This prospective, randomised, double-blind controlled trial was designed to examine the efficacy of low-dose continuous infusion of dexmedetomidine (DEX) on pain/sedation scores and verify the plasma concentration of DEX in postoperative patients recovering in general wards conditions.
Ethics: Ethical approval for this study (Ethical Committee number 547) was provided by the Ethical Committee of Tokyo Women's Medical University, Tokyo, Japan (Chairperson of the committee was Professor Makio Kobayashi) on 6 July 2004.
Thirty-three gynaecological surgery patients with the American Society of Anesthesiologists physical status of I or II (exclusion criteria included propofol allergy, severe liver and/or renal dysfunction, grade II or III A-V block, severe cardiac dysfunction, regular use of β-blockers and obesity) were allocated in a random and double-blind manner to a control group (isotonic saline, n = 11), a DEX-loading (−) group (0.3–0.4 μg kg−1 h−1 infusion, n = 11) or a DEX-loading (+) group (initial 1 h 0.9–1.0 μg kg−1 h−1, then 0.3–0.4 μg kg−1 h−1 infusion, n = 11). Blinding of the anaesthesiologists and the evaluators of effects (the ward nurses) was achieved by isolation of DEX syringe preparation by an independent individual. Randomisation was completed by a computer-generated random list, and placing each patient's group allocation in a sequentially numbered sealed envelope ensured allocation concealment. Finally, patients were enrolled by a trained research nurse. The flowchart of all patients in this study is shown as Figure 1.
To provide continuous venous infusion of DEX and physiological saline, a Coodech Syrinjector, a mobile disposable negative-pressure infusion pump (Daiken Medical, Osaka, Japan), was used, primed with a volume of 120 ml to facilitate patient transport to the general-ward room and up to 20 h while recuperating. The reason for using the Syrinjector for continuous infusion is that it is not necessary to set up the panel of the pump, as is generally required with an electrical pump. Additionally, using the Syrinjector avoided human errors such as excessive overdosing of the drug when using an electric syringe pump, and therefore we considered it could be used continuously, safely and easily in general wards. Also, we confirmed that the Syrinjector could perform a stable continuous infusion because the DEX plasma concentration remained within a reasonable range.
Anaesthesia was induced and maintained with propofol and fentanyl. The fentanyl effect-site concentration was calculated with a handheld computer using Shafer's parameters,1 and was titrated to a final concentration of 1.5–2 ng ml−1 at the end of surgery. After the patient recovered from anaesthesia, DEX (10 μg ml−1) or isotonic saline as a control was placed in the Syrinjector and a flow rate of 5 ml h−1 was selected for loading then 2 ml h−1 in DEX-loading (+) group, or 2 ml h−1 only in DEX-loading (−) group. The infusion was connected to one of the peripheral intravenous lines. Verbal Response Scale (VRS) for pain, Ramsay Score, and total doses of sedative/analgesic drugs, mean blood pressure (MBP), heart rate (HR), SpO2 and respiratory rate were recorded on awakening from anaesthesia, entering the post anaethesia care unit, and 0.5, 1, 1.5, 2, 3, 4, 7, 10, 13, 16 and 19 h after starting the infusion. The number of patients in each group was determined by a preliminary study using power analysis of variance (ANOVA) with ‘R’ version 2.6.0. [In that study, the VRS decreased from 4.7 ± 1.0 to 2.6 ± 1.2 between the control group and the DEX-loading (−) group.] Power analysis on the assumption of type 1 error protection of 0.05 and a power of 0.90 to detect a 2-number reduction in the VRS between the DEX groups and the control group showed that 11 patients were required for each of the three groups receiving DEX or physiological saline. Data are presented as mean ± SD and for statistical analysis, repeated measures of ANOVA with Tukey post-hoc test were performed with a 0.05 two-sided significance level.
To evaluate the DEX infusion speed, we analysed the plasma concentration of DEX 1 and 10 h after starting the infusion using high performance liquid chromatography-mass spectrometry (LC-MS) as reported previously, with small modifications. Briefly, DEX was extracted with a solid-phase column (Oasis HLB, 30 mg ml−1 Waters, Massachusetts) and measured with tandem mass-spectrometry using 100 ng of midazolam as an internal standard (4000 Qtrap, Analytical Biosystems, Foster City, California, USA). The within-day and day-to-day coefficients of variance were 7.5 and 8.2%, respectively, at 0.1 ng ml−1 and 3.5 and 4.2%, respectively, at 1.0 ng ml−1. The limit of detection was 0.02 ng ml−1.
