The Efficacy, Side Effects, and Recovery Characteristics of Dexmedetomidine Versus Propofol When Used for Intraoperative Sedation

Abstract

We evaluated the cardio-respiratory effects of equi-sedative doses of dexmedetomidine and propofol for intraoperative sedation. Secondary comparison end points were time to achieve and terminate sedation and postoperative analgesia and psychomotor performance. Forty patients scheduled for elective surgery provided informed consent and were randomized equally to receive either dexmedetomidine (1 μg/kg initial loading dose for 10 min; maintenance, 0.4–0.7 μg · kg⁻¹ · h⁻¹) or propofol (75 μg · kg⁻¹ · min⁻¹ × 10 min; maintenance, 12.5–75 μg · kg⁻¹ · min⁻¹). Hemodynamic variables (heart rate and mean arterial blood pressure), sedation (visual analog scale and Observer Assessment of Alertness/Sedation), bispectral index score of sedation, ventilation (respiratory rate, O₂ sat, and ETco₂), psychomotor performance (digital symbol substitution test), and pain (visual analog scale) were determined during surgery and up to 95 min after surgery. Intraoperative sedation levels were targeted to achieve a bispectral index score of 70–80. Patient demographics, ASA class, surgical procedure, and baseline cardio-respiratory variables were similar between groups. Sedation was achieved more rapidly with propofol but was similar between groups 25 min after initiating infusions. The average infusion rate for dexmedetomidine was 0.7 μg · kg⁻¹ · h⁻¹ and 38 μg · kg⁻¹ · min⁻¹ for propofol. There were no differences between groups in psychomotor performance and respiratory rate during recovery. The previous use of dexmedetomidine resulted in more sedation, lower blood pressure, and improved analgesia (less morphine use) in recovery.

The α₂-receptor agonist dexmedetomidine has potent sedative properties ^(1,2) and has received Food and Drug Administration approval for use in the intensive care unit for sedation. In addition, dexmedetomidine has analgesia-sparing properties ^(1,3–7). At therapeutic doses, dexmedetomidine is not associated with respiratory depression despite oftentimes profound levels of sedation ^(1,8). Because of these properties (sedation, analgesia, and respiratory-sparing), dexmedetomidine might prove useful in (or outside) the operating room (OR) for sedation. However, it is unknown if the autonomic effects of dexmedetomidine of decreasing sympathetic outflow ^(1,9,10) might result in untoward hemodynamic effects when used for intraoperative sedation. Thus, the purpose of this study was to evaluate cardio-respiratory end points at equi-sedative doses of dexmedetomidine and propofol in the OR. Secondary end points for comparison were time to achieve sedation onset and offset, postoperative analgesia requirements, and psychomotor test performance. These were evaluated in 40 patients scheduled for elective surgical procedures under regional or monitored anesthesia care (MAC).

Methods

After IRB approval, informed consent was obtained from 40 patients scheduled for elective surgery using regional anesthesia and MAC and who met enrollment criteria. An additional five patients were initially enrolled to determine optimal dosing schedules for dexmedetomidine. All patients were adult, 18 yr of age or older, ASA physical status I through III, scheduled for elective procedures associated with postoperative pain, and scheduled for at least a 23-h stay in the hospital. Inclusion criteria included normal renal function and no chronic use of medical therapy that might influence the outcome of the study (such as narcotics). Exclusion criteria included second or third degree heart block and any patient receiving an experimental drug, including dexmedetomidine or other α₂-agonists, within 28 days before scheduled surgery. Patients with a current history of psychiatric disorder or presently on psychotropic medications that, in the judgement of the investigator, might increase the likelihood that the patient would be uncooperative during or after the procedure were excluded. Patients with an ejection fraction of <30%, a history of sleep apnea, or patients with a body weight more than 50% larger than the ideal body weight also were excluded.

