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1.  Dexmedetomidine use in the ICU: Are we there yet? 
Critical Care  2013;17(3):320.
Expanded abstract
Citation
Jakob SM, Ruokonen E, Grounds RM, Sarapohja T, Garratt C, Pocock SJ, Bratty JR, Takala J; Dexmedeto midine for Long-Term Sedation Investigators: Dexmedetomidine vesus midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA 2012, 307:1151-1160.
Background
Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an alpha-2 agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort.
Methods
Objective
The objective was to determine the efficacy of dexmedetomidine versus midazolam or propofol (preferred usual care) in maintaining sedation, reducing duration of mechanical ventilation, and improving patients' interaction with nursing care.
Design
Two phase 3 multicenter, randomized, double-blind trials were conducted.
Setting
The MIDEX (Midazolam vs. Dexmedetomidine) trial compared midazolam with dexmedetomidine in ICUs of 44 centers in nine European countries. The PRODEX (Propofol vs. Dexmedetomidine) trial compared propofol with dexmedetomidine in 31 centers in six European countries and two centers in Russia.
Subjects
The subjects were adult ICU patients who were receiving mechanical ventilation and who needed light to moderate sedation for more than 24 hours.
Intervention
After enrollment, 251 and 249 subjects were randomly assigned midazolam and dexmedetomidine, respectively, in the MIDEX trial, and 247 and 251 subjects were randomly assigned propofol and dexmedetomidine, respectively, in the PRODEX trial. Sedation with dexmedetomidine, midazolam, or propofol; daily sedation stops; and spontaneous breathing trials were employed.
Outcomes
For each trial, investigators tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level (measured by Richmond Agitation Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were the ability of the patient to communicate pain (measured by using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per-protocol (midazolam, n = 233, versus dexmedetomidine, n = 227; propofol, n = 214, versus dexmedetomidine, n = 223) population.
Results
Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% confidence interval (CI) 0.97 to 1.18), and dexmedetomidine/propofol ratio in time at target sedation was 1.00 (95% CI 0.92 to 1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours, interquartile range (IQR) 67 to 337) versus midazolam (164 hours, IQR 92 to 380; P = 0.03) but not with dexmedetomidine (97 hours, IQR 45 to 257) versus propofol (118 hours, IQR 48 to 327; P = 0.24). Patient interaction (measured by using VAS) was improved with dexmedetomidine (estimated score difference versus midazolam 19.7, 95% CI 15.2 to 24.2; P <0.001; and versus propofol 11.2, 95% CI 6.4 to 15.9; P <0.001). Lengths of ICU and hospital stays and mortality rates were similar. Dexmedetomidine versus midazolam patients had more hypotension (51/247 [20.6%] versus 29/250 [11.6%]; P = 0.007) and bradycardia (35/247 [14.2%] versus 13/250 [5.2%]; P <0.001).
Conclusions
Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved the ability of patients to communicate pain compared with midazolam and propofol. Greater numbers of adverse effects were associated with dexmedetomidine.
doi:10.1186/cc12707
PMCID: PMC3706806  PMID: 23731973
2.  Sedative Efficacy of Propofol in Patients Intubated/Ventilated after Coronary Artery Bypass Graft Surgery 
Background:
Sedation after open heart surgery is important in preventing stress on the heart. The unique sedative features of propofol prompted us to evaluate its potential clinical role in the sedation of post-CABG patients.
Objectives:
To compare propofol-based sedation to midazolam-based sedation after coronary artery bypass graft (CABG) surgery in the intensive care unit (ICU).
Patients and Methods:
Fifty patients who were admitted to the ICU after CABG surgery was randomized into two groups to receive sedation with either midazolam or propofol infusions; and additional analgesia was administered if required. Inclusion criteria were as follows: patients 40-60 years old, hemodynamic stability, ejection fraction (EF) more than 40%; exclusion criteria included patients who required intra-aortic balloon pump or inotropic drugs post-bypass. The same protocol of anesthetic medications was used in both groups. Depth of sedation was monitored using the Ramsay sedation score (RSS). Invasive mean arterial pressure (MAP) and heart rate (HR), arterial blood gas (ABG) and ventilatory parameters were monitored continuously after the start of study drug and until the patients were extubated.
Results:
The depth of sedation was almost the same in the two groups (RSS=4.5 in midazolam group vs 4.7 in propofol group; P = 0.259) but the total dose of fentanyl in the midazolam group was significantly more than the propofol group (12.5 mg/hr vs 4 mg/hr) (P = 0.0039). No significant differences were found in MAP (P = 0.51) and HR (P = 0.41) between the groups. The mean extubation time in patients sedated with propofol was shorter than those sedated with midazolam (102 ± 27 min vs 245 ± 42 min, respectively; P < 0.05) but the ICU discharge time was not shorter (47.5 hr vs 36.3 hr, respectively; P = 0.24).
Conclusions:
Propofol provided a safe and acceptable sedation for post-CABG surgical patients, significantly reduced the requirement for analgesics, and allowed for more rapid tracheal extubation than midazolam but did not result in earlier ICU discharge.
doi:10.5812/aapm.17109
PMCID: PMC3961039  PMID: 24660162
Propofol; Analgesics; Coronary Artery Bypass; Deep Sedation; Midazolam; Airway Extubation; Length of Stay
3.  Sedation in the intensive care unit with remifentanil/propofol versus midazolam/fentanyl: a randomised, open-label, pharmacoeconomic trial 
Critical Care  2006;10(3):R91.
Introduction
Remifentanil is an opioid with a unique pharmacokinetic profile. Its organ-independent elimination and short context-sensitive half time of 3 to 4 minutes lead to a highly predictable offset of action. We tested the hypothesis that with an analgesia-based sedation regimen with remifentanil and propofol, patients after cardiac surgery reach predefined criteria for discharge from the intensive care unit (ICU) sooner, resulting in shorter duration of time spent in the ICU, compared to a conventional regimen consisting of midazolam and fentanyl. In addition, the two regimens were compared regarding their costs.
Methods
In this prospective, open-label, randomised, single-centre study, a total of 80 patients (18 to 75 years old), who had undergone cardiac surgery, were postoperatively assigned to one of two treatment regimens for sedation in the ICU for 12 to 72 hours. Patients in the remifentanil/propofol group received remifentanil (6- max. 60 μg kg-1 h-1; dose exceeds recommended labelling). Propofol (0.5 to 4.0 mg kg-1 h-1) was supplemented only in the case of insufficient sedation at maximal remifentanil dose. Patients in the midazolam/fentanyl group received midazolam (0.02 to 0.2 mg kg-1 h-1) and fentanyl (1.0 to 7.0 μg kg-1 h-1). For treatment of pain after extubation, both groups received morphine and/or non-opioid analgesics.
Results
The time intervals (mean values ± standard deviation) from arrival at the ICU until extubation (20.7 ± 5.2 hours versus 24.2 h ± 7.0 hours) and from arrival until eligible discharge from the ICU (46.1 ± 22.0 hours versus 62.4 ± 27.2 hours) were significantly (p < 0.05) shorter in the remifentanil/propofol group. Overall costs of the ICU stay per patient were equal (approximately €1,700 on average).
