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.
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).
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.
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.
analgesia-based sedation; fentanyl; intensive care; morphine; remifentanil
This double-blind, randomized, multicentre study was conducted to compare the efficacy and safety of remifentanil and fentanyl for intensive care unit (ICU) sedation and analgesia.
Intubated cardiac, general postsurgical or medical patients (aged ≥ 18 years), who were mechanically ventilated for 12–72 hours, received remifentanil (9 μg/kg per hour; n = 77) or fentanyl (1.5 μg/kg per hour; n = 75). Initial opioid titration was supplemented with propofol (0.5 mg/kg per hour), if required, to achieve optimal sedation (i.e. a Sedation–Agitation Scale score of 4).
The mean percentages of time in optimal sedation were 88.3% for remifentanil and 89.3% for fentanyl (not significant). Patients with a Sedation–Agitation Scale score of 4 exhibited significantly less between-patient variability in optimal sedation on remifentanil (variance ratio of fentanyl to remifentanil 1.84; P = 0.009). Of patients who received fentanyl 40% required propofol, as compared with 35% of those who received remifentanil (median total doses 683 mg and 378 mg, respectively; P = 0.065). Recovery was rapid (median time to extubation: 1.1 hours for remifentanil and 1.3 hours for fentanyl; not significant). Remifentanil patients who experienced pain did so for significantly longer during extubation (6.5% of the time versus 1.4%; P = 0.013), postextubation (10.2% versus 3.6%; P = 0.001) and post-treatment (13.5% versus 5.1%; P = 0.001), but they exhibited similar haemodynamic stability with no significant differences in adverse event incidence.
Analgesia based sedation with remifentanil titrated to response provided effective sedation and rapid extubation without the need for propofol in most patients. Fentanyl was similar, probably because the dosing algorithm demanded frequent monitoring and adjustment, thereby preventing over-sedation. Rapid offset of analgesia with remifentanil resulted in a greater incidence of pain, highlighting the need for proactive pain management when transitioning to longer acting analgesics, which is difficult within a double-blind study but would be quite possible under normal circumstances.
analgesia; analgesia based sedation; critical care; fentanyl; propofol; remifentanil; renal function; sedation
Hospitals are increasingly forced to consider the economics of technology use. We estimated the incremental cost-consequences of remifentanil-based analgo-sedation (RS) vs. conventional analgesia and sedation (CS) in patients requiring mechanical ventilation (MV) in the intensive care unit (ICU), using a modelling approach.
A Markov model was developed to describe patient flow in the ICU. The hourly probabilities to move from one state to another were derived from UltiSAFE, a Dutch clinical study involving ICU patients with an expected MV-time of two to three days requiring analgesia and sedation. Study medication was either: CS (morphine or fentanyl combined with propofol, midazolam or lorazepam) or: RS (remifentanil, combined with propofol when required). Study drug costs were derived from the trial, whereas all other ICU costs were estimated separately in a Dutch micro-costing study. All costs were measured from the hospital perspective (price level of 2006). Patients were followed in the model for 28 days. We also studied the sub-population where weaning had started within 72 hours.
The average total 28-day costs were €15,626 with RS versus €17,100 with CS, meaning a difference in costs of €1474 (95% CI -2163, 5110). The average length-of-stay (LOS) in the ICU was 7.6 days in the RS group versus 8.5 days in the CS group (difference 1.0, 95% CI -0.7, 2.6), while the average MV time was 5.0 days for RS versus 6.0 days for CS. Similar differences were found in the subgroup analysis.
Compared to CS, RS significantly decreases the overall costs in the ICU.
Optimal sedation and analgesia are of key importance in intensive care. The aim of this study was to assess the quality of sedoanalgesia and outcome parameters in regimens containing midazolam and either fentanyl or remifentanil.
A prospective, randomized, open-label, controlled trial was carried out in the ICU unit of a large teaching hospital in Istanbul over a 9-month period. Thirty-four patients were randomly allocated to receive either a remifentanil-midazolam regimen (R group, n = 17) or a fentanyl-midazolam regimen (F group, n = 17).