Each patient was scheduled for surgical procedures taking place after regional anesthetic blockade with an epidural, spinal, or a peripheral nerve block. In the preoperative holding area, before the start of the surgical procedure, patients were instructed on the proper use of the visual analog scale (VAS) and performed a digit symbol substitution test (DSST) ⁽¹¹⁾. Using a 100-mm VAS, the patients rated their pain, alertness, and nausea. An independent observer rated the alertness of the patient using the Observer’s Assessment of Alertness/Sedation scale ⁽¹²⁾. After preliminary testing/assessments, patients were given 0.7 μg/kg of fentanyl and 0.009 mg/kg of midazolam for sedation and transported to the OR.

After establishing an anesthetic level, a nasal cannula was applied and supplemental oxygen was given throughout the procedure at 2 L/min of fresh gas flow. ETco₂ (infrared spectroscopy) was sampled from one port of the cannula. Standard ASA monitors were used throughout the surgery with cardio-respiratory end points documented at 5-min intervals. Patients were randomized 1:1 to dexmedetomidine (an initial loading dose of 1 μg/kg given for a 10-min period followed by 0.4 μg · kg⁻¹ · h⁻¹) or propofol (75 μg · kg⁻¹ · min⁻¹) until sedation was achieved based on a bispectral index score (BIS) of 70–80. The dexmedetomidine infusion could be increased to a maximum of 1 μg · kg⁻¹ · h⁻¹. The propofol could be titrated as required to achieve the target BIS. On achieving the targeted BIS, surgery was begun, and infusion doses were adjusted to maintain the BIS between 70 and 80, or an Observer’s Assessment of Alertness/Sedation <3. Assessment of sedation with a VAS was performed every 15 min until the end of surgery, at which point the sedation infusions were discontinued.

In the recovery room, sedation assessments and a postanesthesia recovery score (0–10) were recorded at minute 4.5 and 7.5 into the recovery and then every 10 min thereafter for 95 min. The DSST was repeated at 15 and 45 min into recovery. Pain was treated with IV morphine as required. Morphine therapy was titrated per standard postanesthesia care unit (PACU) criteria by a nurse who was blinded to the experimental treatment. A 24-h follow-up phone call was made to assess patient satisfaction with the sedation for their surgical procedure.

Repeated-measures analysis of variance was used to compare continuous variables. Post hoc testing was performed with Scheffé’s F test. Discrete variables were analyzed with χ². P values <0.05 were considered significant. This study was significantly powered to detect a 10% difference in the intraoperative blood pressure or heart rate (HR) with an α of 0.05 and a β of 0.20.

Results

There were no differences between groups in patient characteristics (averages, 62 yr, 174 cm, and 92 kg), ASA classification ⁽²⁾, or cardio-respiratory variables at baseline (mean arterial blood pressure [MAP], 101 mm Hg; HR, 78 bpm; respiratory rate, 17 breaths/min; Spo₂, 97%). Medical histories between groups were not different (dexmedetomidine:propofol, hypertension, 13:11; coronary artery disease, 1:2; gastroesophageal reflux, 6:6; diabetes, 3:5; chronic obstructive pulmonary disease, 3:2; smoking, 6:6; abnormal chest radiograph, 5:7; abnormal electrocardiogram, 8:7). In addition, there was no difference between treatment groups in the performance of the DSST at the presedation baseline (average, 34 correct substitutions in 90 s).

All cardiovascular and sedation scores were changed from presurgery baseline during the intraoperative and recovery periods (Figs. 1, 2, 4, and 5). In contrast, respiratory end points were not changed at any time point from presurgery to PACU discharge. The performance on the DSST at 15 min into the recovery was slightly and significantly decreased from baseline in both treatment groups. This effect had resolved at the 45-min test period despite increased sedation in the Dexmedetomidine-Treated group (Fig. 3).

Figure 1: Targeted sedation during the intraoperative period. Objective (bispectral index score [BIS]) and subjective (Observer Assessment of Alertness/Sedation [OAA/S]) measures of sedation were more rapidly achieved during the intraoperative period when using propofol. *Difference over time compared with baseline values (P < 0.05); †Difference between dexmedetomidine and propofol; ¥Significant interaction (different response between drugs over time).