Conclusion
Compared with midazolam/fentanyl, a remifentanil-based regimen for analgesia and sedation supplemented with propofol significantly reduced the time on mechanical ventilation and allowed earlier discharge from the ICU, at equal overall costs.
doi:10.1186/cc4939
PMCID: PMC1550941  PMID: 16780597
4.  Respiratory effects of dexmedetomidine in the surgical patient requiring intensive care 
Critical Care  2000;4(5):302-308.
The respiratory effects of dexmedetomidine were retrospectively examined in 33 postsurgical patients involved in a randomised, placebo-controlled trial after extubation in the intensive care unit (ICU). Morphine requirements were reduced by over 50% in patients receiving dexmedetomidine. There were no differences in respiratory rates, oxygen saturations, arterial pH and arterial partial carbon dioxide tension (PaCO2) between the groups. Interestingly the arterial partial oxygen tension (PaO2) : fractional inspired oxygen (FIO2) ratios were statistically significantly higher in the dexmedetomidine group. Dexmedetomidine provides important postsurgical analgesia and appears to have no clinically important adverse effects on respiration in the surgical patient who requires intensive care.
Introduction:
The α2-agonist dexmedetomidine is a new class of sedative drug that is being investigated for use in ICU settings. It is an effective agent for the management of sedation and analgesia after cardiac, general, orthopaedic, head and neck, oncological and vascular surgery in the ICU [1]. Cardiovascular stability was demonstrated, with significant reductions in rate-pressure product during sedation and over the extubation period.
Dexmedetomidine possesses several properties that may additionally benefit those critically ill patients who require sedation. In spontaneously breathing volunteers, intravenous dexmedetomidine caused marked sedation with only mild reductions in resting ventilation at higher doses [2]. Dexmedetomidine reduces the haemodynamic response to intubation and extubation [3,4,5] and attenuates the stress response to surgery [6], as a result of the α2-mediated reduction in sympathetic tone. Therefore, it should be possible to continue sedation with dexmedetomidine over the stressful extubation period without concerns over respiratory depression, while ensuring that haemodynamic stability is preserved.
The present study is a retrospective analysis of the respiratory response to dexmedetomidine in 33 postsurgical patients (who were involved in a randomized, double-blind, placebo-controlled trial [1]) after extubation in the ICU.
Methods:
Patients who participated in the present study were admitted after surgery to our general or cardiothoracic ICUs, and were expected to receive at least 6 h of postsurgical sedation and artificial ventilation.
On arrival in the ICU after surgery, patients were randomized to receive either dexmedetomidine or placebo (normal saline) with rescue sedation and analgesia being provided, only if clinically needed, with midazolam and morphine boluses, respectively. Sedation was titrated to maintain a Ramsay Sedation Score [7] of 3 or greater while the patients were intubated, and infusions of study drug were continued for a maximum of 6 h after extubation to achieve a Ramsay Sedation Score of 2 or greater.
The patients were intubated and ventilated with oxygen-enriched air to attain acceptable arterial blood gases, and extubation occurred when clinically indicated. All patients received supplemental oxygen after extubation, which was delivered by a fixed performance device. Assessment of pain was by direct communication with the patient.
Results are expressed as mean ± standard deviation unless otherwise stated. Patient characteristics, operative details and morphine usage were analyzed using the Mann-Whitney U-test. Statistical differences for respiratory measurements between the two groups were determined using analysis of variance for repeated measures, with the Bonferroni test for post hoc comparisons.
Results:
Of the 40 patients who participated in the study, seven patients could not be included in the analysis of respiratory function because they did not receive a study drug infusion after extubation. Consequently, data from 33 patients are used in the analysis of respiratory function; 16 received dexmedetomidine and 17 placebo. Inadequate arterial blood gas analysis was available in five patients (two from the dexmedetomidine group, and three from the placebo group). There were no significant differences in patient characteristics and operative details between the groups.
Requirements for morphine were reduced by more than 50% in patients receiving dexmedetomidine when compared with placebo after extubation (0.003 ± 0.004 vs 0.008 ± 0.006 mg/kg per h; P= 0.040).
There were no statistically significant differences between placebo and dexmedetomidine for oxygen saturations measured by pulse oximetry (P= 0.26), respiratory rate (P= 0.16; Fig. 1), arterial pH (P= 0.77) and PaCO2 (P= 0.75; Fig. 2) for the 6 h after extubation.
The dexmedetomidine group showed significantly higher PaO2: FIO2 ratios throughout the 6-h intubation (P= 0.036) and extubation (P= 0.037) periods (Fig. 3). There were no adverse respiratory events seen in either the dexmedetomidine or placebo group.
Respiratory rate for the 6-h periods before and after extubation. (Filled circle) Dexmedetomidine; (Empty circle) placebo. Values are expressed as mean ± standard deviation.
PaCO2 (PCO2) for the 6-h periods before and after extubation, and baseline values (B) on admission to ICU immediately after surgery. (Filled circle) Dexmedetomidine; (Empty circle) placebo. Values are expressed as mean ± standard deviation.
PaO2 : FIO2 ratio for the 6-h periods before and after extubation, and baseline values (B) on admission to ICU immediately after surgery. (Filled circle) Dexmedetomidine; (Empty circle) placebo. Values are expressed as mean ± standard deviation.
Discussion:
Lack of respiratory depression in patients sedated with α2-adrenoceptor agonists was first reported by Maxwell [8] in a study investigating the respiratory effects of clonidine. However, more recent data suggests that clonidine may cause mild respiratory depression in humans [9], and α2-adrenoceptor agonists are well known to produce profound intraoperative hypoxaemia in sheep [10,11]. The effects of dexmedetomidine on other ventilation parameters also appear to be species specific [12].
Belleville et al [2] investigated the ventilatory effects of a 2-min intravenous infusion of dexmedetomidine on human volunteers. According to those investigators, minute ventilation and arterial PaCO2 were mildly decreased and increased, respectively. There was a rightward shift and depression of the hypercapnic response with infusions of 1.0 and 2.0 μg/kg.
Previous studies that investigated the respiratory effects of dexmedetomidine have only been performed in healthy human volunteers, who have received either single intramuscular injections or short (= 10 min) intravenous infusions of dexmedetomidine. It is therefore reassuring that no deleterious clinical effects on respiration and gas exchange were seen in the patients we studied, who were receiving long-term infusions. However, there are important limitations to the present results. No dose/response curve for dexmedetomidine can be formulated from the data, and further investigation is probably ethically difficult to achieve in the spontaneously ventilating intensive care patient. We also have no data on the ventilatory responses to hypercapnia and hypoxia, which would also be difficult to examine practically and ethically. The placebo group received more than twice as much morphine as patients receiving dexmedetomidine infusions after extubation, but there were no differences in respiratory rate or PaCO2 between the groups. We can not therefore determine from this study whether dexmedetomidine has any benefits over morphine from a respiratory perspective.
There were no differences in oxygen saturations between the groups because the administered oxygen concentration was adjusted to maintain satisfactory gas exchange. Interestingly, however, there were statistically significant higher PaO2 : FIO2 ratios in the dexmedetomidine group. This ratio allows for the variation in administered oxygen to patients during the study period, and gives some clinical indication of alveolar gas exchange. However, this variable was not a primary outcome variable for the present study, and may represent a type 1 error, although post hoc analysis reveals that the data have 80% power to detect a significant difference (α value 0.05). Further studies are obviously required.
