Volatile-Based Short-Term Sedation in Cardiac Surgical Patients: A Prospective Randomized Controlled Trial Angela Jerath, FRCPC, MBBS1; Scott W. Beattie, PhD, MD1; Tony Chandy, MD2; Jacek Karski, FRCPC, MD1; George Djaiani, FRCPC, MD1; Vivek Rao, PhD, FRCSC, MD3; Terrence Yau, FRCSC, MD3; Marcin Wasowicz, PhD, MD1; on behalf of the Perioperative Anesthesia Clinical Trials Group
Objective: To evaluate the differences in extubation times in a group of cardiac surgical patients who were anesthetized and sedated with either IV propofol or inhaled volatile anesthetic agents. Department Anesthesia and Pain Management, Toronto General Hospital, Toronto, ON, Canada. 2 Department Anesthesia and Pain Management, Christian Medical College, Vellore, India. 3 Divison of Cardiac Surgery, Toronto General Hospital, Toronto, ON, Canada. This study was performed at Toronto General Hospital, Toronto, ON, Canada. Dr. Jerath performed the daily running of the study and is the primary author of this article. Dr. Beattie assisted with methodology and development of the article. Drs. Chandy, J. Karski, and G. Djaiani assisted with daily running of the study and proofed the article. Dr. Rao and Yau gave cardiac surgical support for the study. Dr. Wasowicz is primary investigator of the study and helped in the development of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Jerath's institution received grant support from the Career Scientist Award (Dr. Wasowicz), the Academic Medical Organization award (Dr. Wasowicz), and the Merit Award (Dr. Wasowicz). Dr. Beattie received grant support. Dr. Rao served as a board member for Medtronic and CorMatrix Cardiovascular, consulted for Medtronic, lectured for CorMatrix and Medtronic, and has stock in CorMatrix. His institution consulted for Thoratec. Dr. Yau consulted for Heartware. Dr. Wasowicz lectured for the Japanese Society of Anesthesia and received support for article research from the Academic Medical Organization Alternative Founding Plan, Canadian Anesthesiologists’ Society/Canadian Anesthesia Research Foundation, Merit Award, Department of Anesthesia, University of Toronto. His institution received grant support from the Academic Medical Organization Alternative Founding Plan Canadian Anesthesiologists Society/Canadian Anesthesia Research Foundation Merit Award, Department of Anesthesia, University of Toronto and from the Anesthesia Patient Safety Foundation. His institution received support for the development of educational presentations from the Toronto Anesthesia Symposium. This study was not sponsored by Sedana Medical (Sweden), manufacturer of the Anesthesia Conserving Device. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Angela Jerath, FRCPC, MBBS, Department of Anesthesia and Pain Management, Toronto General Hospital, 3-EN, 200 Elizabeth St, Toronto, ON, Canada M5G 2C4. E-mail: [email protected] Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000000938 1
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Design: This was a prospective randomized controlled trial performed between September 2009 and August 2011. Setting: Cardiovascular ICU within a tertiary referral universityaffiliated teaching hospital. Patients: One hundred forty-one patients undergoing coronary artery bypass graft surgery with normal or mildly reduced left ventricular systolic function. Intervention: Participants were randomly assigned to receive anesthesia and postoperative sedation using IV propofol (n = 74) or inhaled volatile (isoflurane or sevoflurane) anesthetic agent (n = 67). Measurements and Main Results: Patients sedated using inhaled volatile agent displayed faster readiness to extubation time at 135 minutes (95–200 min) compared with those receiving IV propofol at 215 minutes (150–280 min) (p < 0.001). Extubation times were faster within the volatile group at 182 minutes (140–255 min) in comparison with propofol group at 291 minutes (210–420 min) (p < 0.001). The volatile group showed a higher prevalence of vasodilatation with hypotension and higher cardiac outputs necessitating greater use of vasoconstrictors. There was no difference in postoperative pain scores, opioid consumption, sedation score, ICU or hospital length of stay, or patient mortality. Conclusions: Inhaled volatile anesthesia and sedation facilitates faster extubation times in comparison with IV propofol for patient undergoing coronary artery bypass graft surgery. (Crit Care Med 2015; 43:1062–1069) Key Words: airway extubation; anesthetics inhalational; critical care; hypnotics and sedatives; isoflurane; propofol
S
edative and analgesic agents are routinely administered within the ICU after cardiac surgery to facilitate tolerance of mechanical ventilation and assist management of pain and anxiety symptoms (1, 2). Current analgosedation practice most commonly uses IV benzodiazepine (midazolam and lorazepam) or propofol in combination with opioids and more recently dexmedetomidine (3–5). These agents are frequently associated with oversedation, prolonged mechanical May 2015 • Volume 43 • Number 5
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Figure 1. Patient flow chart of the study populations. *Patient voluntarily withdrew consent and wished for data to be not included within the final analysis. CABG = coronary artery bypass graft, LV = left ventricle.
ventilation, delirium, and drug-induced hypotension. This can impact fast tracking of cardiac surgical patients leading to longer ICU stays (6, 7). Furthermore, clearance of these IV agents and their active metabolites relies upon adequate kidney and liver function. Therefore, delayed emergence is further exacerbated by advancing age of our complex cardiac surgical patients who have a rising prevalence of hepatic and renal dysfunction (1). Volatile anesthetic agents have an excellent safety record and are theoretically “ideal” ICU sedative agents. There is increasing evidence within both the surgical and medical ICU settings, suggesting that volatile-based sedation promotes faster patient awakening and shorter extubation times (1–3, 8). Feasibility of using these volatile agents in critical care environments has traditionally been hampered by a cumbersome delivery system and the need for an anesthesiologist. The introduction of the Anesthetic Conserving Device (AnaConDa; Sedana Medical, Kungsgatan, Sweden) has overcome most of these problems. AnaConDa is a small lightweight and highly efficient miniature vaporizer, which Critical Care Medicine
can be connected to any type of ICU ventilator that is capable of running isoflurane or sevoflurane sedation. Recently, we completed a randomized controlled trial comparing cardiac outcomes after coronary artery bypass graft (CABG) surgery in patients receiving postoperative sedation with either inhaled volatile anesthetic agents or IV propofol (9). The objective of this a priori specified substudy is to report the results describing the sedation, awakening, and extubation times in the same a cohort of patients using the AnaConDa device and compare it with population receiving propofol (IV sedation).
METHODOLOGY Upon approval from Health Canada (AnaConDa was not licensed in Canada) and our Regional Ethics Board (institutional review board no. 06-0159-BE), we conducted an openlabel, prospective randomized controlled trial assessing cardiac and noncardiac outcomes in cardiac surgical patients receiving either propofol or volatile-based anesthesia and postoperative www.ccmjournal.org
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Patient Characteristics Upon Study Enrolment Table 1.