Figure 2: Cardio-respiratory variables during the intraoperative period. Respiratory rate was maintained at baseline levels throughout surgery in both groups. Heart rate (HR) decreased from baseline similarly for both groups. Immediately and throughout surgery, propofol sedation was associated with lower blood pressures than similarly sedated patients receiving dexmedetomidine. *Difference over time compared with baseline values (P < 0.05); †Difference between dexmedetomidine and propofol.

Figure 4: Pain and sedation scores from the pre- and postoperative period. Visual analog scale for pain (VASpain) was taken in the holding area and at fixed intervals throughout the recovery period. Initially, on entering the recovery room, there was no pain in either treatment group because of the unresolved regional anesthetic that was given for the surgical procedure. Thereafter, pain scores were significantly lower in the group that had received dexmedetomidine during the surgical procedure. Both the Observer Assessment of Alertness/Sedation (OAA/S) and the VAS sedation indicated a significantly greater degree of sedation with the use of dexmedetomidine. *Difference over time compared with baseline values (P < 0.05); †Difference between dexmedetomidine and propofol.

Figure 5: Cardio-respiratory variables from the pre- and postoperative period. Respiratory rate was unchanged from the presurgery rate at all recovery time points. Postoperative heart rates (HRs) were lower in the recovery period but did not differ between groups. Mean arterial blood pressure (MAP) also was lower in the postoperative period, and previous use of dexmedetomidine was associated with significantly lower MAP than the propofol-treated patients. *Difference over time compared with baseline values (P < 0.05); †Difference between dexmedetomidine and propofol; ¥Significant interaction (different response between drugs over time).

Figure 3: Psychomotor tests performed before surgery (holding area) and at 15 and 45 min after surgery. The groups performed similarly during all time points. Both groups had impaired performance on this test 15 min after surgery ended compared with the presurgery value. *Difference over time compared with baseline values (P < 0.05).

During the intraoperative period, there was a significant difference in the time required to achieve targeted levels of sedation. Targeted sedation was achieved within 10 min with propofol but took 25 min with dexmedetomidine (Fig. 1). There were no differences in respiratory end points between treatment groups in the intraoperative period. All patients maintained clinically normal oxygen saturation and ETco₂ concentrations. MAP was significantly reduced during the intraoperative period (Fig. 2), and the reduction was significantly less in patients receiving dexmedetomidine by an average of 11 ± 3 mm Hg (average intraoperative values, dexmedetomidine 86 ± 3 mm Hg versus propofol 75 ± 3 mm Hg). The need for fluid bolus, ephedrine, and phenylephrine did not differ (χ² analysis) between groups (dexmedetomidine:propofol, fluid bolus, 5:10; ephedrine, 7:6; phenylephrine, 2:6 patients).

During recovery, patients who had received dexmedetomidine during the surgery had significantly smaller needs for morphine sulfate (Table 1) and significantly different sedation scores (higher levels of sedation) compared with the Propofol-Treated group (Fig. 4). This persisted throughout the recovery period. There was no difference between treatment groups in the time to achieve an Aldrete score of 9 (Table 1) and the time to eligibility for PACU discharge. In the recovery room, HR and MAP of both treatment groups were significantly lower than before surgery. There were no differences in HR between treatment groups in the recovery period; however, MAP was significantly lower throughout the period of recovery in the Dexmedetomidine group by an average of 13 ± 3 mm Hg (average, dexmedetomidine 74 ± 3 mm Hg versus propofol 87 ± 3 mm Hg). The 24-h follow-up inventory of patient satisfaction revealed that the sedation for their surgical procedure was equally satisfactory between treatment groups.

Table 1: Surgical Procedures and Recovery Events

Discussion

The major findings of this research are as follows: compared with propofol, dexmedetomidine provided a slower onset and offset of sedation. We noted increased intraoperative MAP and a decreased postoperative MAP when sedation was provided with dexmedetomidine, as compared with propofol. Patients receiving dexmedetomidine for sedation during their surgery had significantly lower pain scores in the postoperative period and received less morphine sulfate. Patients in each treatment group performed similarly on the psychomotor testing and met discharge criteria at equivalent times. Respiratory end points were similar between treatment groups throughout the entire study period.