Sedation continued over the extubation period, has been shown to reduce haemodynamic disturbances and myocardial ischaemia [13]. We have previously shown [1] that dexmedetomidine provides cardiovascular stability, with a reduction in rate-pressure product over the extubation period. A sedative agent that has analgesic properties, minimal effects on respiration and offers ischaemia protection would have enormous potential in the ICU. Dexmedetomidine may fulfill all of these roles, but at present we can only conclude that dexmedetomidine has no deleterious clinical effects on respiration when used in doses that are sufficient to provide adequate sedation and effective analgesia in the surgical population requiring intensive care.
PMCID: PMC29047  PMID: 11056756
α2-Adrenoceptor agonist; analgesia; dexmedetomidine; intensive care; postoperative; respiratory; sedation
5.  Efficiency and safety of inhalative sedation with sevoflurane in comparison to an intravenous sedation concept with propofol in intensive care patients: study protocol for a randomized controlled trial 
Trials  2012;13:135.
Background
State of the art sedation concepts on intensive care units (ICU) favor propofol for a time period of up to 72 h and midazolam for long-term sedation. However, intravenous sedation is associated with complications such as development of tolerance, insufficient sedation quality, gastrointestinal paralysis, and withdrawal symptoms including cognitive deficits. Therefore, we aimed to investigate whether sevoflurane as a volatile anesthetic technically implemented by the anesthetic-conserving device (ACD) may provide advantages regarding ‘weaning time’, efficiency, and patient’s safety when compared to standard intravenous sedation employing propofol.
Method/Design
This currently ongoing trial is designed as a two-armed, monocentric, randomized prospective phase II study including intubated intensive care patients with an expected necessity for sedation exceeding 48 h. Patients are randomly assigned to either receive intravenous sedation with propofol or sevoflurane employing the ACD. Primary endpoint is the comparison of the ‘weaning time’ defined as the time required from discontinuation of the sedating agent until sufficient spontaneous breathing occurs. Moreover, sedation depth evaluated by Richmond Agitation Sedation Scale and parameters of patient’s safety (that is, vital signs, laboratory monitoring of organ function) as well as the duration of mechanical ventilation and overall stay on the ICU are analyzed and compared. An intention-to-treat analysis will be carried out with all patients for whom it will be possible to define a wake-up time. In addition, a per-protocol analysis is envisaged. Completion of patient recruitment is expected by the end of 2012.
Discussion
This clinical study is designed to evaluate the impact of sevoflurane during long-term sedation of critically ill patients on ‘weaning time’, efficiency, and patient’s safety compared to the standard intravenous sedation concept employing propofol.
Trial registration
EudraCT2007-006087-30; ISCRTN90609144
doi:10.1186/1745-6215-13-135
PMCID: PMC3502585  PMID: 22883020
Inhalative sedation; Intravenous sedation; Intensive care; Sevoflurane
6.  Comparison of Procedural Sedation for the Reduction of Dislocated Total Hip Arthroplasty 
Introduction: Various types of sedation can be used for the reduction of a dislocated total hip arthroplasty. Traditionally, an opiate/benzodiazepine combination has been employed. The use of other pharmacologic agents, such as etomidate and propofol, have more recently gained popularity. Currently no studies directly comparing these sedation agents have been carried out. The purpose of this study is to compare differences in reduction and sedation outcomes, including recovery times, of these 3 sedation agents.
Methods: We performed a retrospective chart review examining 198 patients who presented with dislocated total hip arthroplasty at 2 academic affiliated medical centers. The patients were grouped according to the type of sedation agent. We calculated percentages of reduction and sedation complications along with recovery times. Reduction complications included fracture, skin or neurovascular injury, and failure of reduction requiring general anesthesia. Sedation complications included use of bag-valve mask and artificial airway, intubation, prolonged recovery, use of a reversal agent, and inability to achieve sedation. We then compared the data for each sedation agent.
Results: We found reduction complications rates of 8.7% in the propofol, 24.7% in the etomidate, and 28.9% in the opiate/benzodiazepine groups. The propofol group was significantly different from the other 2agents (p ≤ 0.01). Sedation complications were found 7.3% of the time in the propofol , 11.7% in the etomidate , and 21.3% in the opiate/benzodiazepine group, (p=0.02 propofol vs. others) . Average recovery times were 25.2 minutes for propofol, 30.8 minutes for etomidate, and 44.4 minutes for opiate/benzodiazepine (p = 0.05 for propofol vs. other agents).
Conclusion: For reduction of dislocated total hip arthroplasty under procedural sedation, propofol appears to have fewer complications and a trend toward more rapid recovery than both etomidate and opiate/benzodiazepine. These data support the use of propofol as first line agent for procedural sedation of dislocated total hip arthroplasty, with fewer complications and a shorter recovery period.
doi:10.5811/westjem.2013.7.15616
PMCID: PMC3952894  PMID: 24696752
7.  Propofol-Based Sedation Does Not Increase Rate of Complication during Percutaneous Endoscopic Gastrostomy Procedure 
Objectives. To evaluate and compare the complication rate of sedation with or without propofol regimen for percutaneous endoscopic gastrostomy (PEG) in a hospital in Thailand. Subjects and Methods. A total of 198 patients underwent PEG procedures by using intravenous sedation (IVS) from Siriraj Hospital, Thailand from August 2006 to January 2009. The primary outcome variable was the overall complication rate. The secondary outcome variables were sedation and procedure related complications, and mortality rate. Results. After matching ASA physical status and indications of procedure, there were 92 PEG procedures in propofol based sedation group (A) and 20 PEG procedures in non-propofol based sedation group (B). All sedation was given by residents or anesthetic nurses directly supervised by staff anesthesiologist in the endoscopy room. There were no significant differences in patients' characteristics, sedation time, indication, complications, anesthetic personnel and mortality rate between the two groups. All complications were easily treated, with no adverse sequelae. Mean dose of fentanyl and midazolam in group A was significantly lower than in group B. Conclusion. Propofol-based sedation does not increase rate of complication during PEG procedure. Additionally, IVS of PEG procedure is relatively safe and effective when performed by physicians in training. Serious complications are none.
doi:10.1155/2011/134819
PMCID: PMC2929499  PMID: 20811547
8.  Tracheotomy does not affect reducing sedation requirements of patients in intensive care – a retrospective study 
Critical Care  2006;10(4):R99.
Introduction
Translaryngeal intubated and ventilated patients often need sedation to treat anxiety, agitation and/or pain. Current opinion is that tracheotomy reduces sedation requirements. We determined sedation needs before and after tracheotomy of intubated and mechanically ventilated patients.
Methods
We performed a retrospective analysis of the use of morphine, midazolam and propofol in patients before and after tracheotomy.