Volatile (n = 67) (%)
Variable
Age, yr Male Body mass index, kg/m
2
Grade 1 left ventricle Myocardial infarction < 30 d
Propofol (n = 74) (%)
65 ± 9
63 ± 10
61 (91)
70 (95)
28.3 ± 4.4
29.9 ± 5.3
50 (74)
55 (74)
7 (10)
5 (7)
Hypertension
48 (72)
57 (77)
Diabetes
12 (18)
27 (37)
Chronic obstructive pulmonary disease
3 (5)
5 (7)
Cerebrovascular disease
8 (12)
8 (11)
sedation. Patients were recruited between September 2009 and August 2011 at a tertiary referral center. This study was registered as a clinical trial at http://www.gov.com (Comparison of propofol based vs volatile based anesthesia and postoperative sedation, National Clinical Trials number 01151254). After obtaining informed written consent, patients undergoing elective CABG surgery with good left or mildly impaired ventricular systolic function (ejection fraction > 40%) were randomized to receive either propofol or volatile-based anesthesia and sedation. A premedication of 1–2 mg sublingual lorazepam was administered to all patients. Patients were randomized to receive either volatile-based or total IV propofol-based (TIVA) anesthesia and postoperative sedation. All other anesthetic and surgical procedures were standardized as previously described (10). Volatile sedation within the ICU was provided via the Anesthetic Conserving Device (AnaConDa; Sedana Medical) (10–12). Patients were excluded if they had a history of malignant hyperthermia, propofol infusion syndrome, or severe liver or kidney dysfunction. Anesthesia was induced using a standardized institutional protocol consisting of 5 μg/kg fentanyl, 0.05–0.1 mg/kg midazolam, 1 mg/kg propofol, and 0.5 mg/kg rocuronium. Anesthesia was maintained within the volatile group using isoflurane or sevoflurane. The choice of volatile agent was left to the discretion of the attending anesthesiologist. Anesthesia was maintained within the TIVA propofol group at infusion rates of 50–75 μg/kg/min. All patients received routine invasive arterial and pulmonary artery catheter monitoring. Intraoperative depth of anesthesia was monitored and adjusted to a bispectral index of 40–60 (Bis Vista; Aspect Medical Systems, Norwood, MA). Further doses of midazolam to maximum of 0.1 mg/kg and f entanyl 10–15 μg/kg were administered to manage the intraoperative surgical stress response. Patients were placed onto cardiopulmonary bypass (CPB) using an aortic and single stage venous cannula with systemic heparinization to achieve an activated clotting time (ACT) 1064
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above 480 seconds. Standardized management of CPB within our institution entails alpha-stat pH management, hypothermic drift to 34°C, and targeted mean arterial pressure between 50 and 70 mm Hg with pump flows of 2.0–2.5 L/min/m2. Myocardial protection was achieved using intermittent antegrade and occasional retrograde blood cardioplegia. Harvesting of the internal mammary artery and saphanous vein are used as coronary bypass graft conduits. After separation from CPB, heparin is neutralized with protamine sulphate using a 1:1 ratio to achieve an ACT within 10% of baseline. Postoperative sedation continued into the cardiovascular ICU using IV propofol at 10–25 μg/kg/min or the same volatile agent used intraoperatively. Volatile-based sedation was performed within the ICU using the AnaConDa. This device was placed between the Y-piece of the breathing circuit and endotracheal tube. Volatile agent is infused into the device at 0.5–5 mL/hr, which vaporizes this medication prior to inhalation. These low infusion rates are assisted by a central carbon filter, which recycles over 80% of the expired agent. The device also contains an antimicrobial filter, heatmoisture exchanger, and a gas sampling port, which allows breath-by-breath end-tidal gas analysis and capnography. Atmospheric pollution was minimized by active scavenging of volatile agents using 2 canisters of Deltasorb (Blue-zone, Ontario, Canada) linked in series from the ventilator expiratory port to wall outlet suction. Deltasorb contains a diamond lattice of silica zeolite (Delatzite), which selectively adsorbs volatile agents and reduces environmental emissions (see Appendix 1, Supplemental Digital Content 1, http://links.lww. com/CCM/B220, for equipment and scavenging setup) (10). Sedation within the volatile group often equated to 0.1–0.3 minimum alveolar concentration independent of patient age. Level of consciousness was monitored using the Richmond Agitation-Sedation Scale (RASS) (13, 14). Sedation in both groups was titrated to RASS –1 to +1. Pain was monitored using the numerical pain score, and postoperative analgesia was managed using a combination of IV opioids, nonsteroidal inflammatory agents, and acetaminophen for all patients. Temporary agitation within both groups was managed by initially assessing and optimizing pain control followed by increasing the sedative infusion rate and/or administration of a small bolus dose if required. Patients were extubated only after they had achieved 1) satisfactory hemodynamic stability (cardiac index, > 2 L/min/m2; mean arterial pressure, > 60 mm Hg), 2) hemostasis (chest tube losses, < 100 mL/hr), 3) awake and able to obey simple commands, and 4) successful completion of a spontaneous breathing trial (Pao2/Fio2 > 200, Paco2 30–50 mm Hg, positive end-expiratory pressure < 5 cm H2O, frequency/tidal volume < 105 breaths/min/L, and positive gag/cough reflex). Symptoms of nausea and vomiting were managed using ondansetron as first-line therapy followed by dimenhydrinate as a second agent if required within both groups. All patients were followed until hospital discharge. This study was powered to a primary outcome assessing whether volatile agents provide significant preconditioning and postconditioning myocardial protective effects by a reduction May 2015 • Volume 43 • Number 5
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range) and analyzed using the Wilcoxon rank sum test.
RESULTS Patient screening, recruitment, and randomization are summarized within the schematic flow chart in Figure 1. A total of 690 patients were assessed for study eligibility, and 176 patients provided informed written consent. From this group, 157 patients were subsequently randomized to receive a study intervention: 78 within the propofol and 79 within the volatile groups. A further 16 patients were lost to follow-up or excluded secondary to prolonged mechanical ventilation (> 14 hr) required after chest reopening or intraoperative complications, monitor failure prior to ICU admission, withdrawal of consent, and a patient with grade 3 left ventricular systolic function. A total of 141 patients (74 propofol and 67 volatile) completed the trial and formulated the basis of our data analysis. Patient perioperative demographics and characteristics are comparable between the volatile and propofol groups (Tables 1 and 2). Postoperatively, the volatile group demonstrated significantly faster median (interquartile range) times to readiness of extubation of 135 (95–200) versus 215 (150–280) (p < 0.001) and actual extubation time 182 Figure 2. Box-whisker plots of readiness to extubation time (A) and extubation time (B) for volatile and (140–255) versus 291 (210– propofol groups. The 25th and 75th percentile form ends of the box, central bar within the box marks the 50th 420) (p < 0.001) compared percentile, data distribution with minimum and maximum values are presented as the whiskers, and the mean is represented by the diamond shape. with propofol group (Fig. 2 and Table 3). There was no in postoperative troponin levels (9). The secondary outcomes, significant difference in pain scores, analgesia requirement, or prevalence of shivering, nausea, and vomiting between the the subject of this report, assess the impact of volatile comtwo groups. The volatile group showed higher cardiac indipared with IV sedation upon extubation times, sedation and ces, with a mean difference of 0.43 (95% CI, 0.2278–0.6298) pain scores, analgesia requirement, shivering, postoperative upon ICU admission. Patients randomized to the volanausea and vomiting, and ICU and hospital length of stay. tile group displayed a significantly higher intraoperative use Categorical variables were described as frequencies (percentages) and analyzed using the Fisher exact test. Continuous of norepinephrine (odds ratio [OR], 3.7; 95% CI, 1.8–7.6; p < 0.001) (Table 2). However, this difference was not seen data were reported using mean (sd) and median (interquartile Critical Care Medicine
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Table 2.
