Introduction
Materials and methods
Results
Epidemiology
First author [Reference] | Year of publication/country | Setting | Study design/Number of patients | Type of infection | Number of patients with sedation | ||||
---|---|---|---|---|---|---|---|---|---|
Type of sedation | Infection | Number of infections |
P
| OR (95% CI) | |||||
Bornstain [29] | 2004/France | Mixed ICUs | Prospective cohort/747 | Early-onset VAP | NR* | 42/80 (52) | 251/667 (37) | 0.03 | 1.9 (1.2-3.1)** |
Schwacha [22] | 2006/USA | Burn unit | Retrospective nested case-control study/374 | Hospital-acquired infection | Opiate analgesics | NR | NR | 0.049§ | 1.2 (1-1.5) |
Metheny [23] | 2006/USA | Mixed ICUs | Prospective cohort/360 | VAP | NR | 150/173 (86) | 132/187 (70) | 0.006 | 2.3 (1.3-4.1)** |
Nseir [24] | 2009/France | Mixed ICU | Prospective cohort/587 | ICU-acquired infection | Remifentanil with or without midazolam | 203/233 (87) | 191/354 (53) | <0.001 | 5.7 (3.7-8.9) |
Pathophysiology
Exposure to risk factors for ICU-acquired infection
Microaspiration
Microcirculatory effects of sedation
Intestinal effects of sedation
Immunomodulatory effects of sedation
Opioids
1. Acute exposure to opioids
2. Chronic exposure to opioids
3. Opioid withdrawal
Benzodiazepines
Propofol
Clonidine and dexmedetomidine
Barbiturates
Mechanism | References | Study design/Number of patients | Main results |
---|---|---|---|
Prolongation of exposure to risk factors | |||
Longer duration of mechanical ventilation, and ICU stay | Prospective cohorts/5183, and 252; respectively | Durations of mechanical ventilation and ICU stay significantly longer in patients receiving sedation compared with those without sedation | |
Microaspiration | |||
Neurologic impairment | [23] | Prospective cohort/360 | Heavy sedation significantly associated with microaspiration confirmed by pepsin-positive tracheal aspirate |
Impaired tubular esophageal motility | [34] | Prospective cohort/21 | Esophageal motility significantly reduced in sedated patients compared to healthy controls |
Microcirculatory disturbances | [35] | Prospective cohort/10 | Sedation induced an increase in cutaneous blood flow, a decrease in reactive hyperemia, and alterations of vasomotions |
Gastrointestinal motility disturbances | |||
Opioids | [40] | Double-blind, placebo-controlled, randomized study comparing the effects of lactulose, polyethylene glycol, or placebo on defecation/308 | Morphine administration associated with a longer time before first defecation, except in the polyethylene glycol group |
Dexmedetomidine and clonidine | [47] | Animal study/NA | Clonidine and dexmedetomidine concentration-dependently increased peristaltic pressure threshold and inhibited peristalsis |
Immunomodulatory effects | - | - | Please see Table 3 for details |
Sedative agent | References | Main results |
---|---|---|
Opioids | Suppression of mitogen-stimulated proliferation of T and B-lymphocytes | |
Suppression of natural killer, and primary antibody production | ||
Inhibition of phagocytosis by macrophages | ||
Suppression of IL2, IL12, INFγ, and NO production | ||
Activation of sympathic nervous system, and the hypothalamic-pituitary-adrenal axis | ||
[84] | Enhancement of Pseudomonas aeruginosa virulence | |
[85] | Reduction of bacterial clearance via impairment of TLR9-NF-κB signaling | |
[86] | Enhancement of cellular apoptosis | |
Benzodiazepines | [105] | Inhibition of IL-1, IL-6, and TNF-α production |
[109] | Supression of macrophage migration and phagocytosis | |
Clonidine and dexmetetomidine | [119] | Reduction of IL-1β, and IL6 production |
[121] | Sympatholytic effects | |
Propofol | Suppression of H2O2, NO, and O* production; improvement of endothelial dysfunction | |
[113] | Suppression of TNF-α, IL-β, IL-10 | |
[114] | Attenuation of leukosequestration, pulmonary edema, and pulmonary hyperpermeability | |
Barbiturates | [124] | Suppression of antigen-specific lymphocyte proliferation, and IL-2 production |
[125] | Suppression of TNF-α mRNA expression | |
[126] | Impairment of phagocytosis |
Discussion
Modulation of sedation to prevent ICU-acquired infection
Daily interruption of continuous sedation
Nurse-implemented sedation protocol
Intervention | First author [Reference] | Year of publication/country | Study design/Number of patients | Main results* |
---|---|---|---|---|
Daily interruption of sedation | Kress [127] | 2000/USA | Randomized controlled/128 | Shorter duration of MV (median 4.9 vs 7.3 d, P = 0.004) |
Daily interruption of sedation, and ventilator weaning protocol | Girard [128] | 2008/USA | Randomized controlled/336 | Higher number of MV-free days (14.7 vs 11.6 days; P = 0.02) Shorter mean duration of ICU stay (9.1 vs 12.9 days; P = 0.01) Reduced ICU mortality (HR 0.68, 95% CI 0.5 to 0.92; P = 0.01) |
Daily interruption of sedation, and early physical therapy | Schweickert [129] | 2009/USA | Randomized controlled/104 | Higher number of MV-free days (23 vs 21 days, P = 0.05) Higher rate of hospital discharge (59% vs 35%, P = 0.02) |