Results
Of 1,788 patients admitted to our intensive care unit during the study period, 129 (7%) were tracheotomized. After the exclusion of patients who received a tracheotomy before or at the day of admittance, 117 patients were left for analysis. The daily dose (DD; the amount of sedatives for each day) divided by the mean daily dose (MDD; the mean amount of sedatives per day for the study period) in the week before and the week after tracheotomy was 1.07 ± 0.93 DD/MDD versus 0.30 ± 0.65 for morphine, 0.84 ± 1.03 versus 0.11 ± 0.46 for midazolam, and 0.62 ± 1.05 versus 0.15 ± 0.45 for propofol (p < 0.01). However, when we focused on a shorter time interval (two days before and after tracheotomy), there were no differences in prescribed doses of morphine and midazolam. Studying the course in DD/MDD from seven days before the placement of tracheotomy, we found a significant decline in dosage. From day -7 to day -1, morphine dosage (DD/MDD) declined by 3.34 (95% confidence interval -1.61 to -6.24), midazolam dosage by 2.95 (-1.49 to -5.29) and propofol dosage by 1.05 (-0.41 to -2.01). After tracheotomy, no further decrease in DD/MDD was observed and the dosage remained stable for all sedatives. Patients in the non-surgical and acute surgical groups received higher dosages of midazolam than patients in the elective surgical group. Time until tracheotomy did not influence sedation requirements. In addition, there was no significant difference in sedation between different patient groups.
Conclusion
In our intensive care unit, sedation requirements were not further reduced after tracheotomy. Sedation requirements were already sharply declining before tracheotomy was performed.
doi:10.1186/cc4961
PMCID: PMC1751026  PMID: 16834768
9.  Safety and efficacy of analgesia-based sedation with remifentanil versus standard hypnotic-based regimens in intensive care unit patients with brain injuries: a randomised, controlled trial [ISRCTN50308308] 
Critical Care  2004;8(4):R268-R280.
Introduction
This randomised, open-label, observational, multicentre, parallel group study assessed the safety and efficacy of analgesia-based sedation using remifentanil in the neuro-intensive care unit.
Methods
Patients aged 18–80 years admitted to the intensive care unit within the previous 24 hours, with acute brain injury or after neurosurgery, intubated, expected to require mechanical ventilation for 1–5 days and requiring daily downward titration of sedation for assessment of neurological function were studied. Patients received one of two treatment regimens. Regimen one consisted of analgesia-based sedation, in which remifentanil (initial rate 9 μg kg-1 h-1) was titrated before the addition of a hypnotic agent (propofol [0.5 mg kg-1 h-1] during days 1–3, midazolam [0.03 mg kg-1 h-1] during days 4 and 5) (n = 84). Regimen two consisted of hypnotic-based sedation: hypnotic agent (propofol days 1–3; midazolam days 4 and 5) and fentanyl (n = 37) or morphine (n = 40) according to routine clinical practice. For each regimen, agents were titrated to achieve optimal sedation (Sedation–Agitation Scale score 1–3) and analgesia (Pain Intensity score 1–2).
Results
Overall, between-patient variability around the time of neurological assessment was statistically significantly smaller when using remifentanil (remifentanil 0.44 versus fentanyl 0.86 [P = 0.024] versus morphine 0.98 [P = 0.006]. Overall, mean neurological assessment times were significantly shorter when using remifentanil (remifentanil 0.41 hour versus fentanyl 0.71 hour [P = 0.001] versus morphine 0.82 hour [P < 0.001]). Patients receiving the remifentanil-based regimen were extubated significantly faster than those treated with morphine (1.0 hour versus 1.93 hour, P = 0.001) but there was no difference between remifentanil and fentanyl. Remifentanil was effective, well tolerated and provided comparable haemodynamic stability to that of the hypnotic-based regimen. Over three times as many users rated analgesia-based sedation with remifentanil as very good or excellent in facilitating assessment of neurological function compared with the hypnotic-based regimen.
Conclusions
Analgesia-based sedation with remifentanil permitted significantly faster and more predictable awakening for neurological assessment. Analgesia-based sedation with remifentanil was very effective, well tolerated and had a similar adverse event and haemodynamic profile to those of hypnotic-based regimens when used in critically ill neuro-intensive care unit patients for up to 5 days.
doi:10.1186/cc2896
PMCID: PMC522854  PMID: 15312228
analgesia-based sedation; fentanyl; intensive care; morphine; remifentanil
10.  Comparison of Dexmedetomidine, Propofol and Midazolam for Short-Term Sedation in Postoperatively Mechanically Ventilated Neurosurgical Patients 
Background: Effective management of analgesia and sedation in the intensive care unit depends on the needs of the patient, subjective and/or objective measurement and drug titration to achieve specific endpoints.
Aim: The present study compared the efficacy of dexmedetomidine, propofol and midazolam for sedation in neurosurgical patients for postoperative mechanical ventilation.
Materials and Methods: Ninety patients aged 20-65 years, ASA physical status I to III, undergoing neurosurgery and requiring postoperative ventilation were included. The patients were randomly divided into three groups of 30 each. Group D received dexmedetomidine 1 mcg/kg over 15 minutes as a loading dose, followed by 0.4-0.7 mcg/kg/h. Group P received propofol 1 mg/kg over 15 minutes as a loading dose, followed by 1-3 mg/kg/h. Group M received midazolam 0.04 mg/kg over 15 minutes as a loading dose, followed by 0.08 mg/kg/h.
Measurements: Heart rate, mean arterial pressure, sedation level, fentanyl requirement, ventilation and extubation time were recorded.
Results: Adequate sedation level was achieved with all three agents. Dexmedetomidine group required less fentanyl for postoperative analgesia. In group D there was a decrease in HR after dexmedetomidine infusion (p<0.05), but there was no significant difference in HR between group P and group M. After administration of study drug there was a significant decrease in MAP comparison to baseline value in all groups at all time intervals (p<0.05), except postextubation period (p>0.05). Extubation time was lowest in group P (p<0.05).
Conclusion: Dexmedetomidine is safer and equally effective agent compared to propofol and midazolam for sedation of neurosurgical mechanically ventilated patients with good hemodynamic stability and extubation time as rapid as propofol. Dexmedetomidine also reduced postoperative fentanyl requirements.
doi:10.7860/JCDR/2014/8797.4817
PMCID: PMC4225903  PMID: 25386451
Hemodynamic changes; Neuroprotection; Opioids
11.  Bispectral index monitoring as an adjunct to nurse-administered combined sedation during endoscopic retrograde cholangiopancreatography 
AIM: To determine whether bispectral index (BIS) monitoring is useful for propofol administration for deep sedation during endoscopic retrograde cholangiopancreatography (ERCP).
METHODS: Fifty-nine consecutive patients with a variety of reasons for ERCP who underwent the procedure at least twice between 1 July 2010 and 30 November 2010. This was a randomized cross-over study, in which each patient underwent ERCP twice, once with BIS monitoring and once with control monitoring. Whether BIS monitoring was done during the first or second ERCP procedure was random. Patients were intermittently administered a mixed regimen including midazolam, pethidine, and propofol by trained nurses. The nurse used a routine practice to monitor sedation using the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) scale or the BIS monitoring. The total amount of midazolam and propofol used and serious side effects were compared between the BIS and control groups.