Intraoperative Surgical Variables
Variable
Volatile (n = 67)
Aortocoronary bypass number Cardiopulmonary bypass time, min
3.6 ± 1
3.6 ± 1
76.7 ± 37.3
p
Propofol (n = 74)
0.77
80.6 ± 36.4
0.76
Inotropic support, n (%)a
36 (54)
29 (39)
0.09
Norepinephrine, n (%)
34 (51)
16 (22)
< 0.001
1 (1)
2 (3)
1,022.4 ± 380.1
1,116.7 ± 320.1
Vasopressin, n (%) Fentanyl, μg
1 0.22
Midazolam, mg
5.4 ± 2.3
5.6 ± 2.8
0.93
Morphine, mg
2.2 ± 4.3
1.6 ± 3.6
0.37
Inotropic support includes use of dopamine, epinephrine, and milrinone.
a
within the ICU with both groups displaying similar norepinephrine requirements (OR, 1.3; 95% CI, 0.7–2.6; p = 0.49). However, use of vasopressin within the ICU was higher within patients receiving volatile (11%) in comparison with patients receiving propofol (4%) (OR, 3.4; 95% CI, 1.0–11.4; p = 0.05). There was no overall difference in ICU discharge times or hospital length of stay. There was no mortality in this trial. We incurred no serious adverse events or technical difficulties using the AnaConDa device during this study.
DISCUSSION This randomized trial demonstrates that volatile anesthetic agents are a viable alternative to standard (IV) sedation currently used in most of cardiac surgical centers. Our study showed that volatile-based sedation facilitates faster extubation compared with propofol when used for short-term postoperative sedation in cardiac surgical patients. However, this advantage did not result in quicker discharge from either the ICU or hospital. The findings of this study may be explained by the pharmacokinetic and dynamic properties displayed by volatile anesthetic agents. The medications demonstrate minimal dependence upon end-organ excretion or metabolism with no significant active metabolites (8, 15). Faster patient awakening and extubation times within the volatile group are thus likely attributable to the low solubility and predominant clearance of the unchanged agent by pulmonary exhalation. With very low systemic accumulation, volatile agents are ideal for facilitating ultra fast-track cardiac surgery and management of our complex, rapidly ageing surgical population with a rising burden of comorbid systemic diseases. Furthermore, ICU sedation is typically achieved at approximately one third of the dosing requirements for general anesthesia. Shivering, nausea, and vomiting are well-known side effects post general inhalational anesthesia. This study showed no statistically significant difference in these outcomes although there was a trend to higher rates of nausea and vomiting within the volatile group. The lower doses of volatile agents required for ICU sedation may partially explain the similar rates of these event in both groups. The current Society of Critical Care Medicine guidelines recommend the use of propofol and dexmedetomidine over 1066
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benzodiazepines for ICU sedation (1). However, propofol is more expensive than benzodiazepines and is associated with hypertriglyceridemia, pancreatitis, and the potential fatal complication of propofol infusion syndrome in 1% patients (1, 16). Dexmedetomidine is a newer sedative agent acting upon central α-2 receptors. It provides lighter sedation with analgesic properties and may reduce the prevalence of delirium in comparison to benzodiazepines (1, 17). The widespread uptake of dexmedetomidine remains challenging given its high cost, greater prevalence of hemodynamic instability, and limited approved duration of use with similar durations of mechanical ventilation to propofol sedation (18–20). These results are in keeping with other trials assessing the use of volatile agents for post–cardiac surgical patients. In 2005, Hanafy et al (21) evaluated the efficacy and safety of isoflurane to midazolam postoperative sedation in 24 CABG patients. Patients sedated with isoflurane demonstrated significantly shorter times to extubation and were following verbal commands 45 minutes and mobilized 6 hours earlier than those who received midazolam. They incurred no serious adverse effects or technical issues. In a larger study of 70 post-CABG surgical patients, Röhm et al (22) evaluated the sedation outcomes in those sedated with either propofol or sevoflurane delivered via AnaConDa. This study demonstrated extubation times of 21.5 minutes in those sedated with sevoflurane compared with 150.5 minutes in those who received propofol. These findings translated into an overall reduction in duration of ventilation by 3.5 hours and hospital length of stay by 3.4 days among the volatile group. However, there was no clear explanation of any additional factors that may have contributed to this significant difference in discharge time. Similar to our results, these investigators found no difference within the prevalence of postoperative shivering, nausea, and vomiting or delirium. More recently, Hellström et al (11) completed a similar study randomizing 100 post-CABG patients to either sevoflurane or propofol sedation. They found sevoflurane provided shorter and more predictable extubation times but with no overall impact upon ICU or hospital length of stay. Analgesic requirements, pain scores, postextubation agitation, and delusional memories were comparable between both May 2015 • Volume 43 • Number 5
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Table 3.
Postoperative and Sedation Outcomes
Variable
Volatile (n = 67)
Shivering, n (%) Nausea and vomiting, n (%)
p
Propofol (n = 74)
6 (10)
9 (13)
0.78
11 (19)
6 (9)
0.12
Pain score 1 hr post extubation
4.1 ± 3.1
3.9 ± 3.0
0.80
4 hr post extubation
3.4 ± 2.4
3.2 ± 2.6
0.54
Rest
2.8 ± 2.1
2.9 ± 2.3
0.86
Cough
5.4 ± 2.5
6.0 ± 2.3
0.16
8.5 ± 8.2
5.9 ± 5.6
0.14
414.1 ± 745.4
528.9 ± 857.1
0.58
15.3 ± 40.7
18.9 ± 88.6
0.27
Pain score, POD 1
Analgesic requirement, mg/12–24 hr Morphine Acetaminophen Indomethacin Percent patients treated with Morphine
83.1
79
0.15
Acetaminophen
39.3
34.5
0.26
Indomethacin
15.1
7.4
0.57
Richmond Agitation Sedation Score POD 0
0.46 ± 1
0.79 ± 1.2
0.24
POD 1
0.81 ± 1
0.72 ± 1.1
0.56
POD 2
0.87 ± 1
0.97 ± 1
0.64
Cardiac index, L/min/m2 ICU admission
2.9 ± 0.7
2.5 ± 0.5
< 0.001
ICU discharge
2.5 ± 0.4
2.6 ± 0.5
0.55
7 (10)
3 (4)
0.19
Inotrope support, n (%)
32 (48)
31 (42)
0.50
Norepinephrine, n (%)
29 (43)
27 (36)
0.49
Vasopressin, n (%)
11 (16)
4 (5)
0.05
Atrial fibrillation, n (%) a
Readiness to extubation time, min (range)
135 (95–200)
215 (150–280)
< 0.001
Extubation time, min (range)
182 (140–255)
292 (210–420)
< 0.001
Readiness to ICU discharge time, min (range)
870 (490–1,710)
895 (670–1,485)
0.22
1,510 (1,340–2,990)
1,493 (1,255–2,690)
0.34
ICU discharge time, min (range) Hospital length of stay, d (range)
6 (5–7)
6 (5–8)
0.79
POD = postoperative day. a Inotropic support includes use of dopamine, epinephrine, and milrinone.
