Sedation is a cornerstone of intensive care unit (ICU) therapy and is required by >85% of patients.1 Sedative medications are used to assist tolerance of endotracheal intubation, mechanical ventilation, invasive procedures, and to manage agitation.2 Midazolam and propofol are 2 of the most commonly used intravenous sedative agents.3,4 Metabolism and clearance of these agents rely on adequate function of renal and hepatic systems, with many agents also producing active metabolites.2 Critically ill patients commonly demonstrate hepatic and renal dysfunction, delaying systemic clearance of these drugs. This is often compounded by oversedation associated with high doses of these agents, which occurs in up to 60% of ICU patients.5 Slow clearance of these agents leads to drug hangover, which slows down patient awakening, return of airway reflexes, and extubation times.2 Furthermore, these intravenous sedatives are associated with delirium.5,6
Volatile-based ICU sedation entails the delivery of inhaled isoflurane, sevoflurane, or desflurane anesthetic agents. These volatile agents have a long tradition of use within the operating room to provide general anesthesia. Their use within the ICU has largely been confined to the management of status asthmaticus and epilepticus.7,8 However, there is increased interest in their use as general ICU sedatives because the early trial performed by Kong et al9 demonstrated faster patient awakening and extubation times. The associated adverse effects of these agents include nausea and vomiting and possible fluoride-induced nephrotoxicity.10 Volatile agents are a novel sedation modality that has the potential to expand our current sedation treatment options. The primary objective of this analysis is to systematically review and meta-analyze the efficacy and safety of volatile agents for sedation among adult patients admitted to critical care units compared with standard intravenous midazolam or propofol sedation.
This review adhered to the methodology as described in the Cochrane Handbook for Systematic Reviews of Interventions.11
Inclusion and Exclusion Criteria
Eligible studies included were published single or multicenter randomized controlled trials (RCTs) in which adult (>18 years of age) ICU patients received either inhaled volatile anesthetic agent or intravenous benzodiazepines or propofol-based sedation. Patients within medical, surgical, and specialized cardiac ICUs were included. There was no restriction to sample size. Quasirandomized trials, crossover, case-control, or case series studies were excluded. Inhaled volatile anesthetic agents include the use of isoflurane, sevoflurane, or desflurane anesthetic agents.
Electronic Search Strategy
Eligible trials were identified using MEDLINE (1946–2015), EMBASE (1947–2015), Web of Science index (1900–2015), and Cochrane Central Register of Controlled Trials. Search terms included volatile anesthetics, intensive care units, randomized controlled trial limited to human, adults, and English language. In addition, we reviewed trial registries to discern both unreported and/or ongoing trials (clinicaltrials.gov). Abstracts required the full article for consideration. We also perused the reference list of identified studies and review articles to identify any other studies.
Methods of Review
The literature search was performed by 2 teams of 2 independent reviewers with the aid of a librarian. Reasons for exclusion were noted. Data were extracted by both teams using a data abstraction form and disagreements resolved by consensus. Trial bias was assessed using the Cochrane Risk of Bias tool.11 The primary outcome for this review was time to extubation (time between discontinuing sedation and tracheal extubation). Secondary outcomes included other clinical sedation and safety outcomes. Additional sedation outcomes were time to obey verbal commands (time between discontinuing sedation to squeezing hand and moving toes on command), proportion of time spent in target sedation, duration of mechanical ventilation, length of stay in the ICU, and length of hospital stay. Patient safety was assessed by nausea and vomiting requiring pharmacological treatment, creatinine levels (12- to 24-hour postsedation or postoperatively), and death. In addition to these outcomes, reviewers extracted the number of patients and type of ICU within each study, age, sex, duration of sedation, sedative agents used, and dose (when available). Primary authors were contacted for missing information.
The primary outcome of time to extubation and other continuous outcomes were assessed using the difference in means (95% confidence interval [CI]). Dichotomous data were assessed using the risk ratio or difference (95% CI). If the full text article had data presented as median, interquartile range, and range, the mean and standard deviation were calculated using the methods outlined by Wan et al12 (unless available from the author). Heterogeneity was assessed via calculation of the I 2 statistic, where values >50% indicated moderate heterogeneity. A random-effects model was used when combined studies demonstrated at least moderate heterogeneity; otherwise, a fixed-effects model was used. Publication bias was assessed using a funnel plot, as well as an Egger regression test for funnel plot asymmetry. A sensitivity analysis was performed using the trim and fill method (with a random-effects model) to impute potentially missing studies generating a symmetric plot.13,14 Data synthesis was completed using Review Manager 5.3 provided by the Cochrane Collaboration (Oxford, United Kingdom) and metafor package in R software v 3.02.11,15 To control for multiple testing, Bonferroni method was used to adjust P values by dividing the conventional P value of .05 by the number of main hypotheses (n = 9). Therefore, P values <.006 were considered statistically significant.