RESULTS: The mean total propofol dose administered was 53.1 ± 32.2 mg in the BIS group and 54.9 ± 30.8 mg in the control group (P = 0.673). The individual propofol dose received per minute during the ERCP procedure was 2.90 ± 1.83 mg/min in the BIS group and 3.44 ± 2.04 mg in the control group (P = 0.103). The median value of the MOAA/S score during the maintenance phase of sedation was comparable for the two groups. The mean BIS values throughout the procedure (from insertion to removal of the endoscope) were 76.5 ± 8.7 for all 59 patients in using the BIS monitor. No significant differences in the frequency of < 80% oxygen saturation, hypotension (< 80 mmHg), or bradycardia (< 50 beats/min) were observed between the two study groups. Four cases of poor cooperation occurred, in which the procedure should be stopped to add the propofol dose. After adding the propofol, the procedure could be conducted successfully (one case in the BIS group, three cases in the control group). The endoscopist rated patient sedation as excellent for all patients in both groups. All patients in both groups rated their level of satisfaction as high (no discomfort). During the post-procedural follow-up in the recovery area, no cases of clinically significant hypoxic episodes were recorded in either group. No other postoperative side effects related to sedation were observed in either group.
CONCLUSION: BIS monitoring trend to slighlty reduce the mean propofol dose. Nurse-administered propofol sedation under the supervision of a gastroenterologist may be considered an alternative under anesthesiologist.
doi:10.3748/wjg.v18.i43.6284
PMCID: PMC3501778  PMID: 23180950
Conscious sedation; Bispectral index monitors; Pancreatic neoplasm; Endoscopic retrograde cholangiopancreatography
12.  Bispectral index score and observer's assessment of awareness/sedation score may manifest divergence during onset of sedation: Study with midazolam and propofol 
Indian Journal of Anaesthesia  2013;57(4):351-357.
Background:
Correlation between the clinical and electroencephalogram-based monitoring has been documented sporadically during the onset of sedation. Propofol and midazolam have been studied individually using the observer's assessment of awareness/sedation (OAA/S) score and Bispectral index score (BIS). The present study was designed to compare the time to onset of sedation for propofol and midazolam using both BIS and OAA/S scores, and to find out any correlation.
Methods:
A total of 46 patients (18-60 years, either sex, American Society of Anesthesiologists (ASA) I/II) posted for infraumbilical surgeries under spinal anaesthesia were randomly allocated to receive either injection propofol 1 mg/kg bolus followed by infusion 3 mg/kg/h (Group P, n=23) or injection midazolam 0.05 mg/kg bolus followed by infusion 0.06 mg/kg/h (Group M, n=23). Spinal anaesthesia was given with 2.5 ml to 3.0 ml of 0.5% bupivacaine heavy. When sensory block reached T6 level, sedation was initiated. The time to reach BIS score 70 and time to achieve OAA/S score 3 from the start of study drug were noted. OAA/S score at BIS score 70 was noted. Data from 43 patients were analyzed using SPSS 12 for Windows.
Results:
Time to reach BIS score 70 using propofol was significantly lower than using the midazolam (P<0.05). Time to achieve OAA/S score 3 using propofol was comparable with midazolam (P=0.358).
Conclusion:
A divergence exists between the time to reach BIS score 70 and time to achieve OAA/S score 3 using midazolam, compared with propofol, during the onset of sedation.
doi:10.4103/0019-5049.118557
PMCID: PMC3800326  PMID: 24163448
Bispectral index score; midazolam; observer's assessment of awareness/sedation score; propofol; sedation
13.  Comparison between Midazolam Used Alone and in Combination with Propofol for Sedation during Endoscopic Retrograde Cholangiopancreatography 
Clinical Endoscopy  2014;47(1):94-100.
Background/Aims
Endoscopic retrograde cholangiopancreatography (ERCP) is an uncomfortable procedure that requires adequate sedation for its successful conduction. We investigated the efficacy and safety of the combined use of intravenous midazolam and propofol for sedation during ERCP.
Methods
A retrospective review of patient records from a single tertiary care hospital was performed. Ninety-four patients undergoing ERCP received one of the two medication regimens, which was administered by a nurse under the supervision of a gastroenterologist. Patients in the midazolam (M) group (n=44) received only intravenous midazolam, which was titrated to achieve deep sedation. Patients in the midazolam pulse propofol (MP) group (n=50) initially received an intravenous combination of midazolam and propofol, and then propofol was titrated to achieve deep sedation.
Results
The time to the initial sedation was shorter in the MP group than in the M group (1.13 minutes vs. 1.84 minutes, respectively; p<0.001). The recovery time was faster in the MP group than in the M group (p=0.031). There were no significant differences between the two groups with respect to frequency of adverse events, pain experienced by the patient, patient discomfort, degree of amnesia, and gag reflex. Patient cooperation, rated by the endoscopist as excellent, was greater in the MP group than in the M group (p=0.046).
Conclusions
The combined use of intravenous midazolam and propofol for sedation during ERCP is more effective than midazolam alone. There is no difference in the safety of the procedure.
doi:10.5946/ce.2014.47.1.94
PMCID: PMC3928499  PMID: 24570889
Propofol; Midazolam; Cholangiopancreatography, endoscopic retrograde; Conscious sedation
14.  A Comparison between Sedative Effect of Propofol-Fentanyl and Propofol-Midazolam Combinations in Microlaryngeal Surgeries 
Considering the growing trend of laryngeal surgeries and the need to protect the airway during and after surgery, among several therapeutic regimens to induce sedation, two regimens of propofol-fentanyl and propofol-midazolam were compared in microlaryngeal surgeries.
Forty ASA I-II class patients undergoing microlaryngeal surgeries and referring routinely for postoperative visits were randomly recruited into two groups. For all the patients, 0.5 mg/Kg of propofol was used as bolus and then, 50 mcg/Kg/min of the drug was infused intravenously. For one group, 0.03 mg/Kg bolus of midazolam and for the other group, 2 mcg/Kg bolus of fentanyl was administered in combination with propofol. Ramsay system was used in order to evaluate the effect of the two drugs in inducing sedation. The need for additional dose, blood pressure, heart rate, arterial blood oxygen saturation, and also recovery time and adverse effects such as nausea/vomiting and recalling intra-operative memories, were assessed.
The patients in the two groups were not statistically different regarding the number of patients, age, sex, preoperative vital signs, the need for additional doses of propofol, systolic blood pressure and mean systolic blood pressure during laryngoscopy. However, mean systolic blood pressure 1 min after removal of laryngoscope returned faster to the baseline in midazolam group (p < 0.01). Mean heart rate returned sooner to the baseline in fentanyl group following removal of stimulation. Besides, heart rate showed a more reduction following administration of fentanyl (p < 0.02). Mean arterial blood oxygen saturation during laryngoscopy significantly decreased in fentanyl group (p < 0.05) compared to the other group. The time it took to achieve a full consciousness was shorter in midazolam group (p < 0.01). Nausea/vomiting was significantly more prevalent in fentanyl group while the patients in midazolam group apparently experienced more of amnesia, comparatively (p < 0.01).
Inducing laryngeal block and local anesthesia using propofol-midazolam regimen is not only associated with a more rapid recovery and less recalling of unpleasant memories, but also better in preventing reduction of arterial oxygen saturation during laryngoscopy compared with propofol-fentanyl regimen.