A strong correlation between Riker Sedation-Agitation Scale (SAS) and Ramsey Scale (RS) measurements was observed. Comparatively, remifentanil provided significantly more potent and rapid analgesia based on Behavioral-Physiological Scale (BPS) measurements and a statistically nonsignificantly shorter time to discharge. On the other hand, remifentanil also caused a significantly sharper fall in heart rate within the first six hours of treatment.
Providing effective analgesia and adequate sedation is a generally accepted goal of intensive care medicine. Due to its rapid, organ independent and predictable metabolism the short acting opioid remifentanil might be particularly useful for analgesia-based sedation in the intensive care unit (ICU). This hypothesis was tested by two studies in this issue of Critical Care. The study by Breen et al. shows that remifentanil does not exert prolonged clinical effects when continuously infused in renal failure patients, although the weak acting metabolite remifentanil acid accumulates. The study by Muellejans et al. reports a multicenter trial comparing a remifentanil versus a fentanyl based regimen in ICU patients. With both substances a target analgesia and sedation level was reached, and no major differences were found when frequent assessments of the sedation level and according readjustments of doses were performed. These results are in accordance with other studies suggesting that the adherence to a clear analgesia-based sedation protocol might be more important then the choice of medications itself.
analgesia; sedation; remifentanil; organ failure
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.
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.
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).
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.
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.
Evaluating depth of sedation in the intensive care unit (ICU) is crucial for the management of mechanically ventilated patients but can be challenging in some situations. Because the depth of hypnosis is correlated with the decrease in photomotor reflex (PMR), we suggest using pupillometric video as an automated, noninvasive, simple, and reproducible technique to evaluate the depth of sedation in ICU patients. We compare the effectiveness of this procedure to the bispectral index (BIS).
Thirty-one patients requiring sedation and ventilation were included in this monocentric, observational study. The posology of hypnotics and morphinics were based on the Richmond Agitation and Sedation Scale (RASS). PMR was measured by the Neurolight® (IDMED) system and BIS value by BIS Vista® (Anandic Medical Systems). RASS, PMR, and BIS were measured three times daily in all patients. Data acquired by pupillometric video included variation in pupillary diameter (ΔPD), latency time (LT), and maximal speed of pupillary constriction (Vmax). These parameters were analyzed after having classified BIS values in three groups (<40 heavy sedation; 40 ≤ BIS ≤ 60 acceptable sedation; >60 light sedation). Exclusion criteria were neurological or ophthalmologic pathologies that could interfere with PMR.
There was a significant difference in Vmax and ΔPD between the BIS < 40 group and 40 ≤ BIS ≤ 60 groups (p < 0.0001 for each) and between the BIS < 40 and BIS > 60 groups (p < 0.0001 for each). There were no significant differences in Vmax and ΔPD between the 40 ≤ BIS ≤ 60 and BIS > 60 groups. There was no correlation between any of the BIS groups and LT.
Vmax and ΔPD seem to be relevant criteria compared with the BIS and the RASS. Pupillometric video monitoring of depth of sedation could be beneficial in ICU patients, especially for those under myorelaxant drugs, where no clinical evaluation of sedation is possible.
Sedation; Photomotor reflex; Video pupillometry; Bispectral index
Analgesia and sedation are usually required for the comfort of the patient and surgeon during tympanoplasty surgery done under local anesthesia. In this study, satisfaction scores and effectiveness of sedation and analgesia with dexmedetomidine were compared with a combination of midazolam-fentanyl.
Materials and Methods:
Ninety patients undergoing tympanoplasty under local anesthesia randomly received either IV dexmedetomidine 1 μg kg-1 over 10 min followed by 0.2 μg kg-1h-1 infusion (Group D) or IV midazolam 0.06 mg kg-1 plus IV fentanyl 1 μg kg-1 over 10 min (Group MF) followed by normal saline infusion at 0.2 ml kg-1h-1. Sedation was titrated to Ramsay sedation score (RSS) of three. Vital parameters, rescue analgesics (fentanyl 1 μg kg-1) and sedatives (midazolam 0.01 mg kg-1), patient and surgeon satisfaction scores were recorded.