Expanded ventilator bundle, including daily interruption of sedation | Papadimos [130] | 2008/USA | Before-after cohort/2968 | Reduced incidence rate of VAP (7.3 vs 19.3/1000 MV-days, P = 0.028) |
Blamoun [131] | 2009/USA | Before-after cohort/NR | Reduced incidence rate of VAP (0 vs 12/1000 MV-days, P = 0.0006) | |
Resar [132] | 2005/USA and Canada | Before-after cohort/NR | Reduced incidence rate of VAP (2.7 vs 6.6/1000 MV-days) | |
Berriel-Cass [133] | 2006/USA | Before-after cohort/NR | Reduced incidence rate of VAP (3.3 vs 8.2/1000 MV-days) | |
Youngquist [134] | 2007/USA | Before-after cohort/NR | Reduced incidence rate of VAP (2.7 vs 6; and 0 vs 2.6/1000 MV-days) | |
Unahalekhaka [135] | 2007/Thailand | Before-after cohort/NR | Reduced incidence rate of VAP (8.3 vs 13.3/1000 MV-days) | |
Nurse-implemented sedation protocol | Brook [137] | 1999/USA | Randomized controlled/321 | Shorter duration of MV (55.9 vs 117.0 hours, P = 0.008) Shorter length of ICU stay (5.7 ± 5.9 vs. 7.5 ± 6.5 days; P = 0.013) |
Arias-Rivera [138] | 2008/Spain | Before-after cohort/356 | Increased rate of successful extubation (P = 0.002) | |
Quenot [142] | 2007/France | Before-after cohort/423 | Reduced incidence of VAP (6 vs 15%, P = 0.005) Shorter duration of MV (4.2 vs 8 days, P = 0.001) |
Comparison of sedative agents
Outcome | First author [Reference] | Year of publication/country | Study design/Number of patients | Main results* |
---|---|---|---|---|
Cytokine responses | von Dossow [143] | 2008/Germany | Randomized controlled study comparing fentanyl with remifentanil/40 patients | IFNγ/IL-10 after concanavalin A stimulation, and SOCS-3 gene expression significantly lower in remifentanil group |
Helmy [145] | 2001/Egypt | Randomized controlled study comparing propofol with midazolam/40 patients | Both agents suppressed IL-8 production Midazolam suppressed production of IL-1β, IL-6, and TNF-α Propofol inhibited IL-2 production and stimulated IFNγ production | |
Memis [111] | 2007/Turkey | Randomized controlled study comparing dexmedetomidine vs midazolam/40 patients | Significant decreases in TNF-α, IL-1β, and IL-6 in dexmedetomidine group | |
Infection and other outcomes | Arya [144] | 2001/India | Randomized controlled study comparing midazolam and morphine with midazolam/33 newborn babies | Comparable rate of infection (6%) in the two groups |
Muellejans [14] | 2006/Germany | Randomized controlled study comparing remifentanil and propofol with fentanyl and midazolam/80 patients | Mean time intervals from arrival at the ICU until extubation (20.7 vs 24.2 hours) and from arrival until eligible discharge from the ICU (46.1 vs 62.4 hours) were significantly (P < 0.05) shorter in the remifentanil/propofol group | |
Rozendaal [15] | 2009/Neatherlands | Randomized controlled study comparing remifentanil and propofol with propofol, midazolam or lorazepam combined with fentanyl or morphine/215 patients | The remifentanil-based regimen reduced median weaning time by 18.9 hours (P = 0.0001), increased the likelihood to be extubated (P = 0.018), and the discharge from the ICU (P = 0.05) | |
Kress [146] | 1996/USA | Randomized controlled study comparing propofol with midazolam/73 patients | Narrower range of wake-up times with a higher likelihood of waking in less than 60 minutes in propofol group | |
Riker [148] | 2009/USA | Randomized controlled double-blind study comparing dexmedetomidine with midazolam/375 patients | Reduced rate of infection (10.2 vs 19.7%, P = 0.02), and shorter time to extunation (median 3.7 vs 5.6 days, P = 0.01) in the dexmedetomidine group | |
Nadal [149] | 1995/Spain | Retrospective cohort comparing patients with thiopental with those without thiopenthal | Higher rate of VAP in patients who received thiopenthal (53 vs 35%) |
Limitations
Future studies
Conclusions
Key messages
-
Several epidemiologic studies suggest a link between sedation and ICU-acquired infection.
-
Prolongation of exposure to risk factors for infection, microaspiration, gastrointestinal motility disturbances, microcirculatory effects and immunomodulatory effects are main mechanisms by which sedation may favor infection in critically ill patients.
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Clinical studies comparing different sedative agents do not provide evidence to recommend the use of a particular agent to reduce ICU-acquired infection rate.
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Sedation strategies aiming to reduce the duration of mechanical ventilation, such as daily interruption of sedatives or nursing-implementing sedation protocol, should be promoted.
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The use of short-acting opioids, propofol, and dexmedetomidine is associated with shorter duration of mechanical ventilation and ICU stay, and might be helpful in preventing ICU-acquired infections.