The initial analysis compared the entire class of volatile agents with all intravenous agents (midazolam or propofol). A priori subgroup analyses were performed comparing volatile agents with midazolam and propofol separately. Sufficient studies were also available to compare sevoflurane with propofol and isoflurane with midazolam separately.
An additional analysis was performed comparing time with extubation outcomes in trials that were sponsored by a pharmaceutical company versus trials that were sponsored by a grant or institution.
We calculated the power and sample size required for the primary outcome, time to extubation, and clinically important outcomes such as ICU length of stay. Using a 2-tailed 2-sample t test with type I error probability of 5%, power of 80%, and standard deviation of 848, a sample of 252 patients (126 per group) would be required to detect a 300-minute difference in extubation time between volatile-based sedation and intravenous midazolam.9,16–18 To detect a reduction in ICU length of stay by 12 hours with a standard deviation of 74, a sample size of 1194 patients (597 per group) would be required.16,18–24
Study Identification and Selection
The initial search identified 2173 records. We removed 506 duplicate records plus an additional 1623 records that failed to meet inclusion criteria (1534 non-ICU or non-volatile trials, 39 reviews/meta-analyses, 27 animal, 13 pediatric, 3 scavenging, and 1 trial update). Forty-four full-text articles were assessed for eligibility, which were reduced to 15 trials with a total of 989 patients for this meta-analysis (Figure 1; Supplemental Digital Content, Supplemental Appendix 1, http://links.lww.com/AA/B532).9,16–29 A full list of search articles that were reviewed and excluded is available from the authors.
Main characteristics of the 15 RCTs are summarized in Table 1. Fourteen trials were parallel RCTs, and 1 trial had 3 arms. Three authors published 2 articles with different reported outcomes that appear to have been conducted within the same clinical trial population.16,17,21,26,28,29 The majority of patients within these trials were male (45%–95%), with the mean age ranging from 52 to 69 years (Table 1). Out of 15 trials, 6 were set within cardiac ICUs, and the remainder were set in surgical and mixed medical-surgical ICUs. Short-term sedation (duration of sedation of <24 hours) is likely to involve 10 trials predominantly set within cardiac ICUs.9,19–25,27,29 Seven trials used sevoflurane, 6 used isoflurane, 1 used desflurane, and 1 trial randomized patients to either sevoflurane or isoflurane sedation.
Selection, performance, detection, attrition, and reporting bias were assessed as high, low, or unclear. The trial dates ranged from 1989 to 2015 (Figure 2). Study quality was highly variable, with many poorly documented trial characteristics within the early studies.
Time to Extubation.
Eight studies totaling 523 patients reported this outcome.9,16–18,20,21,24,27 All 3 volatile agents were represented and compared with either midazolam or propofol. Volatile agents showed faster extubation times in comparison with intravenous sedatives (difference in means, −52.7 minutes; 95% CI, −75.1 to −30.3; P < .00001) but with an I 2 of 92%, indicating high statistical heterogeneity (Figure 3A). Subgroup analyses based on the type of medication were performed. Four studies compared all volatile agents with midazolam in 143 patients and demonstrated that volatile agents reduced extubation time (difference in means, −292.2 minutes; 95% CI, −384.4 to −200.1; P < .00001) with moderate statistical heterogeneity (Figure 3B).9,16–18 Three of these trials with 110 patients allowed direct comparison of isoflurane with midazolam and showed a similar reduction in extubation time (difference in means, −265.2 minutes; 95% CI, −361.8 to −168.7; P < .00001; I 2 0%).9,16,17 Five studies compared all volatile agents (sevoflurane used in 3 trials, desflurane in 1 trial, and sevoflurane or isoflurane used in 1 trial) with intravenous propofol in 399 patients and showed a difference in means of −29.1 minutes (95% CI, −46.7 to −11.4; P = .001) with a high degree of statistical heterogeneity (Figure 3C).18,20,21,24,27 Review of these studies showed that extubation times within both the control and the volatile arms were significantly faster in the trials performed by Meiser et al27 and Hellström et al.21 Removal of these 2 trials showed a reduction in extubation time (difference in means, −146.0; 95% CI, −207.3 to −84.8; P < .00001) with lower heterogeneity (I 2 38%). Four trials with 310 patients compared sevoflurane with propofol and showed a statistically nonsignificant reduction in extubation time (difference in means, −114.3; 95% CI, −215.3 to −13.3; P = .03; I 2 90%).18,20,21,24