Patient and surgeon satisfaction score was better in Group D than Group MF (median interquartile range (IQR) 9 (8-10) vs. 8 (6.5-9.5) and 9 (8.5-9.5) vs. 8 (6.75-9.25), P = 0.0001 for both). Intraoperative heart rate and mean arterial pressure in Group D were lower than the baseline values and the corresponding values in Group MF (P < 0.05). Percentage of patients requiring rescue fentanyl was higher in Group MF than Group D (40% vs. 11.1%, P = 0.01). One patient in Group D while four in Group MF (8.8%) required rescue sedation with midazolam (P > 0.17). Seven patients in Group D had dry mouth vs. none in Group MF (P = 0.006). One patient in Group D had bradycardia with hypotension which was effectively treated.
Dexmedetomidine is comparable to midazolam-fentanyl for sedation and analgesia in tympanoplasty with better surgeon and patient satisfaction. Hemodynamics need to be closely monitored.
Dexmedetomidine; sedation; midazolam fentanyl sedation; monitored anesthesia care; satisfaction scores; surgery; otological
For logistical reasons sedation studies are often carried out in elective surgical patients and the results extrapolated to the general intensive care unit (ICU) population. We question the validity of this approach. We compared the two sedation regimens used in our general ICU in a trial structured to mimic clinical practice as closely as possible.
Forty patients were randomised to intermittent diazepam or continuous midazolam and sedation monitored with hourly sedation scores; 31 patients completed the study. Scores indicating undersedation were more common with diazepam (P <0.01); overall adequate sedation midazolam 64.7%, diazepam 35.7% (P =0.21). No patient exhibited inappropriately prolonged sedation. Cost was: midazolam AUS$1.98/h; diazepam AUS$0.06/h.
Both regimens produced rapid onset of acceptable sedation but undersedation appeared more common with the cheaper diazepam regimen. At least 140 patients should be studied to provide evidence applicable to the general ICU population. Used alone, a sedation score may be an inappropriate outcome measure for a sedation trial.
critical care; midazolam; diazepam; sedatives; nonbarbiturate; therapeutic use; comparative study
An appropriate level of sedation and pharmacological assist are essential during percutaneous transluminal balloon angioplasty (PTA). Ketamine provides good analgesia while preserving airway patency, ventilation, and cardiovascular stability with an opioid sparing effect suggesting that it would be ideal in combination with remifentanil and midazolam in spontaneously breathing patients. We evaluated the effect of a small dose of ketamine added to midazolam and remifentanil on analgesia/sedation for PTA procedures.
Sixty-four patients receiving PTA were enrolled. The Control group received midazolam 1.0 mg i.v. and continuous infusion of remifentanil 0.05 µg/kg/min. The Ketamine group received, in addition, an intravenous bolus of 0.5 mg/kg ketamine. Patients' haemodynamic data were monitored before remifentanil infusion, 5 min after remifentanil infusion, at 1, 3, 5, 30 min after incision, and at admission to the recovery room. Verbal numerical rating scales (VNRS) and sedation [OAA/S (Observer's Assessment of Alertness/Sedation)] scores were also recorded.
The VNRS values at 1, 3, and 5 min after incision and OAA/S scores at 5 min after remifentanil infusion, and 1, 3, and 5 min after incision were lower in the Ketamine group than in the Control group. In the Control group, the VNRS value at 1 min after incision significantly increased and OAA/S values at 3, 5, and 30 min after incision significantly decreased compared to baseline values, while there were no significant changes in the ketamine group.
A small dose of ketamine as an adjunct sedative to the combination of midazolam and remifentanil produced a better quality of sedation and analgesia than without ketamine and provided stable respiration without cardiopulmonary deterioration.