sedation modalities (11). Short-term volatile-based sedation studies within general ICU populations have produced similar outcomes (12, 23). A limited number of studies have assessed the utility of longer volatile-based sedation in ICU populations. Sackey et al (12) compared extubation outcomes in 40 adult general ICU patients randomized to receive either isoflurane or Critical Care Medicine
midazolam sedation for up to 96 hours. Those sedated with isoflurane demonstrated significantly faster extubation times at 10 minutes compared with 250 minutes in those receiving midazolam. Long-term follow-up demonstrated that those sedated with isoflurane incurred fewer episodes of postextubation agitation and unpleasant memories of their ICU stay, which are risk factors for developing long-term www.ccmjournal.org
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neuropsychiatric disorders like posttraumatic stress disorder and depression (24). More recently, Mesnil et al (25) compared sedation outcomes of 60 adult medical-surgical ICU patients sedated using sevoflurane, propofol, or midazolam for 96 hours. This study showed that patients within the sevoflurane group extubated significantly faster at 33 minutes compared with 91 minutes in those sedated with propofol and 260 minutes in the midazolam group. The quality of sedation was superior among the volatile group with fewer daily hypnotic adjustments and the lowest prevalence of postextubation agitation and hallucinations. In addition, this study showed that vasopressor support and opioid consumption was lowest among patients receiving volatile sedation. The analgesic properties demonstrated during this long-term use of sevoflurane may be attributable to central N-methyl d-aspartate receptor antagonism. Our study has several limitations. This subanalysis was performed from a study originally powered to assess cardiac outcomes in patients receiving volatile-based preconditioning and postconditioning (volatile anesthesia and ICU sedation). The sample size calculation did not include assessment of sedation and extubation outcomes. Despite identifying faster extubation times among patients sedated with volatile agents, we did not formally record the time difference between discontinuing sedation and extubation. We recognize this is a single-center open-label, evaluator-blinded trial that is subject to institutional practice bias. Blinding of the AnaConDa setup, scavenging, and end-tidal gas monitoring was considered logistically impossible. Although blinding has been previously performed using Intralipid to mimic propofol and saline to replace the volatile infusion, this still fails to cover the endtidal gas monitoring, which clearly delineates between both study arms (26). In addition, Intralipid can be perceived as another intervention (scavenging of free radicals and promoting mitochondrial fatty acid transport and oxidation). Despite demonstrating shorter wake-up and extubation times, there was no translation in reduction of ICU or hospital length of study within the volatile group. This is not surprising given postoperative cardiac surgical patients often require management of common hemodynamic issues, rhythm disturbance, and weaning of central vasoactive drug support postextubation prior to ICU discharge. Additionally, the intervention time was probably too short to affect this outcome. The results of this study should not be generalized. Our study population included relatively healthy patients (good or mildly impaired left ventricular systolic function) undergoing elective and simple CABG surgery only. Demonstrating any difference in outcomes such as length of stay would be better assessed within a higher risk population who require prolonged sedation and more complex ICU care. In summary, this randomized controlled trial demonstrates that CABG patients who received volatile-based anesthesia and sedation had faster times to readiness and actual extubation times in comparison with those who received IV propofol. However, these differences were not associated with a shorter length of stay. Volatiles offer an alternative sedation strategy for 1068
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ICU sedation. The greater impact of volatile-based sedation would be better assessed in patients who require prolonged ICU sedation, where the reduction in duration of mechanical ventilation may be even greater with significant impact on lowering patient morbidity, length of stay, and healthcare costs.
ACKNOWLEDGMENT We thank Dr. N. Mitsakakis for conducting the statistical analysis for this study.
REFERENCES
1. Barr J, Fraser GL, Puntillo K, et al; American College of Critical Care Medicine: 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 2. Weinert CR, Calvin AD: Epidemiology of sedation and sedation adequacy for mechanically ventilated patients in a medical and surgical intensive care unit. Crit Care Med 2007; 35:393–401 3. Arroliga A, Frutos-Vivar F, Hall J, et al: Use of sedatives and neuromuscular blockers in a cohort of patients receiving mechanical ventilation. Chest 2005; 128:496–506 4. Mehta S, Burry L, Fischer S, et al: Canadian survey of the use of sedatives, analgesics, and neuromuscular blocking agents in critically ill patients Crit Care Med 2006; 34:374–380 5. Payen JF, Chanques G, Mantz J, et al: Current practices in sedation and analgesia for mechanically ventilated critically ill patients: A prospective multicenter patient-based study. Anesthesiology 2007; 106:687–695; quiz 891 6. Milbrandt EB, Deppen S, Harrison PL, et al: Costs associated with delirium in mechanically ventilated patients. Crit Care Med 2004; 32:955–962 7. Jackson DL, Proudfoot CW, Cann KF, et al: The incidence of sub-optimal sedation in the ICU: A systematic review. Crit Care 2009; 13:R204 8. Soukup J, Schärff K, Kubosch K, et al: State of the art: Sedation concepts with volatile anesthetics in critically Ill patients. J Crit Care 2009; 24:535–544 9. Wasowicz M, Jerath A, Djaiani G, et al: Expanding an anesthesiologist role beyond an operating room. Volatile based sedation in cardiac surgical patients. Br J Anaesth 2012; 108:537–555 10. Pickworth T, Jerath A, DeVine R, et al: The scavenging of volatile anesthetic agents in the cardiovascular intensive care unit environment: A technical report. Can J Anaesth 2013; 60:38–43 11. Hellström J, Öwall A, Sackey PV: Wake-up times following sedation with sevoflurane versus propofol after cardiac surgery. Scand Cardiovasc J 2012; 46:262–268 12. Sackey PV, Martling CR, Granath F, et al: Prolonged isoflurane sedation of intensive care unit patients with the Anesthetic Conserving Device. Crit Care Med 2004; 32:2241–2246 13. Sessler CN, Gosnell MS, Grap MJ, et al: The Richmond AgitationSedation Scale: Validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 2002; 166:1338–1344 14. Ely EW, Truman B, Shintani A, et al: Monitoring sedation status over time in ICU patients: Reliability and validity of the Richmond AgitationSedation Scale (RASS). JAMA 2003; 289:2983–2991 15. Roberts DJ, Haroon B, Hall RI: Sedation for critically ill or injured adults in the intensive care unit: A shifting paradigm. Drugs 2012; 72:1881–1916 16. Vasile B, Rasulo F, Candiani A, et al: The pathophysiology of propofol infusion syndrome: A simple name for a complex syndrome. Intensive Care Med 2003; 29:1417–1425 17. Pandharipande PP, Pun BT, Herr DL, et al: Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: The MENDS randomized controlled trial. JAMA 2007; 298:2644–2653 18. Elbaradie S, El Mahalawy FH, Solyman AH: Dexmedetomidine vs. propofol for short-term sedation of postoperative mechanically ventilated patients. J Egypt Natl Canc Inst 2004; 16:153–158 May 2015 • Volume 43 • Number 5
Clinical Investigations 19. Riker RR, Shehabi Y, Bokesch PM, et al; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group: Dexmedetomidine vs midazolam for sedation of critically ill patients: A randomized trial. JAMA 2009; 301:489–499 20. Ruokonen E, Parviainen I, Jakob SM, et al; “Dexmedetomidine for Continuous Sedation” Investigators: Dexmedetomidine versus propofol/midazolam for long-term sedation during mechanical ventilation. Intensive Care Med 2009; 35:282–290 21. Hanafy MA: Clinical evaluation of inhalational sedation following coronary artery bypass grafting. Eg J Anaesth 2005; 21:231–242 22. Röhm KD, Wolf MW, Schöllhorn T, et al: Short-term sevoflurane sedation using the Anaesthetic Conserving Device after cardiothoracic surgery. Intensive Care Med 2008; 34:1683–1689
