ORIGINAL ARTICLE
Intranasal dexmedetomidine in combination with patient-controlled sedation during upper gastrointestinal endoscopy: a randomised trial C. W. Cheung1, Q. Qiu1, J. Liu2, K. M. Chu3 and M. G. Irwin1 1
Department of Anaesthesiology, The University of Hong Kong, Hong Kong Department of Anesthesiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China 3 Department of Surgery, The University of Hong Kong, Hong Kong 2
Correspondence C. W. Cheung, Department of Anaesthesiology, The University of Hong Kong, Room 424, Block K, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong E-mail: [email protected] Conflicts of interest None. Funding This study was supported by the departmental fund, Department of Anaesthesiology, the University of Hong Kong. Submitted 1 November 2014; accepted 11 November 2014; submission 21 August 2014. Citation Cheung CW, Qiu Q, Liu J, Chu KM, Irwin MG. Intranasal dexmedetomidine in combination with patient controlled sedation during upper gastrointestinal endoscopy – a randomised trial. Acta Anaesthesiologica Scandinavica 2014 doi: 10.1111/aas.12445
Background: Sedation using intranasal dexmedetomidine is a convenient and well-tolerated technique. This study evaluated the sedative efficacy of intranasal dexmedetomidine in combination with patient-controlled sedation (PCS) for upper gastrointestinal endoscopy. Methods: In this double-blind, randomised, controlled trial, 50 patients received either intranasal dexmedetomidine 1.5 μg/kg (dexmedetomidine group) or intranasal saline (placebo group) 1 h before the procedure. PCS with propofol and alfentanil was provided for rescue sedation. Additional sedative consumption, perioperative sedation scores using Observer’s Assessment of Alertness/ Sedation (OAA/S) scale, recovery, vital signs, adverse events and patient satisfaction were assessed. Results: Total consumption of PCS propofol and alfentanil was significantly less in the dexmedetomidine than placebo group with a mean difference of −13.8 mg propofol (95% confidence interval −27.3 to −0.3) and −34.5 μg alfentanil (95% confidence interval −68.2 to −0.7) at the completion of the procedure (P = 0.044). Weighted areas under the curve (AUCw) of OAA/S scores were significantly lower in the dexmedetomidine group before, during and after procedures (P < 0.001, P = 0.024 and P = 0.041 respectively). AUCw of heart rate and systolic blood pressure were also significantly lower during the procedure (P = 0.007 and P = 0.022 respectively) with dexmedetomidine. There was no difference in recovery, side effects or satisfaction. Conclusion: Intranasal dexmedetomidine with PCS propofol and alfentanil confers deeper perioperative clinical sedation with significantly less use of additional sedatives during upper gastrointestinal endoscopy.
Editorial comment: what this article tells us Intranasal dexmedetomidine 1.5 μg/kg 1 h before upper gastrointestinal endoscopy was associated with a significant reduction in the need for propofol and alfentanil using patient-controlled sedation. The level of sedation was deeper with dexmedetomidine.
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Discomfort is common during upper gastrointestinal endoscopy, and although it is usually a short procedure, concomitant sedation is frequently used to facilitate examination, reduce fear, anxiety, pain, discomfort and cardiovascular stress. The combination of an opioid and a benzodiazepine is probably the most popular choice globally,1 but this combination also increases the risk of respiratory depression. Propofol has been increasingly used due to its fast onset and offset with deeper sedation, but it has a narrow therapeutic index.2 Dexmedetomidine is a highly selective α2adrenoceptor agonist with sedative and analgesic effects.3 Its desirable properties include decreased requirements for other anaesthetics,4 analgesia and opioid sparing,5 a diminished sympathetic response to stress6 and possible cardioprotection.7 Unlike other sedative medications, it does not produce respiratory depression and appears to not have detrimental effects on post-procedural cognition.8,9 Intranasal administration has been pioneered in our department and is a convenient and well-tolerated technique that results in a fairly predictable and rapid onset in both adults and children.10,11 A limited number of clinical studies have explored the use of intranasal dexmedetomidine in sedation for surgery and clinical procedures.11,12 However, to date, no study has been conducted to explore the clinical use of intranasal dexmedetomidine for sedation in upper gastrointestinal endoscopy, the purpose of this study. Consumption of additional sedatives was used as a measure of efficacy. We hypothesised that total consumption of patient-controlled sedation (PCS) propofol at the completion of the procedure would be significantly less for patients receiving intranasal dexmedetomidine. Perioperative sedation scores, recovery, vital signs, side effects resulting from the use of sedative and analgesic medications, and patient satisfaction were also evaluated. Methods The protocol of this double-blind, randomised, controlled trial was approved by our local Institutional Review Board on 19 July 2008: reference number UW07-212 (Room 901, Administrative Block, Queen Mary Hospital, Hong Kong). It was also registered at ClinicalTrials.gov: registration number NCT01887184. Patients who were scheduled for upper gastrointestinal endoscopy were
