlled trial [ISRCTN43755713]. [See comment]MuellejansBLopezACrossMHBonomeCMorrisonLKirkhamAJCrit Care20048R1R1110.1186/cc239842005914975049Adjunctive dexmedetomidine therapy in the intensive care unit: a retrospective assessment of impact on sedative and analgesic requirements, levels of sedation and analgesia, and ventilatory and hemodynamic parametersMacLarenRForrestLKKiserTHPharmacotherapy20072735135910.1592/phco.27.3.35117316147Current practices in sedation and analgesia for mechanically ventilated critically ill patients: a prospective multicenter patient-based studyPayenJFChanquesGMantzJHerculeCAuriantILeguillouJLBinhasMGentyCRollandCBossonJLAnesthesiology2007106687695quiz 891-89210.1097/01.anes.0000264747.09017.da17413906Epidemiology of sedation and sedation adequacy for mechanically ventilated patients in a medical and surgical intensive care unit. [See comment]WeinertCRCalvinADWeinertCRCalvinADCrit Care Med20073539340110.1097/01.CCM.0000254339.18639.1D17205015Comparative study of propofol versus midazolam in the sedation of critically ill patients: results of a prospective, randomized, multicenter trial. [See comment]ChamorroCde LatorreFJMonteroASánchez-IzquierdoJAJareñoAMorenoJAGonzalezEBarriosMCarpinteroJLMartín-SantosFOteroBGinestalRCrit Care Med19962493293910.1097/00003246-199606000-000108681594A cost analysis of alfentanil+propofol vs morphine+midazolam for the sedation of critically ill patientsManleyNMFitzpatrickRWLongTJonesPWPharmacoeconomics19971224725510.2165/00019053-199712020-0001510170449Sedation in the intensive care unit with remifentanil/propofol versus midazolam/fentanyl: a randomised, open-label, pharmacoeconomic trialMuellejansBMattheyTScholppJSchillMCrit Care200610R9110.1186/cc4939155094116780597Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. [See comment]PandharipandePPPunBTHerrDLMazeMGirardTDMillerRRShintaniAKThompsonJLJacksonJCDeppenSAStilesRADittusRSBernardGRElyEWJAMA20072982644265310.1001/jama.298.22.264418073360A comparison of hypnotic and analgesic based sedation in a general intensive care unitParkGLaneMRogersSBassettPBr J Anaesth200798768210.1093/bja/ael32017158127Continuous infusion of lorazepam versus medazolam in patients in the intensive care unit: sedation with lorazepam is easier to manage and is more cost-effectiveSwartELvan SchijndelRJvan LoenenACThijsLGCrit Care Med1999271461146510.1097/00003246-199908000-0000910470750Prolonged isoflurane sedation of intensive care unit patients with the Anesthetic Conserving DeviceSackeyPVMartlingCRGranathFRadellPJCrit Care Med2004322241224615640636An assessment of the validity of spectral entropy as a measure of sedation state in mechanically ventilated critically ill patientsWalshTSRamsayPLapinlampiTPSarkelaMOViertio-OjaHEMerilainenPTIntensive Care Med20083430831510.1007/s00134-007-0858-x17898996The Brussels sedation scale: use of a simple clinical sedation scale can avoid excessive sedation in patients undergoing mechanical ventilation in the intensive care unit. [See comment]DetricheOBerréJMassautJVincentJLBr J Anaesth19998369870110690129Cost of ICU sedation: comparison of empirical and controlled sedation methodsCostaJCabreLMolinaRCarrascoGClin Intensive Care19945172110150550Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS)ElyEWTrumanBShintaniAThomasonJWWheelerAPGordonSFrancisJSperoffTGautamSMargolinRSesslerCNDittusRSBernardGRJAMA20032892983299110.1001/jama.289.22.298312799407Sedation and analgesia in the critically ill adultFraserGLRikerRRCurr Opin Anaesthesiol20072011912310.1097/ACO.0b013e32808255b417413394Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. [See comment]KressJPPohlmanASO'ConnorMFHallJBN Engl J Med20003421471147710.1056/NEJM20000518342200210816184Efficacy 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. [See comment]GirardTDKressJPFuchsBDThomasonJWSchweickertWDPunBTTaichmanDBDunnJGPohlmanASKinniryPAJacksonJCCanonicoAELightRWShintaniAKThompsonJLGordonSMHallJBDittusRSBernardGRElyEWLancet200837112613410.1016/S0140-6736(08)60105-118191684Randomized Controlled trial comparing dexmedetomidine with lorazepam to reduce delirium in the ICUPandharipandePPFrizellJBunBTMazeMElyEWAnesthesiology2006105A210Propofol vs midazolam for ICU sedation: a Canadian multicenter randomized trialHallRISandhamDCardinalPTweeddaleMMoherDWangXAnisAHChest20011191151115910.1378/chest.119.4.115111296183Stressful memories and psychological distress in adult mechanically ventilated intensive care patients - a 2-month follow-up studySamuelsonKLundbergDFridlundBActa Anaesthesiol Scand20075167167810.1111/j.1399-6576.2007.01292.x17567267Memory in relation to depth of sedation in adult mechanically ventilated intensive care patientsSamuelsonKLundbergDFridlundBIntensive Care Medicine20063266066710.1007/s00134-006-0105-x16520999