The patients were randomized to treatment groups, and the types of surgical procedures performed in each treatment group did not differ (Table 1). All patients achieved targeted sedation levels; however, the patients receiving propofol for sedation achieved levels of sedation more rapidly than those receiving dexmedetomidine. In addition, patients receiving propofol had significantly decreased intraoperative MAP levels (11 mm Hg on average). Previous work from this laboratory has demonstrated a powerful inhibitory effect of propofol on sympathetic outflow ⁽¹³⁾. Dexmedetomidine also is known to decrease sympathetic outflow and circulating catecholamine levels and would therefore be expected to cause decreases of MAP similar to those of propofol ^(1,9,10). However, larger doses of dexmedetomidine have a direct effect at the postsynaptic vascular smooth muscle to cause vasoconstriction, and it is possible that the sympathoinhibitory effects of dexmedetomidine were slightly opposed by direct α₂-mediated vasoconstriction ^(14–16). In contrast, earlier work from this laboratory has demonstrated that propofol has no direct effects on vascular smooth muscle ⁽¹⁷⁾.

Dexmedetomidine also has been associated with decreases in HR, in part because of the sympatholytic effects of this drug, but also because of a vagal mimetic effect ⁽¹⁸⁾. The present study demonstrates similar effects on HR when compared with propofol.

One of the objectives of this research was to explore the possibility of better preservation of respiratory function with the use of dexmedetomidine compared with propofol. Anecdotal reports describe incidents of respiratory depression during infusions of propofol for sedation. However, in the present study, patients receiving propofol did not have significant respiratory depression (defined as a decrease in respiratory rate more than 25% or a decrease in oxygen saturation <90%). This preservation of respiratory function may be related to the study design that did not include a bolus dose of propofol at sedation administration and the close monitoring and frequent patient queries by independent observers in the intraoperative period. Drugs were carefully titrated to the processed electroencephalogram (BIS), and anesthesia caregivers were informed immediately of the need for dose adjustments. Dexmedetomidine has not been associated with respiratory depression despite oftentimes profound levels of sedation ^(1,8).

In the recovery period, several significant effects of dexmedetomidine were noted. For example, patients who had received dexmedetomidine for sedation during the surgical procedure had significantly reduced pain scores and reduced analgesic needs (use of morphine) when compared with the propofol patients. It is now well described that dexmedetomidine has analgesia-sparing components when used for sedation in the intensive care unit setting ^(3,4,6). This study mandated dexmedetomidine be terminated at the end of the surgical procedure. However, the half-life of dexmedetomidine has been described as two hours, and it is likely that the analgesic-sparing properties persisted in the recovery period ⁽¹⁹⁾.

The persistent effects of dexmedetomidine in the recovery room resulted in significantly more sedation when compared with the short-acting propofol. However, patients were easily aroused to perform the psychomotor testing (DSST), and their performance was not importantly impaired compared with the propofol-treated patients. This is consistent with one of the more interesting characteristics of dexmedetomidine, which is the ability to achieve sedation but preserve patient arousability ^(2,6). Patients who had received dexmedetomidine had significantly lower postoperative MAP at an average of 8 mm Hg. This was opposite to that seen during the intraoperative period where blood pressures were higher in the Dexmedetomidine group. Again, this may be related to residual levels of dexmedetomidine in the postoperative period still maintaining sympatholysis, but perhaps levels were too small to cause significant postsynaptic α₂-receptor-mediated vasoconstriction ^(15,16).

In summary, dexmedetomidine achieved similar levels of sedation to propofol, albeit with a slower onset and offset of sedation. Neither dexmedetomidine nor propofol influenced respiratory rate, but propofol resulted in lower MAP during the intraoperative period. In the recovery room, dexmedetomidine was associated with an analgesia-sparing effect, slightly increased sedation, but no compromise of respiratory function or psychomotor responses. Thus, dexmedetomidine may prove to be a useful adjuvant for elective surgery performed under MAC, especially when postoperative pain might be predicted to be worse than usual.