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23. Meiser A, Sirtl C, Bellgardt M, et al: Desflurane compared with propofol for postoperative sedation in the intensive care unit. Br J Anaesth 2003; 90:273–280 24. Sackey PV, Martling CR, Carlswärd C, et al: Short- and long-term follow-up of intensive care unit patients after sedation with isoflurane and midazolam–a pilot study. Crit Care Med 2008; 36:801–806 25. Mesnil M, Capdevila X, Bringuier S, et al: Long-term sedation in intensive care unit: A randomized comparison between inhaled sevoflurane and intravenous propofol or midazolam. Intensive Care Med 2011; 37:933–941 26. Soro M, Gallego L, Silva V, et al: Cardioprotective effect of sevoflurane and propofol during anaesthesia and the postoperative period in coronary bypass graft surgery: A double-blind randomised study. Eur J Anaesthesiol 2012; 29:561–569
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Objective: To evaluate the differences in extubation times in a group of cardiac surgical patients who were anesthetized and sedated with either IV propofol or inhaled volatile anesthetic agents. Department Anesthesia and Pain Management, Toronto General Hospital, Toronto, ON, Canada. 2 Department Anesthesia and Pain Management, Christian Medical College, Vellore, India. 3 Divison of Cardiac Surgery, Toronto General Hospital, Toronto, ON, Canada. This study was performed at Toronto General Hospital, Toronto, ON, Canada. Dr. Jerath performed the daily running of the study and is the primary author of this article. Dr. Beattie assisted with methodology and development of the article. Drs. Chandy, J. Karski, and G. Djaiani assisted with daily running of the study and proofed the article. Dr. Rao and Yau gave cardiac surgical support for the study. Dr. Wasowicz is primary investigator of the study and helped in the development of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Jerath's institution received grant support from the Career Scientist Award (Dr. Wasowicz), the Academic Medical Organization award (Dr. Wasowicz), and the Merit Award (Dr. Wasowicz). Dr. Beattie received grant support. Dr. Rao served as a board member for Medtronic and CorMatrix Cardiovascular, consulted for Medtronic, lectured for CorMatrix and Medtronic, and has stock in CorMatrix. His institution consulted for Thoratec. Dr. Yau consulted for Heartware. Dr. Wasowicz lectured for the Japanese Society of Anesthesia and received support for article research from the Academic Medical Organization Alternative Founding Plan, Canadian Anesthesiologists’ Society/Canadian Anesthesia Research Foundation, Merit Award, Department of Anesthesia, University of Toronto. His institution received grant support from the Academic Medical Organization Alternative Founding Plan Canadian Anesthesiologists Society/Canadian Anesthesia Research Foundation Merit Award, Department of Anesthesia, University of Toronto and from the Anesthesia Patient Safety Foundation. His institution received support for the development of educational presentations from the Toronto Anesthesia Symposium. This study was not sponsored by Sedana Medical (Sweden), manufacturer of the Anesthesia Conserving Device. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Angela Jerath, FRCPC, MBBS, Department of Anesthesia and Pain Management, Toronto General Hospital, 3-EN, 200 Elizabeth St, Toronto, ON, Canada M5G 2C4. E-mail: [email protected] Copyright © 2015 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved. DOI: 10.1097/CCM.0000000000000938 1
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Design: This was a prospective randomized controlled trial performed between September 2009 and August 2011. Setting: Cardiovascular ICU within a tertiary referral universityaffiliated teaching hospital. Patients: One hundred forty-one patients undergoing coronary artery bypass graft surgery with normal or mildly reduced left ventricular systolic function. Intervention: Participants were randomly assigned to receive anesthesia and postoperative sedation using IV propofol (n = 74) or inhaled volatile (isoflurane or sevoflurane) anesthetic agent (n = 67). Measurements and Main Results: Patients sedated using inhaled volatile agent displayed faster readiness to extubation time at 135 minutes (95–200 min) compared with those receiving IV propofol at 215 minutes (150–280 min) (p < 0.001). Extubation times were faster within the volatile group at 182 minutes (140–255 min) in comparison with propofol group at 291 minutes (210–420 min) (p < 0.001). The volatile group showed a higher prevalence of vasodilatation with hypotension and higher cardiac outputs necessitating greater use of vasoconstrictors. There was no difference in postoperative pain scores, opioid consumption, sedation score, ICU or hospital length of stay, or patient mortality. Conclusions: Inhaled volatile anesthesia and sedation facilitates faster extubation times in comparison with IV propofol for patient undergoing coronary artery bypass graft surgery. (Crit Care Med 2015; 43:1062–1069) Key Words: airway extubation; anesthetics inhalational; critical care; hypnotics and sedatives; isoflurane; propofol
S
edative and analgesic agents are routinely administered within the ICU after cardiac surgery to facilitate tolerance of mechanical ventilation and assist management of pain and anxiety symptoms (1, 2). Current analgosedation practice most commonly uses IV benzodiazepine (midazolam and lorazepam) or propofol in combination with opioids and more recently dexmedetomidine (3–5). These agents are frequently associated with oversedation, prolonged mechanical May 2015 • Volume 43 • Number 5
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Figure 1. Patient flow chart of the study populations. *Patient voluntarily withdrew consent and wished for data to be not included within the final analysis. CABG = coronary artery bypass graft, LV = left ventricle.
ventilation, delirium, and drug-induced hypotension. This can impact fast tracking of cardiac surgical patients leading to longer ICU stays (6, 7). Furthermore, clearance of these IV agents and their active metabolites relies upon adequate kidney and liver function. Therefore, delayed emergence is further exacerbated by advancing age of our complex cardiac surgical patients who have a rising prevalence of hepatic and renal dysfunction (1). Volatile anesthetic agents have an excellent safety record and are theoretically “ideal” ICU sedative agents. There is increasing evidence within both the surgical and medical ICU settings, suggesting that volatile-based sedation promotes faster patient awakening and shorter extubation times (1–3, 8). Feasibility of using these volatile agents in critical care environments has traditionally been hampered by a cumbersome delivery system and the need for an anesthesiologist. The introduction of the Anesthetic Conserving Device (AnaConDa; Sedana Medical, Kungsgatan, Sweden) has overcome most of these problems. AnaConDa is a small lightweight and highly efficient miniature vaporizer, which Critical Care Medicine
can be connected to any type of ICU ventilator that is capable of running isoflurane or sevoflurane sedation. Recently, we completed a randomized controlled trial comparing cardiac outcomes after coronary artery bypass graft (CABG) surgery in patients receiving postoperative sedation with either inhaled volatile anesthetic agents or IV propofol (9). The objective of this a priori specified substudy is to report the results describing the sedation, awakening, and extubation times in the same a cohort of patients using the AnaConDa device and compare it with population receiving propofol (IV sedation).
METHODOLOGY Upon approval from Health Canada (AnaConDa was not licensed in Canada) and our Regional Ethics Board (institutional review board no. 06-0159-BE), we conducted an openlabel, prospective randomized controlled trial assessing cardiac and noncardiac outcomes in cardiac surgical patients receiving either propofol or volatile-based anesthesia and postoperative www.ccmjournal.org
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Patient Characteristics Upon Study Enrolment Table 1.
