The utility of bispectral index monitoring for sedated patients treated with low-dose remifentanil
The aim of the present study was to determine the effect of low-dose remifentanil on the monitoring quality of the Bispectral index for mechanically ventilated patients. Twelve patients who underwent elective surgery and required mechanical ventilation post-operatively were enrolled in this study with written informed consent. Eligible patients were divided into two groups. Patients in the remifentanil group received low-dose remifentanil (0.05–0.125 μg/kg/min) and propofol (1–3 mg/kg/h). Patients in the control group received propofol (1–3 mg/kg/h). Levels of sedation were evaluated by both the Richmond Agitation Sedation Scale (RASS) and BIS monitor (A2000-XP, version 4.0, Aspect Medical Systems, Newton, USA). Monitoring quality was assessed by a correlation between RASS and BIS values. These values were assessed by single regression analysis and a P value of <0.05 was considered significant. There was a significant correlation between RASS and BIS values (P = 3 × 10−12, R2 = 0.67) in the remifentanil group, but not in the control group (P = 0.50, R2 = 0.057). The administration of low-dose remifentanil makes BIS a more precise tool for sedated patients under mechanical ventilation in the ICU.
KeywordsBispectral indexRemifentanilRichmond agitation sedation scaleMonitoring quality
Bispectral index (BIS) is one of the most popular objective methods for assessment of sedation in the operating room, and its high efficacy has been verified in many studies [1–5]. However, noise contamination decreases monitoring quality and the validity of BIS in the intensive care unit (ICU) has been controversial [6–10]. As a result, the grade of recommendation for BIS was C by the clinical practice guidelines of the Society of Critical Care Medicine (SCCM) . On the other hand, the Richmond Agitation Sedation Scale (RASS) has high reliability and validity in adult ICU patients . However, this scoring system is a subjective method and may cause unnecessary patient behavior, agitation, or arousals .
The advantage of sedation using remifentanil has been reported in many studies [13–16] and it is used worldwide for sedation in the ICU. However, randomized studies have never tried to examine the relationship between RASS and BIS values in patients sedated with remifentanil.
Therefore, the aim of the present study was to examine whether the administration of low-dose remifentanil improved the monitoring quality of BIS during mechanical ventilation.
2 Materials and methods
A randomized, open-label, single-center, and prospective observation study was conducted in accordance with good clinical practice and the guidelines set out in the Declaration of Helsinki. With the approval of the local Ethics Committee, written informed consent was obtained from all patients.
Patients who had undergone elective surgery and received overnight mechanical ventilation were enrolled in this study. Patients were excluded if one of the following conditions existed: use of neuromuscular blocking agents in the ICU or preexisting central nervous system impairments.
Eligible patients were randomly assigned to two treatment groups; a remifentanil group and a control group. Patients in the remifentanil group (n = 6) were sedated with remifentanil and propofol. Patients in the control group (n = 6) were sedated with propofol. A computer generated random list was used for randomization.
All patients underwent balanced anesthesia with sevoflurane, propofol, remifentanil, fentanyl, and rocuronium. Epidural anesthesia was performed if necessary.
The level of sedation was assessed every 2 h by ICU nurses using RASS and BIS (A2000-XP, version 4.0, Aspect Medical Systems, Newton, USA) until weaning started. The smoothing rate of BIS was 30 s and no artifact removal methods were introduced. The number of ICU nurses was 30 and all were trained to record only the last BIS value of each observation period and then immediately record RASS scores.
2.1 Treatment protocols
2.1.1 Remifentanil group
On arrival in the ICU, both remifentanil and propofol infusion was continued at an initial rate at 0.05–0.125 μg/kg/min and 1–3 mg/kg/h, respectively. Remifentanil was increased by 0.025 μg/kg/min every 5 min depending on clinical symptoms up to a maximum of 0.2 μg/kg/min. If an adequate level of sedation was not achieved with the maximum dose of remifentanil, the patient received a bolus dose of propofol (0.3 mg/kg), the infusion rate of which was increased up to a maximum of 3 mg/kg/h. In the case of excessive sedation, the propofol infusion rate was reduced first. When weaning was started, both remifentanil and propofol infusions were stopped and patients received a bolus administration of fentanyl (1–2 μg/kg).
2.1.2 Control group
Just before arriving in the ICU, patients received a bolus administration of fentanyl 1–2 μg/kg and remifentanil infusion was stopped. Propofol infusion was continued at an initial rate of 1–3 mg/kg/h. In case of insufficient sedation, additional bolus doses of propofol (0.3 mg/kg) were given and the propofol infusion rate was increased up to a maximum of 3 mg/kg/h. When weaning was started, propofol infusion stopped.
2.1.3 Ventilation protocols
The mode of mechanical ventilation was synchronized intermittent mandatory ventilation (SIMV) in all patients: tidal volume; 6–8 ml/kg, respiratory rate; 10–20/min, positive end expiratory pressure (PEEP); 5 cm H2O, and pressure support (PS); 5 cm H2O, FIO2; 0.4–0.6. When weaning was started, the mode of mechanical ventilation was changed to continuous positive airway pressure with PS: PEEP; 5 cm H2O, and PS; 5 cm H2O.
2.1.4 Weaning, extubation protocols
The weaning process was started on the morning after the day of the operation if no surgical complication was anticipated and if there were no sign of respiratory or hemodynamic impairments or acute organ insufficiency. For treatment of pain after extubation, both groups received fentanyl (a bolus of 1–2 μg/kg) and/or other analgesics at the investigator’s discretion. Extubation was performed if the following conditions were achieved; tidal volume > 4 ml/kg, respiratory rate 10–25/min, P/F ratio > 200, and PaCO2 < 55 mmHg, and patients had no hemodynamic instability and were able to follow commands.
