Anesth Analg 2003;96:834-838
© 2003 International Anesthesia Research Society
CRITICAL CARE AND TRAUMA
Sequential Use of Midazolam and Propofol for Long-Term Sedation in Postoperative Mechanically Ventilated Patients
Masataka Saito, MD*,
Yoshiaki Terao, MD*,
Makoto Fukusaki, MD
,
Tetsuji Makita, MD
,
Osamu Shibata, MD*, and
Koji Sumikawa, MD*
*Department of Anesthesiology and
Intensive Care Unit, Nagasaki University School of Medicine, Nagasaki, Japan; and
Department of Anesthesia, Nagasaki Rosai Hospital, Sasebo, Japan
Address correspondence and reprint requests to Masataka Saito, MD, Department of Anesthesiology, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. Address e-mail to parsifal{at}net.nagasaki-u.ac.jp
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Abstract
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Acute withdrawal syndromes, including agitation and a long weaning time, are common adverse effects after long-term sedation with midazolam. We performed this study to determine whether the sequential use of midazolam and propofol could reduce adverse effects as compared with midazolam alone. We studied 26 patients receiving mechanical ventilation for three or more days after surgery. Patients were randomly assigned to two groups. In Group M, patients were sedated with midazolam alone. In Group M-P, midazolam was switched to propofol approximately 24 h before the expected stopping of sedation. The level of sedation was maintained at 4 or 5 on the Ramsay sedation scale. The sedation agitation scale was evaluated for 24 h after extubation. The recovery time from stopping of sedation to extubation was significantly shorter in Group M-P (1.3 ± 0.4 h) compared with Group M (4.0 ± 2.4 h). The incidence of agitation in Group M-P (8%) was significantly less frequent than that in Group M (54%). The results indicate that sequential use of midazolam and propofol for long-term sedation could reduce the incidence of agitation compared with midazolam alone.
IMPLICATIONS: Our study indicates that sequential use of midazolam and propofol could reduce the incidence of agitation compared with midazolam alone.
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Introduction
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Postoperative patients who require mechanical ventilation often receive sedation to relieve anxiety, to tolerate the endotracheal tube, to facilitate nursing care, and to reduce the oxygen consumption associated with agitation and dyssynchrony with the mechanical ventilator. Propofol and midazolam are often used for sedation in mechanically ventilated patients. Propofol has several advantageous effects, such as a lack of accumulation and a short recovery time. Favorable characteristics of midazolam are mild cardiovascular depression and a lower risk of bloodstream infection and hypertriglyceridemia (1). However, both sedatives have adverse effects in long-term sedation. Midazolam causes acute withdrawal syndrome consisting of extreme agitation, disorientation, paranoid delusion, and hallucinations (2) and prolonged recovery from drug accumulation. Propofol causes hypertriglyceridemia and cardiovascular depression and is expensive (1).
Although Carrasco et al. (3) demonstrated that synergistic sedation with midazolam and propofol is effective and safe, compared with one drug, there is no study evaluating the efficacy of sequential use of midazolam and propofol for long-term sedation. This study was performed to determine whether sequential use of midazolam and propofol could reduce adverse effects, compared with midazolam alone, for long-term sedation.
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Methods
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This study was approved by the Ethics Committee of the Nagasaki University School of Medicine and was conducted in the intensive care unit (ICU) of Nagasaki University Hospital from July 1999 to November 2001. Informed, written consent was obtained from each patient. We studied 35 patients (32 men and 3 women). The study’s inclusion criteria included the following signs: (a) transthoracic esophageal replacement surgery or resection and reconstruction of malignant tumors of the head and neck; (b) radical resection of cancer; (c) ASA physical status I or II; and (d) age older than 20 yr. In our institution, prolonged mechanical ventilation is a routine practice in these patients. Twenty patients had total esophageal replacement surgery: five had tongue tumor resection and reconstruction; five had maxillary tumor resection and reconstruction; and five had other oral cavity tumor resection and reconstruction. The study’s exclusion criteria included the following signs: (a) a fraction of inspired oxygen (FIO2) of >0.6; (b) air leaks from the chest tube; (c) body temperature >39°C; (d) prolongation of the sedative period with propofol; and (e) shortening of the sedative period with midazolam. In those cases in which it was considered clinically indicated, reoperation, early extubation, or prolongation of extubation was performed.
All patients received conventional intensive care therapy according to clinical requirements. The attending physicians adjusted the vasopressor drug (dopamine) to maintain an adequate mean arterial blood pressure (MAP). The attending physicians adjusted the ventilator settings to maintain clinically appropriate gas exchange. Hemodynamic monitoring consisted of continuous recordings of electrocardiograms, heart rate, arterial blood pressure, and central venous pressure.