Volatile (n = 67) (%)
Variable
Age, yr Male Body mass index, kg/m
2
Grade 1 left ventricle Myocardial infarction < 30 d
Propofol (n = 74) (%)
65 ± 9
63 ± 10
61 (91)
70 (95)
28.3 ± 4.4
29.9 ± 5.3
50 (74)
55 (74)
7 (10)
5 (7)
Hypertension
48 (72)
57 (77)
Diabetes
12 (18)
27 (37)
Chronic obstructive pulmonary disease
3 (5)
5 (7)
Cerebrovascular disease
8 (12)
8 (11)
sedation. Patients were recruited between September 2009 and August 2011 at a tertiary referral center. This study was registered as a clinical trial at http://www.gov.com (Comparison of propofol based vs volatile based anesthesia and postoperative sedation, National Clinical Trials number 01151254). After obtaining informed written consent, patients undergoing elective CABG surgery with good left or mildly impaired ventricular systolic function (ejection fraction > 40%) were randomized to receive either propofol or volatile-based anesthesia and sedation. A premedication of 1–2 mg sublingual lorazepam was administered to all patients. Patients were randomized to receive either volatile-based or total IV propofol-based (TIVA) anesthesia and postoperative sedation. All other anesthetic and surgical procedures were standardized as previously described (10). Volatile sedation within the ICU was provided via the Anesthetic Conserving Device (AnaConDa; Sedana Medical) (10–12). Patients were excluded if they had a history of malignant hyperthermia, propofol infusion syndrome, or severe liver or kidney dysfunction. Anesthesia was induced using a standardized institutional protocol consisting of 5 μg/kg fentanyl, 0.05–0.1 mg/kg midazolam, 1 mg/kg propofol, and 0.5 mg/kg rocuronium. Anesthesia was maintained within the volatile group using isoflurane or sevoflurane. The choice of volatile agent was left to the discretion of the attending anesthesiologist. Anesthesia was maintained within the TIVA propofol group at infusion rates of 50–75 μg/kg/min. All patients received routine invasive arterial and pulmonary artery catheter monitoring. Intraoperative depth of anesthesia was monitored and adjusted to a bispectral index of 40–60 (Bis Vista; Aspect Medical Systems, Norwood, MA). Further doses of midazolam to maximum of 0.1 mg/kg and f entanyl 10–15 μg/kg were administered to manage the intraoperative surgical stress response. Patients were placed onto cardiopulmonary bypass (CPB) using an aortic and single stage venous cannula with systemic heparinization to achieve an activated clotting time (ACT) 1064
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above 480 seconds. Standardized management of CPB within our institution entails alpha-stat pH management, hypothermic drift to 34°C, and targeted mean arterial pressure between 50 and 70 mm Hg with pump flows of 2.0–2.5 L/min/m2. Myocardial protection was achieved using intermittent antegrade and occasional retrograde blood cardioplegia. Harvesting of the internal mammary artery and saphanous vein are used as coronary bypass graft conduits. After separation from CPB, heparin is neutralized with protamine sulphate using a 1:1 ratio to achieve an ACT within 10% of baseline. Postoperative sedation continued into the cardiovascular ICU using IV propofol at 10–25 μg/kg/min or the same volatile agent used intraoperatively. Volatile-based sedation was performed within the ICU using the AnaConDa. This device was placed between the Y-piece of the breathing circuit and endotracheal tube. Volatile agent is infused into the device at 0.5–5 mL/hr, which vaporizes this medication prior to inhalation. These low infusion rates are assisted by a central carbon filter, which recycles over 80% of the expired agent. The device also contains an antimicrobial filter, heatmoisture exchanger, and a gas sampling port, which allows breath-by-breath end-tidal gas analysis and capnography. Atmospheric pollution was minimized by active scavenging of volatile agents using 2 canisters of Deltasorb (Blue-zone, Ontario, Canada) linked in series from the ventilator expiratory port to wall outlet suction. Deltasorb contains a diamond lattice of silica zeolite (Delatzite), which selectively adsorbs volatile agents and reduces environmental emissions (see Appendix 1, Supplemental Digital Content 1, http://links.lww. com/CCM/B220, for equipment and scavenging setup) (10). Sedation within the volatile group often equated to 0.1–0.3 minimum alveolar concentration independent of patient age. Level of consciousness was monitored using the Richmond Agitation-Sedation Scale (RASS) (13, 14). Sedation in both groups was titrated to RASS –1 to +1. Pain was monitored using the numerical pain score, and postoperative analgesia was managed using a combination of IV opioids, nonsteroidal inflammatory agents, and acetaminophen for all patients. Temporary agitation within both groups was managed by initially assessing and optimizing pain control followed by increasing the sedative infusion rate and/or administration of a small bolus dose if required. Patients were extubated only after they had achieved 1) satisfactory hemodynamic stability (cardiac index, > 2 L/min/m2; mean arterial pressure, > 60 mm Hg), 2) hemostasis (chest tube losses, < 100 mL/hr), 3) awake and able to obey simple commands, and 4) successful completion of a spontaneous breathing trial (Pao2/Fio2 > 200, Paco2 30–50 mm Hg, positive end-expiratory pressure < 5 cm H2O, frequency/tidal volume < 105 breaths/min/L, and positive gag/cough reflex). Symptoms of nausea and vomiting were managed using ondansetron as first-line therapy followed by dimenhydrinate as a second agent if required within both groups. All patients were followed until hospital discharge. This study was powered to a primary outcome assessing whether volatile agents provide significant preconditioning and postconditioning myocardial protective effects by a reduction May 2015 • Volume 43 • Number 5
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range) and analyzed using the Wilcoxon rank sum test.
RESULTS Patient screening, recruitment, and randomization are summarized within the schematic flow chart in Figure 1. A total of 690 patients were assessed for study eligibility, and 176 patients provided informed written consent. From this group, 157 patients were subsequently randomized to receive a study intervention: 78 within the propofol and 79 within the volatile groups. A further 16 patients were lost to follow-up or excluded secondary to prolonged mechanical ventilation (> 14 hr) required after chest reopening or intraoperative complications, monitor failure prior to ICU admission, withdrawal of consent, and a patient with grade 3 left ventricular systolic function. A total of 141 patients (74 propofol and 67 volatile) completed the trial and formulated the basis of our data analysis. Patient perioperative demographics and characteristics are comparable between the volatile and propofol groups (Tables 1 and 2). Postoperatively, the volatile group demonstrated significantly faster median (interquartile range) times to readiness of extubation of 135 (95–200) versus 215 (150–280) (p < 0.001) and actual extubation time 182 Figure 2. Box-whisker plots of readiness to extubation time (A) and extubation time (B) for volatile and (140–255) versus 291 (210– propofol groups. The 25th and 75th percentile form ends of the box, central bar within the box marks the 50th 420) (p < 0.001) compared percentile, data distribution with minimum and maximum values are presented as the whiskers, and the mean is represented by the diamond shape. with propofol group (Fig. 2 and Table 3). There was no in postoperative troponin levels (9). The secondary outcomes, significant difference in pain scores, analgesia requirement, or prevalence of shivering, nausea, and vomiting between the the subject of this report, assess the impact of volatile comtwo groups. The volatile group showed higher cardiac indipared with IV sedation upon extubation times, sedation and ces, with a mean difference of 0.43 (95% CI, 0.2278–0.6298) pain scores, analgesia requirement, shivering, postoperative upon ICU admission. Patients randomized to the volanausea and vomiting, and ICU and hospital length of stay. tile group displayed a significantly higher intraoperative use Categorical variables were described as frequencies (percentages) and analyzed using the Fisher exact test. Continuous of norepinephrine (odds ratio [OR], 3.7; 95% CI, 1.8–7.6; p < 0.001) (Table 2). However, this difference was not seen data were reported using mean (sd) and median (interquartile Critical Care Medicine
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Table 2.
Intraoperative Surgical Variables
Variable
Volatile (n = 67)
Aortocoronary bypass number Cardiopulmonary bypass time, min
3.6 ± 1
3.6 ± 1
76.7 ± 37.3
p
Propofol (n = 74)
0.77
80.6 ± 36.4
0.76
Inotropic support, n (%)a
36 (54)
29 (39)
0.09
Norepinephrine, n (%)
34 (51)
16 (22)
< 0.001
1 (1)
2 (3)
1,022.4 ± 380.1
1,116.7 ± 320.1
Vasopressin, n (%) Fentanyl, μg
1 0.22
Midazolam, mg
5.4 ± 2.3
5.6 ± 2.8
0.93
Morphine, mg
2.2 ± 4.3
1.6 ± 3.6
0.37
Inotropic support includes use of dopamine, epinephrine, and milrinone.
a
within the ICU with both groups displaying similar norepinephrine requirements (OR, 1.3; 95% CI, 0.7–2.6; p = 0.49). However, use of vasopressin within the ICU was higher within patients receiving volatile (11%) in comparison with patients receiving propofol (4%) (OR, 3.4; 95% CI, 1.0–11.4; p = 0.05). There was no overall difference in ICU discharge times or hospital length of stay. There was no mortality in this trial. We incurred no serious adverse events or technical difficulties using the AnaConDa device during this study.