Ketamine; Pain scale; Remifentanil; Sedation
Critically ill patients are routinely provided analgesia and sedation to prevent pain and anxiety, permit invasive procedures, reduce stress and oxygen consumption, and improve synchrony with mechanical ventilation. Regional preferences, patient history, institutional bias, and individual patient and practitioner variability, however, create a wide discrepancy in the approach to sedation of critically ill patients. Untreated pain and agitation increase the sympathetic stress response, potentially leading to negative acute and long-term consequences. Oversedation, however, occurs commonly and is associated with worse clinical outcomes, including longer time on mechanical ventilation, prolonged stay in the intensive care unit, and increased brain dysfunction (delirium and coma). Modifying sedation delivery by incorporating analgesia and sedation protocols, targeted arousal goals, daily interruption of sedation, linked spontaneous awakening and breathing trials, and early mobilization of patients have all been associated with improvements in patient outcomes and should be incorporated into the clinical management of critically ill patients. To improve outcomes, including time on mechanical ventilation and development of acute brain dysfunction, conventional sedation paradigms should be altered by providing necessary analgesia, incorporating propofol or dexmedetomidine to reach arousal targets, and reducing benzodiazepine exposure.
fentanyl; propofol; dexmedetomidine; Behavioral Pain Scale; Richmond Agitation-Sedation Scale; Sedation-Agitation Scale; Confusion Assessment Method for the ICU
To compare the efficacy and safety of dexmedetomidine and fentanyl for sedation in mechanically ventilated premature neonates.
This was a retrospective, observational case-control study in a level III neonatal intensive care unit. Forty-eight premature neonates requiring mechanical ventilation were included. Patients received fentanyl (n=24) or dexmedetomidine (n=24) for pain or sedation. Each group also received fentanyl and lorazepam boluses as needed for agitation. The primary outcomes were efficacy and frequency of acute adverse events associated with each drug. Days on mechanical ventilation, stooling patterns, feeding tolerance, and neurologic outcomes were also evaluated.
There were no significant differences in baseline demographics between the dexmedetomidine and fentanyl patients. Patients in the dexmedetomidine group required less adjunctive sedation and had more days free of additional sedation in comparison to fentanyl (54.1% vs. 16.5%, p<0.0001). There were no differences in hemodynamic parameters between the 2 groups. Duration of mechanical ventilation was shorter in the dexmedetomidine group (14.4 vs. 28.4 days, p<0.001). Meconium passage (7.5 vs. 22.4 days, p<0.0002) and time from initiation to achievement of full enteral feeds (26.8 vs. 50.8 days, p<0.0001) were shorter in the dexmedetomidine group. Incidence of culture-positive sepsis was lower in the dexmedetomidine group (48% vs. 88%). The incidence of either severe intraventricular hemorrhage or periventricular leukomalacia was not statistically significantly reduced (2% vs. 7%).
Dexmedetomidine was safe and effective for sedation in the premature neonates included in this study. Prospective randomized-controlled trials are needed before routine use of dexmedetomidine can be recommended.
dexmedetomidine; fentanyl; mechanical ventilation; neonate; sedation
This prospective study evaluated the effects of continuous sedation using midazolam, with or without remifentanil, on postoperative nausea and vomiting (PONV) in patients undergoing myringoplasty.
Materials and Methods
Sixty patients undergoing myringoplasty were sedated with midazolam in the presence of remifentanil (group MR), or after saline injection instead of remifentanil (group M).
Three patients (10%) in group M complained of nausea; two vomited. Four patients (13%) in group MR complained of nausea and vomited within 24 h after surgery. Rescue drugs were given to the six patients who vomited. No significant difference was detected between the two groups regarding the incidence or severity of nausea, incidence of vomiting, or need for rescue drugs.
Midazolam-based continuous sedation can reduce PONV after myringoplasty. Compared with midazolam alone, midazolam with remifentanil produced no difference in the incidence or severity of nausea, incidence of vomiting, or need for rescue drugs.