Subgroup analyses were also performed based on the duration of sedation. Three longer-term sedation trials (duration of sedation >24 hours), with 130 patients predominantly performed in mixed medical-surgical ICUs showed a large reduction in time to extubation (difference in means, −314.5 minutes; 95% CI, −452.2 to −176.7; P < .00001; I 2 30%).16–18 Five short-term sedation trials (duration of sedation <24 hours) with 393 patients were largely performed for postoperative sedation and showed a smaller reduction in time to extubation (difference in means, −30.9 minutes; 95% CI, −49.2 to −12.7; P = .0009; I 2 92%).9,20,21,24,27 As mentioned previously, removal of trials performed by Meiser et al27 and Hellström et al21 maintained faster extubation times within the volatile groups (difference in means, −156.6; 95% CI, −230.0 to −83.1; P < .0001) with lower statistical heterogeneity (I 2 56%). The influence of pharmaceutical or industry sponsorship was reviewed, with 4 trials receiving commercial sponsorship, 3 trials were grant or internally funded, and funding for 1 older trial was unknown (Table 1). The type of funding did not negatively impact the above findings, with reductions in time to extubation remaining larger within the nonindustry funded trials (difference in means, −195.8; 95% CI, −311.6 to −79.9).
Other Sedation Outcomes.
Four studies assessed the time to obey verbal commands upon discontinuing sedation (Table 2). There was no significant difference in this outcome (difference in means, −26.2; 95% CI, −59.4 to 7.2; P = .12; I 2 71%).9,16,17,27 Only 2 studies with 73 patients assessed the proportion of time patients spent within a target sedation range.17,18 There was no significant difference between inhaled volatile and intravenous agents (difference in means, −1.1; 95% CI, −13.8 to 11.5; P = .86; I 2 0%). Duration of mechanical ventilation was available in 4 trials (3 short-term and 1 longer-term sedation trial) using sevoflurane.18–21 With 341 patients, duration of mechanical ventilation was not different between volatile and intravenous sedation groups (difference in means, −2.0 hours; 95% CI, −3.9 to −.2; P = .03) and showed high heterogeneity (I 2 66%). As mentioned previously, removal of the trial by Hellström et al21 reduced the duration of mechanical ventilation using sevoflurane sedation (difference in means, −3.1 hours; 95% CI, −4.5 to −1.6; P < .0001) with improved statistical heterogeneity (I 2 0%).
Nausea and vomiting were reported in 4 trials totaling 363 patients (Table 2).20,21,24,27 There was no significant difference in nausea and vomiting between the 2 sedation modalities (risk ratio, 1.2; 95% CI, .7 to 2.2; I 2 13%). Serum fluoride levels were measured during and after sedation within 3 trials.19,25,26 All trials showed that fluoride levels were significantly elevated within the volatile group in comparison with standard intravenous sedatives, with levels often peaking 12 to 16 hours after discontinuation of sedation.25,26 Serum fluoride levels were not combined for additional analysis, given marked differences in timing of measurement and how the results were reported. However, 5 trials with 446 patients have reported serum creatinine levels during and after sedation periods. Serum creatinine levels were combined at 12 to 24 hours after sedation (or after surgery in 1 short-term sedation trial), given that it was a consistent time point, and fluoride levels remain high within the postsedation period.19,24–26,29 The studies included 4 short-term and 1 longer-term sedation trial. No difference in serum creatinine was seen (difference in means, .7; 95% CI, −5.4 to 6.8; P = .83; I 2 0%; Table 2). Assessment of cardiovascular stability has been performed by measuring various hemodynamic indices (heart rate, blood pressure, cardiac index, systemic vascular resistance index, stroke volume variation, and central venous pressure) and the use of vasoactive drugs.9,18,23,27,29 A single long-term sedation trial performed by Mesnil et al18 demonstrated that significantly fewer patients receiving sevoflurane sedation required vasoactive drug support in comparison with midazolam and propofol sedation. However, the majority of trials have shown no difference in patient hemodynamics between inhalational and intravenous sedation techniques.
Death and Length of Stay.
In-hospital mortality was assessed in 3 trials with 241 patients. There was no significant difference between types of sedation (risk difference, 0; 95% CI, −.02 to .03; P = .95; I 2 0%).9,17,24 Length of ICU stay and length of hospital stay were assessed in 8 and 6 trials, respectively. Both outcomes showed no significant difference between the 2 sedation modalities (Table 2).