DISCUSSION This randomized trial demonstrates that volatile anesthetic agents are a viable alternative to standard (IV) sedation currently used in most of cardiac surgical centers. Our study showed that volatile-based sedation facilitates faster extubation compared with propofol when used for short-term postoperative sedation in cardiac surgical patients. However, this advantage did not result in quicker discharge from either the ICU or hospital. The findings of this study may be explained by the pharmacokinetic and dynamic properties displayed by volatile anesthetic agents. The medications demonstrate minimal dependence upon end-organ excretion or metabolism with no significant active metabolites (8, 15). Faster patient awakening and extubation times within the volatile group are thus likely attributable to the low solubility and predominant clearance of the unchanged agent by pulmonary exhalation. With very low systemic accumulation, volatile agents are ideal for facilitating ultra fast-track cardiac surgery and management of our complex, rapidly ageing surgical population with a rising burden of comorbid systemic diseases. Furthermore, ICU sedation is typically achieved at approximately one third of the dosing requirements for general anesthesia. Shivering, nausea, and vomiting are well-known side effects post general inhalational anesthesia. This study showed no statistically significant difference in these outcomes although there was a trend to higher rates of nausea and vomiting within the volatile group. The lower doses of volatile agents required for ICU sedation may partially explain the similar rates of these event in both groups. The current Society of Critical Care Medicine guidelines recommend the use of propofol and dexmedetomidine over 1066
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benzodiazepines for ICU sedation (1). However, propofol is more expensive than benzodiazepines and is associated with hypertriglyceridemia, pancreatitis, and the potential fatal complication of propofol infusion syndrome in 1% patients (1, 16). Dexmedetomidine is a newer sedative agent acting upon central α-2 receptors. It provides lighter sedation with analgesic properties and may reduce the prevalence of delirium in comparison to benzodiazepines (1, 17). The widespread uptake of dexmedetomidine remains challenging given its high cost, greater prevalence of hemodynamic instability, and limited approved duration of use with similar durations of mechanical ventilation to propofol sedation (18–20). These results are in keeping with other trials assessing the use of volatile agents for post–cardiac surgical patients. In 2005, Hanafy et al (21) evaluated the efficacy and safety of isoflurane to midazolam postoperative sedation in 24 CABG patients. Patients sedated with isoflurane demonstrated significantly shorter times to extubation and were following verbal commands 45 minutes and mobilized 6 hours earlier than those who received midazolam. They incurred no serious adverse effects or technical issues. In a larger study of 70 post-CABG surgical patients, Röhm et al (22) evaluated the sedation outcomes in those sedated with either propofol or sevoflurane delivered via AnaConDa. This study demonstrated extubation times of 21.5 minutes in those sedated with sevoflurane compared with 150.5 minutes in those who received propofol. These findings translated into an overall reduction in duration of ventilation by 3.5 hours and hospital length of stay by 3.4 days among the volatile group. However, there was no clear explanation of any additional factors that may have contributed to this significant difference in discharge time. Similar to our results, these investigators found no difference within the prevalence of postoperative shivering, nausea, and vomiting or delirium. More recently, Hellström et al (11) completed a similar study randomizing 100 post-CABG patients to either sevoflurane or propofol sedation. They found sevoflurane provided shorter and more predictable extubation times but with no overall impact upon ICU or hospital length of stay. Analgesic requirements, pain scores, postextubation agitation, and delusional memories were comparable between both May 2015 • Volume 43 • Number 5
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Table 3.
Postoperative and Sedation Outcomes
Variable
Volatile (n = 67)
Shivering, n (%) Nausea and vomiting, n (%)
p
Propofol (n = 74)
6 (10)
9 (13)
0.78
11 (19)
6 (9)
0.12
Pain score 1 hr post extubation
4.1 ± 3.1
3.9 ± 3.0
0.80
4 hr post extubation
3.4 ± 2.4
3.2 ± 2.6
0.54
Rest
2.8 ± 2.1
2.9 ± 2.3
0.86
Cough
5.4 ± 2.5
6.0 ± 2.3
0.16
8.5 ± 8.2
5.9 ± 5.6
0.14
414.1 ± 745.4
528.9 ± 857.1
0.58
15.3 ± 40.7
18.9 ± 88.6
0.27
Pain score, POD 1
Analgesic requirement, mg/12–24 hr Morphine Acetaminophen Indomethacin Percent patients treated with Morphine
83.1
79
0.15
Acetaminophen
39.3
34.5
0.26
Indomethacin
15.1
7.4
0.57
Richmond Agitation Sedation Score POD 0
0.46 ± 1
0.79 ± 1.2
0.24
POD 1
0.81 ± 1
0.72 ± 1.1
0.56
POD 2
0.87 ± 1
0.97 ± 1
0.64
Cardiac index, L/min/m2 ICU admission
2.9 ± 0.7
2.5 ± 0.5
< 0.001
ICU discharge
2.5 ± 0.4
2.6 ± 0.5
0.55
7 (10)
3 (4)
0.19
Inotrope support, n (%)
32 (48)
31 (42)
0.50
Norepinephrine, n (%)
29 (43)
27 (36)
0.49
Vasopressin, n (%)
11 (16)
4 (5)
0.05
Atrial fibrillation, n (%) a
Readiness to extubation time, min (range)
135 (95–200)
215 (150–280)
< 0.001
Extubation time, min (range)
182 (140–255)
292 (210–420)
< 0.001
Readiness to ICU discharge time, min (range)
870 (490–1,710)
895 (670–1,485)
0.22
1,510 (1,340–2,990)
1,493 (1,255–2,690)
0.34
ICU discharge time, min (range) Hospital length of stay, d (range)
6 (5–7)
6 (5–8)
0.79
POD = postoperative day. a Inotropic support includes use of dopamine, epinephrine, and milrinone.