Midazolam; myringoplasty; PONV; remifentanil
Sedation protocols are needed for neurointensive patients. The aim of this pilot study was to describe sedation practice at a neurointensive care unit and to assess the feasibility and efficacy of a new sedation protocol. The primary outcomes were a shift from sedation-based to analgesia-based sedation and improved pain management. The secondary outcomes were a reduction in unplanned extubations and duration of sedation.
This was a two-phase (before-after), prospective controlled study at a university-affiliated, 14-bed neurointensive care unit in Denmark. The sample included patients requiring mechanical ventilation for at least 48 hours treated with continuous sedative and analgesic infusions or both. During the observation phase the participants (n = 106) were sedated as usual (non-protocolized), and during the intervention phase the participants (n = 109) were managed according to a new sedation protocol.
Our study showed a shift toward analgo-sedation, suggesting feasibility of the protocol. We found a significant reduction in the use of propofol (P < .001) and midazolam (P = .001) and an increase in fentanyl (P < .001) and remifentanil (P = .003). Patients selected for daily sedation interruption woke up faster, and estimates of pain free patients increased from 56.8% to 82.7% (P < .001), suggesting efficacy of the protocol. The duration of sedation and unplanned extubations were unchanged.
Our pilot study showed feasibility and partial efficacy of our protocol. Some neurointensive patients might not benefit from protocolized practice. We recommend an interdisciplinary effort to target patients requiring less sedation, as issues of oversedation and inadequate pain management still need more attention.
Recent animal studies demonstrated immunosuppressive effects of opioid withdrawal resulting in a higher risk of infection. The aim of this study was to determine the impact of remifentanil discontinuation on intensive care unit (ICU)-acquired infection.
This was a prospective observational cohort study performed in a 30-bed medical and surgical university ICU, during a one-year period. All patients hospitalised in the ICU for more than 48 hours were eligible. Sedation was based on a written protocol including remifentanil with or without midazolam. Ramsay score was used to evaluate consciousness. The bedside nurse adjusted sedative infusion to obtain the target Ramsay score. Univariate and multivariate analyses were performed to determine risk factors for ICU-acquired infection.
Five hundred and eighty-seven consecutive patients were included in the study. A microbiologically confirmed ICU-acquired infection was diagnosed in 233 (39%) patients. Incidence rate of ICU-acquired infection was 38 per 1000 ICU-days. Ventilator-associated pneumonia was the most frequently diagnosed ICU-acquired infection (23% of study patients). Pseudomonas aeruginosa was the most frequently isolated microorganism (30%). Multivariate analysis identified remifentanil discontinuation (odds ratio (OR) = 2.53, 95% confidence interval (CI) = 1.28 to 4.99, P = 0.007), simplified acute physiology score II at ICU admission (1.01 per point, 95% CI = 1 to 1.03, P = 0.011), mechanical ventilation (4.49, 95% CI = 1.52 to 13.2, P = 0.006), tracheostomy (2.25, 95% CI = 1.13 to 4.48, P = 0.021), central venous catheter (2.9, 95% CI = 1.08 to 7.74, P = 0.033) and length of hospital stay (1.05 per day, 95% CI = 1.03 to 1.08, P < 0.001) as independent risk factors for ICU-acquired infection.
Remifentanil discontinuation is independently associated with ICU-acquired infection.
Dexmedetomidine is an α2-receptor agonist administered by continuous infusion in the intensive care unit (ICU) for sedation of critically ill patients who are undergoing mechanical ventilation following intubation. Relative to ICU patients receiving midazolam (a γ-aminobutyric acid agonist) for sedation, those receiving dexmedetomidine spent less time on ventilation, had fewer episodes of delirium, and had a lower incidence of tachycardia and hypertension.
To assess the economic impact, in a Canadian context, of dexmedetomidine, relative to midazolam, for sedation in the ICU.