A funnel plot on the meta-analysis looking at time to extubation using 8 trials shows a lack of negative trials and a positive publication bias (Figure 4A). Egger regression test for funnel plot asymmetry was also significant (P < .0001). The trim and fill method imputed 4 studies to improve symmetry of the funnel plot, with the adjusted mean difference of extubation times estimated at −37.9 minutes (95% CI, −62.7 to −13.1; P = .003).
Our results show that the use of inhaled volatile agents reduces time to tracheal extubation in comparison with standard intravenous sedatives by about 53 minutes. This is most striking in the comparison of all volatile agents, including isoflurane specifically, with midazolam (265–292 minutes). Similar findings were noted in comparisons with propofol, although the clinical difference was smaller (29 minutes). Clearance of volatile agents through simple pulmonary exhalation with minimal systemic metabolism is likely to account for the faster extubation times. Benzodiazepines demonstrated a larger difference in extubation times than propofol. This is likely attributable to different pharmacokinetic properties of these intravenous agents, with propofol possessing faster systemic clearance with no significant metabolites in comparison with midazolam.2,30
Despite volatile agents demonstrating faster extubation times, this failed to translate into shorter lengths of stay. However, this analysis identified no difference in nausea and vomiting or in-hospital mortality in patients sedated using volatile agents. These mortality findings have been further supported by a recent retrospective study of 200 surgical ICU patients sedated with either isoflurane or midazolam/propofol for >96 hours.31 Risk-adjusted analysis demonstrated that volatile-based sedation was associated with lower in-hospital death (adjusted odds ratio .35; 95% CI, .18 to .68; P = .002) and 1-year mortality (adjusted odds ratio .41; 95% CI, .21 to .81; P = .01). The low incidence of nausea and vomiting among patients receiving volatile agents is likely secondary to the low doses required for ICU sedation, which are approximately one third (.3 minimum alveolar concentration) the dose required for general anesthesia. With several studies showing elevated serum fluoride levels with the use of volatile agents, we failed to demonstrate any nephrotoxic effects up to 24 hours after sedation.17,19,26 These findings are in keeping with case series demonstrating similar findings.32,33
This study has several limitations. This analysis included many older trials in which current standards of randomization, allocation concealment, and selective reporting criteria were not formally documented within the article. The current trials are small, with variation in study quality, analgesic regimens, use of daily sedation breaks, reporting depth of sedation, type of sedative drug, and duration of use, which may have added to the clinical heterogeneity and affected treatment outcomes. Comparison of all volatile agents with intravenous sedatives was initially performed, given that pulmonary clearance of volatile agents is a unique class effect that avoids systemic metabolism required by our traditional intravenous agents. However, additional subanalyses were performed given that the different pharmacokinetic properties of midazolam, propofol, and between the volatile agents with desflurane showing the fastest clearance, followed by sevoflurane and isoflurane. These subanalyses confirmed faster extubation times using volatile-based sedation with reduced statistical heterogeneity. Furthermore, heterogeneity was improved after removal of the trials performed by Meiser et al27 and Hellström et al,21 which showed faster extubation times in both control and volatile arms. These may have been influenced by institutional weaning protocols, dose of opioids, and use of regional analgesia techniques. Faster emergence within the trial performed by Meiser et al27 may be influenced by the use of desflurane and the common use of epidural analgesia within this surgical population. Lower doses of intraoperative opioid and midazolam were noted within the cardiac surgical population of the trial performed by Hellström et al21 in comparison with other similar studies.20,21,24 We also note that faster extubation times without a positive translation on other important ICU outcomes, such as length of stay or mortality, may not be clinically meaningful. This meta-analysis is underpowered, at 58.5%, to detect a clinically meaningful reduction in the ICU length of stay of 12 hours. Currently, we lack a large, well-powered clinical trial to assess these clinically important ICU end points, and additional research is required to evaluate whether volatile-based sedation truly impacts patient care beyond extubation times. The funnel plot reveals that there is a large publication bias with current trials reporting predominantly positive results. We used a nonparametric method called trim and fill that imputed the studies missing from the meta-analysis to improve symmetry of the funnel plot and demonstrated that faster extubation times were still evident using volatile agents. This technique assumes that data should be symmetrical and may be affected by study heterogeneity. Despite statistical correction of these results, negative trials are lacking in the literature and data from ongoing active trials, and undertaking a larger clinical study would be valuable to assess these agents.34,35 Although meta-analyses combine similar studies, they may still be underpowered to assess certain clinical outcomes and increase the chance of type II error.36 Given our findings and the potential benefit of volatile agents to improve outcomes for critical care patients, a large well-conducted clinical trial is now required.