Patients were prospectively randomized to receive either midazolam (Group M; n = 18) or midazolam and propofol sequentially (Group M-P; n = 17). All patients received analgesia with buprenorphine at a fixed dose of 0.625 µg · kg-1 · h-1 continuously and received additional bolus doses (0.002 mg/kg) during potentially painful procedures (4,5). Midazolam was used for the induction and maintenance of IV sedation after admission to the ICU. The initial dose was 0.04 mg · kg-1 · h-1, and this was adjusted to achieve a desired level of sedation—4 or 5 on the Ramsay sedation scale—every 4 h. In those cases in which it was considered clinically indicated, a bolus of 0.1 mg/kg was administered. The dose was adjusted by varying it by a 10% increase or decrease to maintain an adequate level of sedation. The depth of sedation was determined by the nurses every 4 h. In addition to the judgment on the depth of sedation, MAP and heart rate were recorded simultaneously. In Group M, patients were sedated with midazolam throughout the sedative period. In Group M-P, midazolam was switched to propofol approximately 24 h before the expected stopping of sedation. In Group M-P, the initial dose of propofol was 1 mg · kg-1 · h-1 and was adjusted by the same procedure as midazolam. The bolus dose of propofol was 1 mg/kg, different from midazolam. Infusion of the sedative drug was discontinued when patients were judged to be ready for extubation. Patients were tracheally extubated when they recovered a normal level of consciousness and met the following criteria: PaO2/FIO2 ratio of >200, respiratory rate of 10–20 breaths/min, and vital capacity of >10 mL/kg. The recovery time from stopping of sedation until extubation was recorded.
Patients were prospectively monitored by the nurses by using the Sedation Agitation Scale (SAS) during the 24 h after extubation. The SAS was developed to quantify and compare the degree of agitation and sedation (6), and the classification of score was as follows: +3, immediate threat to safety; +2, dangerously agitated; +1, agitated; 0, calm and cooperative; -1, oversedated; -2, very oversedated; and -3, unarousable. A diagnosis of agitation was determined by the criterion SAS 
1. A bolus of 5 mg of haloperidol was given when the patients showed SAS scores of 1. Serum triglyceride concentration was measured at admission and at the stopping of sedation.
Results are expressed as mean ± SD. Intergroup and intragroup statistical analyses were performed with the Mann-Whitney U-test and Wilcoxon’s test, respectively. Dichotomous variables were analyzed with Fisher’s exact probability test. P < 0.05 was considered statistically significant.
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Results
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Thirty-five consecutive patients were entered in the study, with 18 randomized to Group M and 17 randomized to Group M-P. Twenty-six (13 in Group M and 13 in Group M-P) of these 35 were eligible for inclusion in the study. Reasons for exclusion included an FIO2 of >0.6 and body temperature >39°C (one in Group M); air leaks (one in Group M); shortening of the sedative period with midazolam because of reoperation (one in Group M and one in Group M-P) or early extubation (two in Group M and two in Group M-P); and prolongation of the sedative period with propofol because of worsening of the general condition (one in Group M-P).
Thirteen patients received midazolam as a sole drug (Group M), and 13 patients received midazolam and propofol sequentially (Group M-P). There was no significant difference in age, sex, weight, body surface area, or duration of stay in ICU between the two groups (Table 1).
The number of supplementary boluses of buprenorphine was similar between the two groups. No statistically significant differences were detected regarding the duration of sedation or intubation between the groups. There were no significant differences in the duration of sedation with midazolam, the mean maintenance doses of midazolam, or the total dose of midazolam between the groups. The duration of sedation with propofol was 24.3 ± 0.8 h, and the mean maintenance dose of propofol was 1.5 ± 0.7 mg · kg-1 · h-1 in Group M-P (Table 2).
During the last 24 h of the sedative period (the period of propofol), 6 assessments of sedation per patient, for a total of 72 assessments of sedation, were made in both groups. The efficacy of the percentage of assessment was similar between the groups. The number of supplementary boluses of sedative was similar between groups. The number of infusion rate readjustments was similar between groups (Table 3).
The recovery time was shorter in Group M-P than in Group M. Seven of 13 patients in Group M were diagnosed with agitation, compared with 1 of 13 patients in Group M-P (Table 4). There was no significant change in serum triglyceride by propofol infusion in Group M-P (from 111 ± 37 mg/dL to 107 ± 51 mg/dL) or in Group M (from 90 ± 41 mg/dL to 96 ± 39 mg/dL). Seven patients in Group M and one patient in Group M-P were administered haloperidol because of agitation.
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Discussion
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These results show that the sequential use of midazolam and propofol for long-term sedation showed a less frequent incidence of agitation and a faster recovery compared with midazolam alone, and no patients showed hypertriglyceridemia. Although the ideal sedative for ICU use would have a rapid onset, short duration of action, lack of accumulation, ease of titration and administration, and no cardiovascular and respiratory depression (7), no ideal sedative is available. Midazolam and propofol are most frequently used for sedation in the mechanically ventilated patient (8). Although there are many studies demonstrating that these two drugs are equally safe and effective for short-term sedation, each drug has some adverse effects when used for long-term sedation (9,10).