This economic evaluation was based on a cost–consequences analysis, from the perspective of the Canadian health care system. The selected time horizon was an ICU stay (maximum 30 days). Clinical data were obtained from a previously published prospective, randomized, double-blind trial comparing dexmedetomidine and midazolam. This evaluation considered the costs of the medications, mechanical ventilation, and delirium episodes, as well as costs associated with adverse events requiring an intervention. All costs were adjusted to 2010 and are reported in Canadian dollars.
The average cost of the medication was higher for dexmedetomidine than midazolam ($1929.57 versus $180.10 per patient), but the average costs associated with mechanical ventilation and management of delirium were lower with dexmedetomidine than with midazolam ($2939 versus $4448 for ventilation; $2127 versus $3012 for delirium). The overall cost per patient was lower with dexmedetomidine than with midazolam ($7022 versus $7680). Deterministic sensitivity analysis confirmed the robustness of the difference.
The use of dexmedetomidine was, in most contexts, a more favourable strategy than the use of midazolam, in terms of clinical consequences and economic impact. Dexmedetomidine was less expensive than midazolam and was associated with lower occurrence of delirium and shorter duration of mechanical ventilation.
dexmedetomidine; sedation; intensive care unit; economic evaluation; dexmédétomidine; sédation; unité de soins intensifs; évaluation économique
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.
We performed a retrospective analysis of the use of morphine, midazolam and propofol in patients before and after tracheotomy.
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.
In our intensive care unit, sedation requirements were not further reduced after tracheotomy. Sedation requirements were already sharply declining before tracheotomy was performed.
Sedation and analgesia are provided by using different agents and techniques in different countries. The goal is to achieve early spontaneous breathing and to obtain an awake and cooperative pain-free patient. It was the aim of this study to conduct a survey of the agents and techniques used for analgesia and sedation in intensive care units in Germany.
A survey was sent by mail to 261 hospitals in Germany. The anesthesiologists running the intensive care unit were asked to fill in the structured questionnaire about their use of sedation and analgesia.
A total of 220 (84%) questionnaires were completed and returned. The RAMSAY sedation scale was used in 8% of the hospitals. A written policy was available in 21% of hospitals. For short-term sedation in most hospitals, propofol was used in combination with sufentanil or fentanyl. For long-term sedation, midazolam/fentanyl was preferred. Clonidine was a common part of up to two-thirds of the regimens. Epidural analgesia was used in up to 68%. Neuromuscular blocking agents were no longer used.
In contrast to the US 'Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult', our survey showed that in Germany different agents, and frequently neuroaxial techniques, were used.
In most extracorporeal membrane oxygenation (ECMO) centers patients are heavily sedated to prevent accidental decannulation and bleeding complications. In ventilated adults not on ECMO, daily sedation interruption protocols improve short- and long-term outcome. This study aims to evaluate safety and feasibility of sedation interruption following cannulation in neonates on ECMO.
Prospective observational study in 20 neonates (0.17–5.8 days of age) admitted for ECMO treatment. Midazolam (n = 20) and morphine (n = 18) infusions were discontinued within 30 min after cannulation. Pain and sedation were regularly assessed using COMFORT-B and visual analog scale (VAS) scores. Midazolam and/or morphine were restarted and titrated according to protocolized treatment algorithms.
Median (interquartile range, IQR) time without any sedatives was 10.3 h (5.0–24.1 h). Median interruption duration for midazolam was 16.5 h (6.6–29.6 h), and for morphine was 11.2 h (6.7–39.4 h). During this period no accidental extubations, decannulations or bleeding complications occurred.
This is the first study to show that interruption of sedatives and analgesics following cannulation in neonates on ECMO is safe and feasible. Interruption times are 2–3 times longer than reported for adult ICU patients not on ECMO. Further trials are needed to substantiate these findings and evaluate short- and long-term outcomes.