PMCID: PMC3813093  PMID: 24250451
Sedation; Microlaryngeal surgery; Propofol; Midazolam; Fentanyl
15.  Decreased duration of mechanical ventilation when comparing analgesia-based sedation using remifentanil with standard hypnotic-based sedation for up to 10 days in intensive care unit patients: a randomised trial [ISRCTN47583497] 
Critical Care  2005;9(3):R200-R210.
Introduction
This randomised, open-label, multicentre study compared the safety and efficacy of an analgesia-based sedation regime using remifentanil with a conventional hypnotic-based sedation regime in critically ill patients requiring prolonged mechanical ventilation for up to 10 days.
Methods
One hundred and five randomised patients received either a remifentanil-based sedation regime (initial dose 6 to 9 μg kg-1 h-1 (0.1 to 0.15 μg kg-1 min-1) titrated to response before the addition of midazolam for further sedation (n = 57), or a midazolam-based sedation regime with fentanyl or morphine added for analgesia (n = 48). Patients were sedated to an optimal Sedation–Agitation Scale (SAS) score of 3 or 4 and a pain intensity (PI) score of 1 or 2.
Results
The remifentanil-based sedation regime significantly reduced the duration of mechanical ventilation by more than 2 days (53.5 hours, P = 0.033), and significantly reduced the time from the start of the weaning process to extubation by more than 1 day (26.6 hours, P < 0.001). There was a trend towards shortening the stay in the intensive care unit (ICU) by 1 day. The median time of optimal SAS and PI was the same in both groups. There was a significant difference in the median time to offset of pharmacodynamic effects when discontinuing study medication in patients not extubated at 10 days (remifentanil 0.250 hour, comparator 1.167 hours; P < 0.001). Of the patients treated with remifentanil, 26% did not receive any midazolam during the study. In those patients that did receive midazolam, the use of remifentanil considerably reduced the total dose of midazolam required. Between days 3 and 10 the weighted mean infusion rate of remifentanil remained constant with no evidence of accumulation or of a development of tolerance to remifentanil. There was no difference between the groups in SAS or PI score in the 24 hours after stopping the study medication. Remifentanil was well tolerated.
Conclusion
Analgesia-based sedation with remifentanil was well tolerated; it reduces the duration of mechanical ventilation and improves the weaning process compared with standard hypnotic-based sedation regimes in ICU patients requiring long-term ventilation for up to 10 days.
doi:10.1186/cc3495
PMCID: PMC1175879  PMID: 15987391
16.  Isoflurane compared with midazolam for sedation in the intensive care unit. 
BMJ : British Medical Journal  1989;298(6683):1277-1280.
OBJECTIVE--To compare isoflurane with midazolam for sedation of ventilated patients. DESIGN--Randomised control study. Setting--Intensive care unit in university teaching hospital. PATIENTS--Sixty patients aged 18-76 who required mechanical ventilation. INTERVENTIONS--Sedation with either 0.1-0.6% isoflurane in an air-oxygen mixture (30 patients) or a continuous intravenous infusion of midazolam 0.01-0.20 mg/kg/h (30 patients). Sedation was assessed initially and hourly thereafter on a six point scale. Incremental intravenous doses of morphine 0.05 mg/kg were given for analgesia as required. The trial sedative was stopped when the patient was judged ready for weaning from ventilatory support or at 24 hours (whichever was earlier). END POINT--Achievement of a predetermined level of sedation for as much of the time as possible. MAIN RESULTS--Isoflurane produced satisfactory sedation for a greater proportion of time (86%) than midazolam (64%), and patients sedated with isoflurane recovered more rapidly from sedation. CONCLUSION--Isoflurane is a promising alternative technique for sedation of ventilated patients in the intensive care unit.
PMCID: PMC1836531  PMID: 2500195
17.  Carbon dioxide accumulation during analgosedated colonoscopy: Comparison of propofol and midazolam 
AIM: To characterize the profiles of alveolar hypoventilation during colonoscopies performed under sedoanalgesia with a combination of alfentanil and either midazolam or propofol.
METHODS: Consecutive patients undergoing routine colonoscopy were randomly assigned to sedation with either propofol or midazolam in an open-labeled design using a titration scheme. All patients received 4 μg/kg per body weight alfentanil for analgesia and 3 L of supplemental oxygen. Oxygen saturation (SpO2) was measured by pulse oximetry (POX), and capnography (PcCO2) was continuously measured using a combined dedicated sensor at the ear lobe. Instances of apnea resulting in measures such as stimulation of the patient, a chin lift, a mask maneuver, or withholding of sedation were recorded. PcCO2 values (as a parameter of sedation-induced hypoventilation) were compared between groups at the following distinct time points: baseline, maximal rise, termination of the procedure and 5 min after termination of the procedure. The number of patients in both study groups who regained baseline PcCO2 values (± 1.5 mmHg) five minutes after the procedure was determined.
RESULTS: A total of 97 patients entered this study. The data from 14 patients were subsequently excluded for clinical procedure-related reasons or for technical problems. Therefore, 83 patients (mean age 62 ± 13 years) were successfully randomized to receive propofol (n = 42) or midazolam (n = 41) for sedation. Most of the patients were classified as American Society of Anesthesiologists (ASA) II [16 (38%) in the midazolam group and 15 (32%) in the propofol group] and ASA III [14 (33%) and 13 (32%) in the midazolam and propofol groups, respectively]. A mean dose of 5 (4-7) mg of IV midazolam and 131 (70-260) mg of IV propofol was used during the procedure in the corresponding study arms. The mean SpO2 at baseline (%) was 99 ± 1 for the midazolam group and 99 ± 1 for the propofol group. No cases of hypoxemia (SpO2 < 85%) or apnea were recorded. However, an increase in PcCO2 that indicated alveolar hypoventilation occurred in both groups after administration of the first drug and was not detected with pulse oximetry alone. The mean interval between the initiation of sedation and the time when the PcCO2 value increased to more than 2 mmHg was 2.8 ± 1.3 min for midazolam and 2.8 ± 1.1 min for propofol. The mean maximal rise was similar for both drugs: 8.6 ± 3.7 mmHg for midazolam and 7.4 ± 3.2 mmHg for propofol. Five minutes after the end of the procedure, the mean difference from the baseline values was significantly lower for the propofol treatment compared with midazolam (0.9 ± 3.0 mmHg vs 4.3 ± 3.7 mmHg, P = 0.0000169), and significantly more patients in the propofol group had regained their baseline value ± 1.5 mmHg (32 of 41 vs 12 of 42, P = 0.0004).
CONCLUSION: A significantly higher number of patients sedated with propofol had normalized PcCO2 values five minutes after sedation when compared with patients sedated with midazolam.
doi:10.3748/wjg.v18.i38.5389
PMCID: PMC3471107  PMID: 23082055
Colonoscopy; Deep sedation; Propofol; Hypoventilation; Blood gas monitoring; Transcutaneous
18.  Propofol versus Midazolam for Upper Gastrointestinal Endoscopy in Cirrhotic Patients: A Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2015;10(2):e0117585.
Background
Sedation during gastrointestinal endoscopy is often achieved using propofol or midazolam in general population. However, impaired protein synthesis, altered drug metabolism, and compromised hepatic blood flow in patients with liver cirrhosis might affect the pharmacokinetics of sedatives, placing cirrhotic patients undergoing endoscopy at a greater risk of adverse events. The objective of this study was to assess comparative efficacies and safety of propofol and midazolam in cirrhotic patients undergoing endoscopy.