2.1.5 Adverse events
Any adverse events were recorded until discharge from the ICU such as muscle rigidity, shivering, pain, bradycardia, hypotension, or respiratory insufficiency.
2.2 Statistical analyses
The relationship between RASS and BIS values were assessed by single regression analysis. P values of <0.05 were considered significant.
The mean mechanical ventilation time was 8 h in our ICU. If values of α < 0.05, β < 0.05 were considered significant and the correlation coefficient was 0.7, at least 20 data sets were required in each group. Because at least 4 data sets in each patient were expected to be obtained, at least 5 patients were needed in each group. Twelve patients were then recruited considering exclusion.
Pseudoaneurysm in abdominal aorta
Pseudoaneurysm in right colic artery
Mean ± SD
66 ± 10
164 ± 11
55 ± 14
20.5 ± 4.8
Mean ± SD
65 ± 17
168 ± 7
50 ± 16
17.6 ± 4.0
Sedatives and analgesics
Postoperative epidural analgesia
0.05 → 0.1
2.0 → 1.4
1.5 → 0.9
1.8 → 2.8
1.9 → 1.4
1.7 → 1.0
The present study indicates that the correlation coefficient between RASS and BIS values increased in sedated patients treated with remifentanil. This finding suggested that the administration of low-dose remifentanil improved the monitoring quality of BIS during mechanical ventilation.
No randomized studies have ever tried to examine the relationship between RASS and BIS values on mechanically ventilated patients who were sedated with remifentanil in the ICU. In a non-randomized study, Haenggi et al.  demonstrated that BIS was slightly more accurate than Entropy or EEG measures, resulting in a high prediction probability regarding the relationship between RASS and BIS values (0.85). The same result was obtained in the present study. However, the present study is the first randomized study that examined the reliability and validity of BIS on patients sedated with remifentanil during mechanical ventilation in the ICU.
Among several assessment scales, there is sufficient evidence to show that RASS has high reliability and validity in adult ICU patients . However, this scoring system is subjective and may cause unnecessary patient behavior such as agitation and/or arousals . On the other hand, BIS is objective and no stimuli is necessary to evaluate sedation levels. As an objective assessment scale, BIS would be desirable in the ICU.
The use of remifentanil diminishes spontaneous breathing. Even though the remifentanil administration rate is 0.05 μg/kg/min, spontaneous breathing is suppressed and apnea occurs in approximately half of patients sedated with propofol and remifentanil . The combination of diaphragmatic inactivity and mechanical ventilation for prolonged periods (more than 18 h) is associated with atrophy of myofibers in the diaphragm . Preserving spontaneous breathing attenuates ventilator-induced diaphragmatic atrophy . Thus, administration of remifentanil may not be effective in patients who have chronic respiratory insufficiency. On the other hand, adequate sedation contributes to the decreased incidence of unnecessary arousals and agitation in patients, indicating a time reduction in the patients’ care provided by ICU nurses . Therefore, treatment with remifentanil may be suitable only for patients who do not have chronic respiratory insufficiency and receive overnight ventilation under BIS monitoring.
There are several limitations in the present study because it is a preliminary small study on the monitoring quality of BIS in the ICU. First, electromyogram (EMG) data was not obtained because the recording data should be based on actual clinical practice and, therefore, should be simple. Improvements in the quality of BIS monitoring may be brought about by decreases in noise contamination such as EMG . EMG data may be important and can be used with BIS values because Ranna et al.  reported a high correlation between BIS and EMG (R2 = 0.88). Improvements in the monitoring quality of BIS caused by remifentanil can be elucidated when the correlation between RASS and BIS values are shown. Second, the number of patients enrolled was small (n = 12). Therefore, information regarding adverse events was not enough to evaluate the safe use and cost effectiveness of remifentanil in the ICU. Among the reported adverse events, muscle rigidity and shivering may have been observed more if a larger number of patients were enrolled. Muscle rigidity and shivering cause noise contamination, which decreases the reliability of BIS monitoring quality. However, muscle rigidity and shivering were not reported in previous studies using low-dose remifentanil (<0.2 μg/kg/min) in the ICU [14–16]. The infusion rate was lower (0.05–0.125 μg/kg/min) in the protocol of the present study, so muscle rigidity and shivering should not have occurred. Although remifentanil is considerably more expensive than fentanyl, Muellejans et al.  showed that the administration of remifentanil saved personnel costs during periods of ICU stay because of a shorter weaning time, leading to earlier extubation and an earlier discharge from the ICU. They concluded that administration of remifentanil may even lead to overall reductions in costs during periods of hospitalization, depending on the dosing algorithm. In the present study, the number of patients enrolled was small; therefore, it was difficult to confirm whether sedation with remifentanil saved medical costs over sedation without remifentanil. However, the dose of remifentanil in the present study was much lower (0.05–0.125 μg/kg/min) than previous studies (0.7–1.0 μg/kg/min) . Third, in spite of computer randomization, there were biases between the two groups in gender and diagnosis because of the small size of the study.
In conclusion, this preliminary study suggests that BIS monitoring to assess sedation levels in the ICU is available in patients treated with low-dose remifentanil. However, a large-scale study will be required to confirm the value of BIS monitoring for patients with low-dose remifentanil.
Conflict of interest