sedation modalities (11). Short-term volatile-based sedation studies within general ICU populations have produced similar outcomes (12, 23). A limited number of studies have assessed the utility of longer volatile-based sedation in ICU populations. Sackey et al (12) compared extubation outcomes in 40 adult general ICU patients randomized to receive either isoflurane or Critical Care Medicine
midazolam sedation for up to 96 hours. Those sedated with isoflurane demonstrated significantly faster extubation times at 10 minutes compared with 250 minutes in those receiving midazolam. Long-term follow-up demonstrated that those sedated with isoflurane incurred fewer episodes of postextubation agitation and unpleasant memories of their ICU stay, which are risk factors for developing long-term www.ccmjournal.org
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neuropsychiatric disorders like posttraumatic stress disorder and depression (24). More recently, Mesnil et al (25) compared sedation outcomes of 60 adult medical-surgical ICU patients sedated using sevoflurane, propofol, or midazolam for 96 hours. This study showed that patients within the sevoflurane group extubated significantly faster at 33 minutes compared with 91 minutes in those sedated with propofol and 260 minutes in the midazolam group. The quality of sedation was superior among the volatile group with fewer daily hypnotic adjustments and the lowest prevalence of postextubation agitation and hallucinations. In addition, this study showed that vasopressor support and opioid consumption was lowest among patients receiving volatile sedation. The analgesic properties demonstrated during this long-term use of sevoflurane may be attributable to central N-methyl d-aspartate receptor antagonism. Our study has several limitations. This subanalysis was performed from a study originally powered to assess cardiac outcomes in patients receiving volatile-based preconditioning and postconditioning (volatile anesthesia and ICU sedation). The sample size calculation did not include assessment of sedation and extubation outcomes. Despite identifying faster extubation times among patients sedated with volatile agents, we did not formally record the time difference between discontinuing sedation and extubation. We recognize this is a single-center open-label, evaluator-blinded trial that is subject to institutional practice bias. Blinding of the AnaConDa setup, scavenging, and end-tidal gas monitoring was considered logistically impossible. Although blinding has been previously performed using Intralipid to mimic propofol and saline to replace the volatile infusion, this still fails to cover the endtidal gas monitoring, which clearly delineates between both study arms (26). In addition, Intralipid can be perceived as another intervention (scavenging of free radicals and promoting mitochondrial fatty acid transport and oxidation). Despite demonstrating shorter wake-up and extubation times, there was no translation in reduction of ICU or hospital length of study within the volatile group. This is not surprising given postoperative cardiac surgical patients often require management of common hemodynamic issues, rhythm disturbance, and weaning of central vasoactive drug support postextubation prior to ICU discharge. Additionally, the intervention time was probably too short to affect this outcome. The results of this study should not be generalized. Our study population included relatively healthy patients (good or mildly impaired left ventricular systolic function) undergoing elective and simple CABG surgery only. Demonstrating any difference in outcomes such as length of stay would be better assessed within a higher risk population who require prolonged sedation and more complex ICU care. In summary, this randomized controlled trial demonstrates that CABG patients who received volatile-based anesthesia and sedation had faster times to readiness and actual extubation times in comparison with those who received IV propofol. However, these differences were not associated with a shorter length of stay. Volatiles offer an alternative sedation strategy for 1068
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ICU sedation. The greater impact of volatile-based sedation would be better assessed in patients who require prolonged ICU sedation, where the reduction in duration of mechanical ventilation may be even greater with significant impact on lowering patient morbidity, length of stay, and healthcare costs.
ACKNOWLEDGMENT We thank Dr. N. Mitsakakis for conducting the statistical analysis for this study.
REFERENCES
1. Barr J, Fraser GL, Puntillo K, et al; American College of Critical Care Medicine: 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 2. Weinert CR, Calvin AD: Epidemiology of sedation and sedation adequacy for mechanically ventilated patients in a medical and surgical intensive care unit. Crit Care Med 2007; 35:393–401 3. Arroliga A, Frutos-Vivar F, Hall J, et al: Use of sedatives and neuromuscular blockers in a cohort of patients receiving mechanical ventilation. Chest 2005; 128:496–506 4. Mehta S, Burry L, Fischer S, et al: Canadian survey of the use of sedatives, analgesics, and neuromuscular blocking agents in critically ill patients Crit Care Med 2006; 34:374–380 5. Payen JF, Chanques G, Mantz J, et al: Current practices in sedation and analgesia for mechanically ventilated critically ill patients: A prospective multicenter patient-based study. Anesthesiology 2007; 106:687–695; quiz 891 6. Milbrandt EB, Deppen S, Harrison PL, et al: Costs associated with delirium in mechanically ventilated patients. Crit Care Med 2004; 32:955–962 7. Jackson DL, Proudfoot CW, Cann KF, et al: The incidence of sub-optimal sedation in the ICU: A systematic review. Crit Care 2009; 13:R204 8. Soukup J, Schärff K, Kubosch K, et al: State of the art: Sedation concepts with volatile anesthetics in critically Ill patients. J Crit Care 2009; 24:535–544 9. Wasowicz M, Jerath A, Djaiani G, et al: Expanding an anesthesiologist role beyond an operating room. Volatile based sedation in cardiac surgical patients. Br J Anaesth 2012; 108:537–555 10. Pickworth T, Jerath A, DeVine R, et al: The scavenging of volatile anesthetic agents in the cardiovascular intensive care unit environment: A technical report. Can J Anaesth 2013; 60:38–43 11. Hellström J, Öwall A, Sackey PV: Wake-up times following sedation with sevoflurane versus propofol after cardiac surgery. Scand Cardiovasc J 2012; 46:262–268 12. Sackey PV, Martling CR, Granath F, et al: Prolonged isoflurane sedation of intensive care unit patients with the Anesthetic Conserving Device. Crit Care Med 2004; 32:2241–2246 13. Sessler CN, Gosnell MS, Grap MJ, et al: The Richmond AgitationSedation Scale: Validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 2002; 166:1338–1344 14. Ely EW, Truman B, Shintani A, et al: Monitoring sedation status over time in ICU patients: Reliability and validity of the Richmond AgitationSedation Scale (RASS). JAMA 2003; 289:2983–2991 15. Roberts DJ, Haroon B, Hall RI: Sedation for critically ill or injured adults in the intensive care unit: A shifting paradigm. Drugs 2012; 72:1881–1916 16. Vasile B, Rasulo F, Candiani A, et al: The pathophysiology of propofol infusion syndrome: A simple name for a complex syndrome. Intensive Care Med 2003; 29:1417–1425 17. Pandharipande PP, Pun BT, Herr DL, et al: Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: The MENDS randomized controlled trial. JAMA 2007; 298:2644–2653 18. Elbaradie S, El Mahalawy FH, Solyman AH: Dexmedetomidine vs. propofol for short-term sedation of postoperative mechanically ventilated patients. J Egypt Natl Canc Inst 2004; 16:153–158 May 2015 • Volume 43 • Number 5
Clinical Investigations 19. Riker RR, Shehabi Y, Bokesch PM, et al; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group: Dexmedetomidine vs midazolam for sedation of critically ill patients: A randomized trial. JAMA 2009; 301:489–499 20. Ruokonen E, Parviainen I, Jakob SM, et al; “Dexmedetomidine for Continuous Sedation” Investigators: Dexmedetomidine versus propofol/midazolam for long-term sedation during mechanical ventilation. Intensive Care Med 2009; 35:282–290 21. Hanafy MA: Clinical evaluation of inhalational sedation following coronary artery bypass grafting. Eg J Anaesth 2005; 21:231–242 22. Röhm KD, Wolf MW, Schöllhorn T, et al: Short-term sevoflurane sedation using the Anaesthetic Conserving Device after cardiothoracic surgery. Intensive Care Med 2008; 34:1683–1689
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23. Meiser A, Sirtl C, Bellgardt M, et al: Desflurane compared with propofol for postoperative sedation in the intensive care unit. Br J Anaesth 2003; 90:273–280 24. Sackey PV, Martling CR, Carlswärd C, et al: Short- and long-term follow-up of intensive care unit patients after sedation with isoflurane and midazolam–a pilot study. Crit Care Med 2008; 36:801–806 25. Mesnil M, Capdevila X, Bringuier S, et al: Long-term sedation in intensive care unit: A randomized comparison between inhaled sevoflurane and intravenous propofol or midazolam. Intensive Care Med 2011; 37:933–941 26. Soro M, Gallego L, Silva V, et al: Cardioprotective effect of sevoflurane and propofol during anaesthesia and the postoperative period in coronary bypass graft surgery: A double-blind randomised study. Eur J Anaesthesiol 2012; 29:561–569
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