Methods
Randomized, controlled trials comparing propofol with midazolam in cirrhotic patients undergoing gastrointestinal endoscopy were selected. We performed the meta-analysis, using a random-effect model, the Review Manager, Version 5.2, statistical software package (Cochrane Collaboration, Oxford, UK) according to the PRISMA guidelines.
Results
Five studies between 2003 and 2012, including 433 patients, were included. Propofol provided a shorter time to sedation (weight mean difference: -2.76 min, 95% confidence interval: -3.00 to -2.51) and a shorter recovery time (weight mean difference -6.17 min, 95% confidence interval: -6.81 to -5.54) than midazolam did. No intergroup difference in the incidence of hypotension, bradycardia, or hypoxemia was observed. Midazolam was associated with the deterioration of psychometric scores for a longer period than propofol.
Conclusion
This meta-analysis suggests that Propofol sedation for endoscopy provides more rapid sedation and recovery than midazolam does. The risk of sedation-related side effects for propofol does not differ significantly from that of midazolam. The efficacy of propofol in cirrhotic patients undergoing endoscopy is superior to those of midazolam.
doi:10.1371/journal.pone.0117585
PMCID: PMC4315567  PMID: 25646815
19.  Midazolam and propofol used alone or sequentially for long-term sedation in critically ill, mechanically ventilated patients: a prospective, randomized study 
Critical Care  2014;18(3):R122.
Introduction
Midazolam and propofol used alone for long-term sedation are associated with adverse effects. Sequential use may reduce the adverse effects, and lead to faster recovery, earlier extubation and lower costs. This study evaluates the effects, safety, and cost of midazolam, propofol, and their sequential use for long-term sedation in critically ill mechanically ventilated patients.
Methods
A total of 135 patients who required mechanical ventilation for >3 days were randomly assigned to receive midazolam (group M), propofol (group P), or sequential use of both (group M-P). In group M-P, midazolam was switched to propofol until the patients passed the spontaneous breathing trial (SBT) safety screen. The primary endpoints included recovery time, extubation time and mechanical ventilation time. The secondary endpoints were pharmaceutical cost, total cost of ICU stay, and recollection to mechanical ventilation-related events.
Results
The incidence of agitation following cessation of sedation in group M-P was lower than group M (19.4% versus 48.7%, P = 0.01). The mean percentage of adequate sedation and duration of sedation were similar in the three groups. The recovery time, extubation time and mechanical ventilation time of group M were 58.0 (interquartile range (IQR), 39.0) hours, 45.0 (IQR, 24.5) hours, and 192.0 (IQR, 124.0) hours, respectively; these were significantly longer than the other groups, while they were similar between the other two groups. In the treatment-received analysis, ICU duration was longer in group M than group M-P (P = 0.016). Using an intention-to-treat analysis and a treatment-received analysis, respectively, the pharmaceutical cost of group M-P was lower than group P (P <0.01) and its ICU cost was lower than group M (P <0.01; P = 0.015). The proportion of group M-P with unbearable memory of the uncomfortable events was lower than in group M (11.7% versus 25.0%, P <0.01), while the proportion with no memory was similar (P >0.05). The incidence of hypotension in group M-P was lower than group (P = 0.01).
Conclusion
Sequential use of midazolam and propofol was a safe and effective sedation protocol, with higher clinical effectiveness and better cost-benefit ratio than midazolam or propofol used alone, for long-term sedation of critically ill mechanically ventilated patients.
Trial registration
Current Controlled Trials ISRCTN01173443. Registered 25 February 2014.
doi:10.1186/cc13922
PMCID: PMC4095601  PMID: 24935517
20.  Arousal time from sedation during spinal anaesthesia for elective infraumbilical surgeries: Comparison between propofol and midazolam 
Indian Journal of Anaesthesia  2014;58(4):403-409.
Background and Aims:
Studies have already compared propofol and midazolam as sedatives during regional anaesthesia. A few studies have focused on recovery characteristics and very few have utilised both instrumental and clinical sedation monitoring for assessing recovery time. This study was designed primarily to compare arousal time from sedation using propofol with that of midazolam during spinal anaesthesia for infraumbilical surgeries, while depth of sedation was monitored continuously with bispectral index (BIS) monitor. The correlation between the BIS score and observer's assessment of awareness/sedation (OAA/S) score during recovery from sedation was also studied.
Methods:
A total of 110 patients were randomly assigned to receive either propofol (Group P, n = 55) or midazolam (Group M, n = 55). Patients in the Group P received bolus of propofol (1 mg/kg), followed by infusion at 3 mg/kg/h; Group M received bolus of midazolam (0.05 mg/kg), followed by infusion at 0.06 mg/kg/h and titration until BIS score 70 was achieved and maintained between 65 and 70. OAA/S score was noted at BIS 70 and again at BIS 90 during recovery. The time to achieve OAA/S score 5 was noted. Spearman's correlation was calculated between the arousal time from sedation and the time taken to reach an OAA/S score of 5 in both the study groups.
Results:
Arousal time from sedation was found lower for Group P compared to Group M (7.54 ± 3.70 vs. 15.54 ± 6.93 min, respectively, P = 0.000). The time taken to reach OAA/S score 5 was also found to be lower for Group P than Group M (6.81 ± 2.54 min vs. 13.51 ± 6.24 min, respectively, P = 0.000).
Conclusion:
A shorter arousal time from sedation during spinal anaesthesia can be achieved using propofol compared with midazolam, while depth of sedation was monitored with BIS monitor and OAA/S score. Both objective and clinical scoring correlate strongly during recovery from sedation.
doi:10.4103/0019-5049.138972
PMCID: PMC4155284  PMID: 25197107
Bispectral index monitoring; midazolam; propofol; sedation; spinal anaesthesia
21.  Comparison of Propofol-Remifentanil Versus Propofol-Ketamine Deep Sedation for Third Molar Surgery 
Anesthesia Progress  2012;59(3):107-117.
This study aimed to compare continuous intravenous infusion combinations of propofol-remifentanil and propofol-ketamine for deep sedation for surgical extraction of all 4 third molars. In a prospective, randomized, double-blinded controlled study, participants received 1 of 2 sedative combinations for deep sedation for the surgery. Both groups initially received midazolam 0.03 mg/kg for baseline sedation. The control group then received a combination of propofol-remifentanil in a ratio of 10 mg propofol to 5 μg of remifentanil per milliliter, and the experimental group received a combination of propofol-ketamine in a ratio of 10 mg of propofol to 2.5 mg of ketamine per milliliter; both were given at an initial propofol infusion rate of 100 μg/kg/min. Each group received an induction loading bolus of 500 μg/kg of the assigned propofol combination along with the appropriate continuous infusion combination . Measured outcomes included emergence and recovery times, various sedation parameters, hemodynamic and respiratory stability, patient and surgeon satisfaction, postoperative course, and associated drug costs. Thirty-seven participants were enrolled in the study. Both groups demonstrated similar sedation parameters and hemodynamic and respiratory stability; however, the ketamine group had prolonged emergence (13.6 ± 6.6 versus 7.1 ± 3.7 minutes, P = .0009) and recovery (42.9 ± 18.7 versus 24.7 ± 7.6 minutes, P = .0004) times. The prolonged recovery profile of continuously infused propofol-ketamine may limit its effectiveness as an alternative to propofol-remifentanil for deep sedation for third molar extraction and perhaps other short oral surgical procedures, especially in the ambulatory dental setting.
doi:10.2344/12-00001.1
PMCID: PMC3468288  PMID: 23050750
Propofol; Ketamine; Remifentanil; Deep sedation; TIVA
22.  A Randomized Evaluation of Bispectral Index-Augmented Sedation Assessment in Neurological Patients 
Neurocritical care  2009;11(1):20-27.