Neonate; Extracorporeal membrane oxygenation; Sedation; Daily interruption
Pain relief during labour is a topic of major interest in the Netherlands. Epidural analgesia is considered to be the most effective method of pain relief and recommended as first choice. However its uptake by pregnant women is limited compared to other western countries, partly as a result of non-availability due to logistic problems. Remifentanil, a synthetic opioid, is very suitable for patient controlled analgesia. Recent studies show that epidural analgesia is superior to remifentanil patient controlled analgesia in terms of pain intensity score; however there was no difference in satisfaction with pain relief between both treatments.
The proposed study is a multicentre randomized controlled study that assesses the cost-effectiveness of remifentanil patient controlled analgesia compared to epidural analgesia. We hypothesize that remifentanil patient controlled analgesia is as effective in improving pain appreciation scores as epidural analgesia, with lower costs and easier achievement of 24 hours availability of pain relief for women in labour and efficient pain relief for those with a contraindication for epidural analgesia.
Eligible women will be informed about the study and randomized before active labour has started. Women will be randomly allocated to a strategy based on epidural analgesia or on remifentanil patient controlled analgesia when they request pain relief during labour. Primary outcome is the pain appreciation score, i.e. satisfaction with pain relief.
Secondary outcome parameters are costs, patient satisfaction, pain scores (pain-intensity), mode of delivery and maternal and neonatal side effects.
The economic analysis will be performed from a short-term healthcare perspective. For both strategies the cost of perinatal care for mother and child, starting at the onset of labour and ending ten days after delivery, will be registered and compared.
This study, considering cost effectiveness of remifentanil as first choice analgesia versus epidural analgesia, could strongly improve the care for 180.000 women, giving birth in the Netherlands yearly by giving them access to pain relief during labour, 24 hours a day.
Trial registration number
Dutch Trial Register NTR2551, http://www.trialregister.nl
Analgesia; Labour; Remifentanil; Patient controlled analgesia; Epidural
Objectives—This study compared intranasal midazolam (INM) with a combination of intravenous ketamine and intravenous midazolam (IVKM) for sedation of children requiring minor procedures in the emergency department.
Method—A single blinded randomised clinical trial was conducted in the emergency department of a major urban paediatric hospital. Subjects requiring sedation for minor procedures were randomised to receive either INM (0.4 mg/kg) or intravenous ketamine (1 mg/kg) plus intravenous midazolam (0.1 mg/kg). Physiological variables and two independent measures of sedation (Sedation Score and Visual Analogue Sedation Scale) were recorded before sedation and at regular intervals during the procedure and recovery period. Times to adequate level of sedation and to discharge were compared.
Results—Fifty three patients were enrolled over a 10 month period. Sedation was sufficient to complete the procedures in all children receiving IVKM and in 24 of the 26 receiving INM. Onset of sedation was an average of 5.3 minutes quicker with IVKM than with INM (95%CI 3.2, 7.4 minutes, p<0.001). Children given INM were discharged an average of 19 minutes earlier than those given IVKM (95%CI 4, 33 minutes, p=0.02). Mean Sedation Scores and Visual Analogue Sedation Scale scores for the 30 minutes after drug administration were significantly better in children given IVKM compared with INM (2.4 and 1.8 versus 3.5 and 3.8, respectively). Both doctors and parents were more satisfied with sedation by intravenous ketamine and midazolam.
Conclusions—Intravenous ketamine plus midazolam used in an appropriate setting by experienced personnel provides an excellent means of achieving sedation suitable for most non-painful minor procedures for children in the emergency department. This combination is superior to INM in terms of speed of onset and consistency of effect. INM delivered via aerosol spray has a more variable effect but may still be adequate for the completion of many of these procedures.
This open label, multicentre study was conducted to assess the times to offset of the pharmacodynamic effects and the safety of remifentanil in patients with varying degrees of renal impairment requiring intensive care.
A total of 40 patients, who were aged 18 years or older and had normal/mildly impaired renal function (estimated creatinine clearance ≥ 50 ml/min; n = 10) or moderate/severe renal impairment (estimated creatinine clearance <50 ml/min; n = 30), were entered into the study. Remifentanil was infused for up to 72 hours (initial rate 6–9 μg/kg per hour), with propofol administered if required, to achieve a target Sedation–Agitation Scale score of 2–4, with no or mild pain.