Hantson et al. (11) reported a withdrawal syndrome of midazolam. Propofol withdrawal has not been well described but appears to resemble benzodiazepine withdrawal (12). Although withdrawal syndrome can occur in patients with alcoholism or patients accustomed to taking anxiolytics or hypnotics, this study population did not include these patients. Although the reason for the decreased incidence of agitation in Group M-P is not clear, the following explanation is possible: withdrawal syndrome could occur in mechanically ventilated patients who received a large dose of midazolam for an extended duration (longer than three days) (13). In this study, there was no significant difference in the duration of infusion, the maintenance dose, or the total dose of midazolam between groups. It has been reported that withdrawal syndrome is more severe with short-acting benzodiazepines than long-acting sedatives and that the rapid decline of plasma concentration would cause withdrawal syndrome (14). Because midazolam is a water-soluble benzodiazepine with a rapid onset and a short duration of action, withdrawal syndrome, including agitation, could occur immediately after its discontinuation. These results indicate that propofol infusion for 24 hours would mask the agitation associated with discontinuation of midazolam infusion. Haloperidol could act to attenuate the signs or symptoms of acute withdrawal syndrome (15).
Agitation could occur in myocardial ischemia or cerebral ischemia and could result in potentially dangerous outcomes, such as self-extubation or the removal of other medical devices. The cost of agitation in terms of procedures to remedy these removals may be several hundred dollars per incident. Agitated patients are usually unable to contribute to diagnostic assessments or therapeutic procedures. The adequate control of agitation with sedation and analgesic therapy is an important goal of ICU care (16).
Because the Ramsay sedation scale could evaluate only the state of sedation, we used the SAS to evaluate agitation after extubation. Riker et al. (6) developed the SAS to quantify and compare the degree of agitation and sedation and confirmed the interrater reliability and construct validity of the revised SAS to apply to ICU patients (17).
In this study, we compared the recovery time, defined as the time between the stopping of sedation and tracheal extubation. The recovery time in Group M-P was shorter than that in Group M. However, the difference was, on the average, three hours, and there was no significant difference in the total sedation time, total intubation time, or ICU stay period. Thus, with respect to the shorting of recovery time, the sequential use of midazolam and propofol seems not to have significant advantage.
Propofol has been used for sedation because of its short elimination half-life and lack of accumulation (18). Nevertheless, hypertriglyceridemia limits the general use of propofol for prolonged sedation (longer than three days) (4,18). Because we limited the propofol infusion to approximately 24 hours, no patient had hypertriglyceridemia in Group M-P. Although cardiovascular depression is one of the adverse effects in propofol sedation, hypotension did not appear during propofol infusion because we switched midazolam to propofol without a loading dose.
In this study, there was no difference in the percentage of adequate level of sedation, the number of bolus infusions, or changes of infusion rate during the period of propofol, in accordance with the findings of previous studies with either midazolam or propofol (5,10). In our study population, sequential use of midazolam and propofol was effective for sedation.
In this study, we applied relatively long-term mechanical ventilation. The reason for this practice is as follows. Bartels et al. (19) conducted a prospective and randomized trial of prolonged ventilation (>24 hours) after esophagectomy as compared with early extubation (within 6 hours after surgery) and reported that after transthoracic esophagectomy, hospital lethality increased after early extubation. Extended transthoracic esophagectomy with three-field lymphadenectomy may result in local injury to the trachea, recurrent nerves, and bronchial artery and may impair respiratory function and cough reflex, leading to pneumonia and atelectasis. Therefore, long-term postoperative mechanical ventilation has been routinely performed to prevent such complications at several institutes in Japan (20). Because soft-tissue edema and hemorrhage of the operative upper airway area for the first 48 hours after oral and maxillofacial (OMF) surgery can cause respiratory depression (21), delayed tracheal extubation is recommended in OMF surgery (22). Although surgical tracheostomy after OMF surgery guarantees airway patency, it is accompanied by serious complications in 5% of cases, and the procedure has a mortality as frequent as 2% compared with the endotracheal tube (23).
Admittedly, because the study was not blinded, a theoretical bias by the nurses might have been present. However, since there were more than 24 nurses who could be randomly involved in the care of each patient during the stay in the ICU, the likelihood of bias was extremely remote.
In conclusion, these results indicate that compared with sedation with midazolam alone, the sequential use of midazolam and propofol reduces the incidence of agitation after the stopping of sedation and still maintains the quality of sedation. Thus, the sequential use of midazolam and propofol is a useful method for long-term sedation.
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Footnotes
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Presented in part at the annual meeting of the American Society of Anesthesiologists, New Orleans, LA, October 13–17, 2001.
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References
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Accepted for publication November 7, 2002.
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Abstract
Introduction