Objective
To assess whether monitoring sedation status using bispectral index (BIS) as an adjunct to clinical evaluation was associated with a reduction in the total amount of sedative drug used in a 12 h period.
Design
Prospective randomized controlled clinical trial.
Setting
Tertiary care neurocritical care unit.
Patients
Sixty-seven mechanically ventilated adult patients receiving continuous intravenous sedation with propofol.
Interventions
Sedation monitoring using clinical assessment with the Ramsay scale (Ramsay-alone group) or clinical assessment plus BIS monitoring (BIS-augmentation group). Subjects were randomized to Ramsay-alone (n = 35), or BIS-augmentation (n = 32). Nurses adjusted the dose of propofol to a Ramsay of 4, or a Ramsay of 4 and BIS between 60 and 70.
Measurements and Main Results
Patients in the BIS-augmentation group received significantly less propofol by volume (93.5 ml vs. 157.8 ml, respectively; P < .015), and had lower infusion rates (14.6 vs. 27.9 mcg/kg/min; P = .003). There is a lower risk of propofol infusion exceeding manufacturer’s recommended dosing guides in the BIS-augmentation group versus the Ramsay-alone group (0 vs. 23%, P = .0052). The BIS-augmentation group woke up much quicker than those in the Ramsay-alone group (1.2 vs. 7.5 min; P < .0001).
Conclusions
BIS-augmented sedation monitoring resulted in a marked reduction in the total dose of sedative used to achieve the same level of clinical sedation resulting in shortened time to wake up without any measurable adverse effects. Physiologic sedation assessment tools may provide a useful means of improving the care of sedated critically ill patients.
doi:10.1007/s12028-008-9184-6
PMCID: PMC2706915  PMID: 19184556
Sedation assessment; Nursing care; Critical care; Neurofunction monitoring; Neurocritical care
23.  Safety and Efficacy of Deep Sedation with Propofol Alone or Combined with Midazolam Administrated by Nonanesthesiologist for Gastric Endoscopic Submucosal Dissection 
Gut and Liver  2012;6(4):464-470.
Background/Aims
Endoscopic submucosal dissection (ESD) is accepted as a treatment for gastric neoplasms and usually requires deep sedation. The aim of this study was to evaluate the safety and efficacy profiles of deep sedation induced by continuous propofol infusion with or without midazolam during ESD.
Methods
A total of 135 patients scheduled for ESDs between December 2008 and June 2010 were included in this prospective study and were randomly assigned to one of two groups: the propofol group or the combination group (propofol plus midazolam).
Results
The propofol group reported only one case of severe hypoxemia with no need of mask ventilation or intubation. Additionally, 18 cases of mild hypotension were observed in the propofol group, and 11 cases were observed in the combination group. The combination group had a lower mean total propofol dose (378 mg vs 466 mg, p<0.012), a longer mean recovery time (10.5 minutes vs 7.9 minutes, p=0.027), and a lower frequency of overall adverse events (32.8% vs 17.6%, p=0.042).
Conclusions
Deep sedation induced by continuous propofol infusion was shown to be safe during ESD. The combination of continuous propofol infusion and intermittent midazolam injection can decrease the total dose and infusion rate of propofol and the overall occurrence of adverse events.
doi:10.5009/gnl.2012.6.4.464
PMCID: PMC3493727  PMID: 23170151
Deep sedation; Propofol; Midazolam; Endoscopy; Gastrointestinal
24.  The effect of interruption to propofol sedation on auditory event-related potentials and electroencephalogram in intensive care patients 
Critical Care  2004;8(6):R483-R490.
Introduction
In this observational pilot study we evaluated the electroencephalogram (EEG) and auditory event-related potentials (ERPs) before and after discontinuation of propofol sedation in neurologically intact intensive care patients.
Methods
Nineteen intensive care unit patients received a propofol infusion in accordance with a sedation protocol. The EEG signal and the ERPs were measured at the frontal region (Fz) and central region (Cz), both during propofol sedation and after cessation of infusion when the sedative effects had subsided. The EEG signal was subjected to power spectral estimation, and the total root mean squared power and spectral edge frequency 95% were computed. For ERPs, we used an oddball paradigm to obtain the N100 and the mismatch negativity components.
Results
Despite considerable individual variability, the root mean squared power at Cz and Fz (P = 0.004 and P = 0.005, respectively) and the amplitude of the N100 component in response to the standard stimulus at Fz (P = 0.022) increased significantly after interruption to sedation. The amplitude of the N100 component (at Cz and Fz) was the only parameter that differed between sedation levels during propofol sedation (deep versus moderate versus light sedation: P = 0.016 and P = 0.008 for Cz and Fz, respectively). None of the computed parameters correlated with duration of propofol infusion.
Conclusion
Our findings suggest that use of ERPs, especially the N100 potential, may help to differentiate between levels of sedation. Thus, they may represent a useful complement to clinical sedation scales in the monitoring of sedation status over time in a heterogeneous group of neurologically intact intensive care patients.
doi:10.1186/cc2984
PMCID: PMC1065074  PMID: 15566595
electroencephalogram; event-related potentials; intensive care; propofol; sedation
25.  Comparison of Midazolam Alone versus Midazolam Plus Propofol during Endoscopic Submucosal Dissection 
Clinical Endoscopy  2011;44(1):22-26.
Background/Aims
For proper sedation during endoscopic submucosal dissection (ESD), propofol has been widely used. This study aimed to compare the levels of sedation and tolerance of patients treated with midazolam (M group) and a combination of midazolam and propofol (MP group) during ESD.
Methods
A total of 44 consecutive patients undergoing ESD were randomly assigned to the two groups. In the M group, 2 mg of midazolam was given repeatedly to maintain after a loading dose of 5 mg. The MP group initially received 5 mg of midazolam and 20 mg of propofol. Then, we increased the dosage of propofol by 20 mg gradually.
Results
The average amount of midazolam was 12 mg in the M group. In the M group, 10 patients were given propofol additionally, since they failed to achieve proper sedation. The average amount of propofol was 181 mg in the MP group. Procedure time, vital signs and rates of complications were not significantly different between two groups. Movement of patients and discomfort were lower in the MP group.
Conclusions
During ESD, treatment with propofol and a low dose of midazolam for sedation provides greater satisfaction for endoscopists compared to midazolam alone.
doi:10.5946/ce.2011.44.1.22
PMCID: PMC3363047  PMID: 22741108
Endoscopic submucosal dissection; Sedation; Midazolam; Propofol

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