There was no evidence of increased offset time with increased duration of exposure to remifentanil in either group. The time to offset of the effects of remifentanil (at 8, 24, 48 and 72 hours during scheduled down-titrations of the infusion) were more variable and were statistically significantly longer in the moderate/severe group than in the normal/mild group at 24 hours and 72 hours. These observed differences were not clinically significant (the difference in mean offset at 72 hours was only 16.5 min). Propofol consumption was lower with the remifentanil based technique than with hypnotic based sedative techniques. There were no statistically significant differences between the renal function groups in the incidence of adverse events, and no deaths were attributable to remifentanil use.
Remifentanil was well tolerated, and the offset of pharmacodynamic effects was not prolonged either as a result of renal dysfunction or prolonged infusion up to 72 hours.
analgesia based sedation; critical care; offset times; pharmacodynamics; remifentanil; renal function; safety
Adequate assessment and control of sedation play crucial roles in the proper performance of mechanical ventilation.
A total of 30 patients with various pulmonary diseases were prospectively enrolled. The study population was randomized into two groups. The sedation assessment group (SAG) received active protocol-based control of sedation, and in the empiric control group (ECG), the sedation levels were empirically adjusted. Subsequently, daily interruption of sedation (DIS) was conducted in the SAG.
In the SAG, the dose of midazolam was significantly reduced by control of sedation (day 1, 1.3±0.5 µg/kg/min; day 2, 0.9±0.4 µg/kg/min; p<0.01), and was significantly lower than the ECG on day 2 (p<0.01). Likewise, on day 2, sedation levels were significantly lower in the SAG than in the ECG. Significant relationship was found between Ramsay sedation scale and Richmond agitation-sedation scale (RASS; rs=-0.57), Ramsay Sedation Scale and Bispectral Index (BIS; rs=0.77), and RASS and BIS (rs=-0.79). In 10 patients, who didn't require re-sedation after DIS, BIS showed the earliest and most significant changes among the sedation scales. Ventilatory parameters showed significant but less prominent changes, and hemodynamic parameters didn't show significant changes. No seriously adverse events ensued after the implementation of DIS.
Active assessment and control of sedation significantly reduced the dosage of sedatives in patients receiving mechanical ventilation. DIS, conducted in limited cases, suggested its potential efficacy and tolerability.
Conscious Sedation; Ventilators, Mechanical; Hypnotics and Sedatives; Consciousness Monitors
Even with an adequate pain assessment, critically ill patients under sedation experience pain during procedures in the intensive care unit (ICU). We evaluated the effects of adjunctive administration of Remifentanil, a short-acting drug, in deeply sedated patient on variation of Bispectral Index (BIS) during a fiberoptic bronchoscopy.
A prospective, randomized, blinded, placebo-controlled study was conducted in 18-bed ICU. Patients needing a tracheal fibroscopy under deep sedation (midazolam (0.1 mg/kg per hour) fentanyl (4 μg/kg per hour)) and neuromuscular blocking (atracurium 0.5 mg/kg) were included in the study. A continuous monitoring of BIS, arterial pressure, and heart rate were realized before, during, and after the fiberoptic exam. An adjunctive continuous placebo or Remifentanil infusion was started just before the fiberoptic exam with a target effect-site concentration of 4 ng/ml using a Base Primea pump.
Mean arterial pressure and heart rates were comparable between the placebo and Remifentanil groups at all times of the procedure. We did not observe differences in the variation of BIS values between the two groups during procedure. We described no change in BIS values relative to the placebo group in this population.
In deeply sedated and paralyzed patients, receiving analgesic support based on a scale score an additional administration of short-acting analgesic drug, such as Remifentanil, seems not to be necessary for acute pain control.
Pain; Intensive care; Bispectral index; Remifentanil