The demographic parameters observed were similar in the three groups. Throughout the study period, the changes in the values of SpO2 and respiratory rate were not significant among the groups and these parameters remained within normal limits (SpO2 >96% without any oxygen supplementation and respiratory rate >8 breaths min−1). The amount of DEX administered during 1 h loading from the start of the infusion was 0.93 ± 0.14 μg kg−1 h−1 in the DEX-loading (+) group and subsequently 0.37 ± 0.06 μg kg−1 h−1. In contrast, it was 0.37 ± 0.04 μg kg−1 h−1 in the DEX-loading (−) group throughout the course of the study. The VRS during the observation period in the DEX-loading (+) group, the DEX-loading (−) group and the control group averaged 2.3 ± 0.5, 2.3 ± 0.6 and 4.3 ± 0.4, respectively. Thus, a significantly lower VRS was recorded in both DEX groups than in the control group (P < 0.05). The VRS value difference between the DEX-loading (+) and DEX-loading (−) group was insignificant. The VRS values are shown in Figure 2. The mean Ramsay Scores in the DEX-loading (+) group, the DEX-loading (−) group and the control group were 2.2 ± 0.1, 2.1 ± 0.1 and 2.2 ± 0.1, respectively. No significant differences were observed among the three groups. The average HR value throughout the study period was 62 ± 3 beats min−1 in the DEX-loading (+) group, 68 ± 2 beats min−1 in the DEX-loading (−) group, and 72 ± 3 beats min−1 in the control group. The HR of the patients in the DEX-loading (+) group was significantly lower than in the control group, at some points. The MBP was significantly lower in the DEX groups (P < 0.01). There were no significant haemodynamic differences between the DEX-loading (+) and loading (−) groups during the study period. Haemodynamic instability, defined as requiring treatment, was not observed throughout the study. The total dose of pentazocine administered for acute pain relief was significantly lower in both the DEX groups than in the control group (P < 0.05) and a significantly lower dose of hydroxyzine was used as a sedative in both of the DEX groups compared to the control group (Figure 3). Hydroxyzine was used for sedation when the Ramsay score was less than 2, and pentazocine was used for analgesia when the VRS was over 5. As shown in Figure 3, the total amount of hydroxyzine used in the control group was significantly higher than the DEX groups and as a result caused similar sedative status as indicated by the Ramsay score regardless of the analgesic status, which was significantly different from the DEX groups. The DEX plasma concentration in the DEX-loading (+) group 1 h after starting the infusion was 0.64 ± 0.22 ng ml−1, and after 10 h it was 0.46 ± 0.13 ng ml−1. In the DEX-loading (−) group the corresponding values were 0.20 ± 0.05 ng ml−1 and 0.45 ± 0.14 ng ml−1.
DEX provides an important degree of postsurgical analgesia and appears to have no clinically important adverse effects on respiration in surgical patients requiring intensive care or in healthy volunteers.2–4 This limited respiratory effect is considered to be an advantage of DEX in terms of general ward use. Despite these advantages, the fact that DEX induces cardiovascular side-effects5 which might lead to haemodynamic instability, such as hypertension, hypotension and bradycardia, could be a problem for using DEX in general wards. Therefore, careful consideration should be given to the decision to administer DEX. To use DEX in the general ward safely, only appropriate concentrations should be used, and extra care should be taken when using higher concentrations. The clinically effective plasma concentration of DEX is reported to range from 0.3 to 1.2 ng ml−1. In this study, we obtained approximately 0.45 ng ml−1 plasma concentration of DEX 10 h after starting the infusion in both DEX groups. This was confirmed to be a clinically relevant effective plasma concentration. However, when we evaluated the plasma concentration 1 h after starting the DEX infusion, it was 0.64 ng ml−1 in the DEX-loading (+) group, whereas it was 0.20 ng ml−1 in the DEX-loading (−) group, the latter of which was below the clinically effective concentration. On the contrary, rapid loading of DEX might induce excessive systemic hypertension,6,7 so in this study, DEX was loaded for 1 h very slowly and, therefore, no excessive hypertension occurred.
A limitation of our study was that the patients who received DEX postoperatively had only gynaecological surgery in the lower abdominal region. If the area of the surgery was greater, or when the operation becomes more invasive, it might be necessary to titrate the DEX infusion rate.
In conclusion, DEX administered with this infusion method provided significantly lower VRS values without clinically problematic side-effects. We also confirmed clinically effective DEX plasma concentrations. For the reasons discussed above, we consider this low-dose DEX continuous infusion method to be useful for postoperative management after gynaecological surgery, even in general wards.
The authors gratefully acknowledge the assistance of nursing staff in PACU and the gynaecological general ward. We had institutional (Department of Anesthesiology) funding only for this work. None of the authors has any conflicts of interest.
1. Shafer SL, Varvel JR, Aziz N, Scott JC. Pharmacokinetics of fentanyl administered by computer-controlled infusion pump. Anesthesiology
2. Venn RM, Bradshaw CJ, Spencer R, et al. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia
3. Venn RM, Grounds RM. Comparison between dexmedetomidine and propofol for sedation in the intensive care unit: patient and clinician perceptions. Br J Anaesth
4. Hsu YW, Cortinez LI, Robertson KM, et al. Dexmedetomidine pharmacodynamics: part I – crossover comparison of the respiratory effects of dexmedetomidine and remifentanil in healthy volunteers. Anesthesiology
5. Kamibayashi T, Maze M. Clinical uses of alpha2-adrenergic agonists. Anesthesiology
6. Ebert TJ, Hall JE, Barney JA, et al. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology
7. Talke P, Lobo E, Brown R. Systemically administered alpha2-agonist-induced peripheral vasoconstriction in humans. Anesthesiology