An important outcome that we were unable to address is the impact upon ICU-related delirium. Several studies did measure and demonstrate no significant difference in the incidence of postextubation agitation, hallucinations, and delusional memories, but combining these data was not performed given varied definitions and measurement tools.20,21,27,28 Sedation, particularly with benzodiazepine agents, is a recognized risk factor for developing delirium, which affects 30% to 80% of ICU patients.6,37 Unfortunately, the current trials provide limited information on this outcome, and the effect of either short-term or longer-term use of volatile agents remains unknown. Furthermore, dexmedetomidine has recently become available, and its use in the ICU has gained considerable attention. At present, there are no trials comparing volatiles with dexmedetomidine and whether the above advantages of volatiles would remain requires additional investigation.
In 2013, the Society of Critical Care Medicine updated guidelines and combined the overlapping management of sedation, pain, and delirium for ICU patients.2 Given the association of benzodiazepines with drug-induced delirium, tolerance, withdrawal, and slow systemic clearance in ICU patients with drug hangover, there is rising interest in identifying alternative sedation modalities. Prolonged use of propofol is often prohibitive given its higher cost, risk of hemodynamic instability, and hypertriglyceridemia.2 The use of volatile agents within the ICU poses a novel and attractive sedative option. This class of drug confers several advantages over standard intravenous medications, including rapid onset, bronchodilation, hemodynamic stability at low sedation doses, and breath-by-breath end-tidal gas monitoring that correlates with cerebral concentration that aids drug titration to minimize oversedation.7,30 However, the use of volatile agents in critical care environments requires specialized drug delivery systems, gas scavenging, and education of critical care nurses and intensivists with no anesthesia background regarding this technique. There has also been concern surrounding the potential of neurotoxicity of volatile and intravenous agents (ketamine, benzodiazepines, and propofol) in vulnerable, developing pediatric brains and cognitive dysfunction in elderly patients.38–41 This area of research has produced conflicting results, with evidence that volatile agents may also provide neuroprotection.42,43 Clinical studies have been limited by the inability to separate the effects of volatile agents from the surgical stress response, comorbidities, and the underlying clinical disease process.44,45 Recent results from the multicenter General Anesthesia Spinal trial demonstrated no difference in cognitive outcomes in infants undergoing inguinal herniorrhaphy surgery who received either sevoflurane-based general or awake regional anesthesia.46
Our results indicate that volatile agents promote rapid extubation and may be the ultimate fast-track agent for postoperative patients and promote faster weaning in complex ICU patients requiring longer-term sedation. These findings were greater in comparison with the use of intravenous midazolam than propofol. However, there is limited literature assessing the safety and efficacy of these agents in the short term and the longer term, and the current trials demonstrate marked heterogeneity and high probability of publication bias. Currently, these data do not support the regular use of this technique, but given the current data and potential of these agents to improve patient outcomes, a well-designed, adequately powered RCT within a homogeneous population to truly understand the potential clinical effects of this sedation modality is required.
The authors thank Drs M. Steurer and P. Sackey for providing information for this analysis.
Name: Angela Jerath, FRCPC, FANZCA, MBBS, BSc.
Contribution: This author helped to study the concept, collect and analyze the data, and develop the manuscript.
Name: Jonathan Panckhurst, MBChB.
Contribution: This author helped collect the data.
Name: Matteo Parotto, PhD, MD.
Contribution: This author helped collect and analyze the data and prepare the manuscript.
Name: Nicholas Lightfoot, FANZCA, MBChB.
Contribution: This author helped collect and analyze the data and prepare the manuscript.
Name: Marcin Wasowicz, PhD, MD.
Contribution: This author helped prepare and review the manuscript.
Name: Niall D. Ferguson, FRCPC, MSc.
Contribution: This author helped to review the manuscript.
Name: Andrew Steel, FRCPC, FFICM, FRCA, MBBS, BSc.
Contribution: This author helped to review the manuscript.
Name: W. Scott Beattie, PhD, FRCPC.
Contribution: This author helped study the concept and review the manuscript.
Conflicts of Interest: This analysis includes a trial conducted by the author group.24,35 The authors have no financial conflicts of interest.
This manuscript was handled by: Avery Tung, MD, FCCM.
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