recruited by the investigators after being admitted into the day ward of the hospital. The nature of the study was explained and written consent was obtained from all participants. Eligibility included American Society of Anesthesiologists physical status I to III and age between 18 and 60 years. Exclusion criteria included clinical history or electrocardiographic evidence of heart block, ischaemic heart disease, asthma, sleep apnoea syndrome, BMI > 35 kg/m2, impaired liver (preoperative serum albumin level less than 30 g/l) or renal function (creatinine > 120 μmol/l) or known renal or hepatic disease, alcohol consumption in excess of 28 units per week, pregnancy, patient refusal, known psychiatric illness, chronic sedative use, and regular use of or known allergy to dexmedetomidine, propofol and opioids. Patients were randomly allocated to receive either dexmedetomidine (dexmedetomidine group) or 0.9% saline (placebo group) intranasally 1 h before upper gastrointestinal endoscopy. A computer-generated random sequence was used for drug allocation, and this was prepared by a statistician who was unaware of the clinical nature of the study. The patients did not receive any premedication. Explanation was given with respect to PCS with propofol and alfentanil being provided as required. Patients were told that they could press the button of the PCS machine until they felt relaxed enough before the procedure. During the procedure, PCS was also used if the patient felt a need for further relaxation or if discomfort was experienced. Study medications were prepared according to the generated random sequence by an anaesthesiologist who did not know the nature of the study. The prepared study medications were then given to a research assistant, which were then passed onto another anaesthesiologist responsible for the sedation of the patients in the endoscopy room. Both the investigators and the subjects were blinded to the study medications. Moreover, both preparations were clear solutions; therefore, patients, medical and nursing staff, and data collection staff were all blind to the allocated drug. Patients were sent to a room beside the endoscopy suite about 1 h before the procedure. Sedation scores using Observer Assessment of Alertness/ Sedation (OAA/S) scale and heart rate, blood pressure, SpO2 and respiratory rate (S/5 Anaesthesia Monitor, Datex-Ohmeda, WI, USA) were Acta Anaesthesiologica Scandinavica 59 (2015) 215–223
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recorded at baseline and every 5 min thereafter. OAA/S scale was developed to measure the level of alertness in subjects who are sedated on a 1–5 scale, with 5 being most alert.13 A blinded research assistant was responsible for data collection. Either placebo (0.015 ml/kg, placebo group) or undiluted dexmedetomidine 0.015 ml/kg (1.5 μg/kg, Precedex, Hospira Inc., Lake Forest, IL, USA; 100 mcg/ml, dexmedetomidine group) was administered intranasally 1 h before the procedure. After baseline testing, an investigator administered the study preparation divided in two equal volumes to each naris with the patient in a semi-recumbent position and the head of the bed elevated at a 20- to 40-degree angle. OAA/S scale was assessed every 15 min after the study drug administration while vital sign measurements were recorded every 5 min. Patients were then transferred to the procedure room for upper gastrointestinal endoscopy. Before the procedure started, three sprays of 10% lignocaine were administered to the oropharynx. Patients were given the handset of a patientcontrolled analgesia (PCA) pump (Graseby 3300 Syringe Pump, Smiths Medical, London, UK). On pressing the button, they would receive a bolus dose of 0.5 ml which contained 4.8 mg of propofol and 12 μg of alfentanil mixed together.14 Lockout time was set at zero. However, as the PCA pump was programmed to deliver a bolus dose of 0.5 ml at 200 ml/h on the patient’s demand and the pump took 9 s to deliver the bolus, the effective lockout time was around 9 s. Sedation was deemed adequate to start the procedure if the patients subjectively felt relaxed. OAA/S and vital signs were monitored every 5 min during the endoscopy. If oxygen desaturation developed (SpO2 < 92%), oxygen 3 l/min was administered via a nasal cannula. PCS propofol and alfentanil were terminated and disconnected from the patient when the endoscope was completely removed. After the procedure, patients were transferred to the post-anaesthetic care unit (PACU) beside the endoscopy room where monitoring of OAA/S and vital signs continued every 5 min for 30 min before discharge back to the day ward. Recovery was assessed as fitness for discharge using the post-anaesthetic discharge (PAD) scoring system that is commonly used in ambulatory surgery.15 It was assessed from 1 h post-
operation until the PAD score was equal to or more than 9. Side effects resulting from the use of sedative and analgesic medications were recorded. Satisfaction of sedation was graded by patients using Numerical Rating Scale (zero being least satisfied and 10 being most satisfied). Our primary outcome measure was total consumption of PCS propofol at procedure completion, which was used as a measure of sedative efficacy. A pilot study at our centre found that the total mean ± standard deviation (SD) propofol consumption using PCS propofol and alfentanil for upper gastrointestinal endoscopy was 41.3 ± 23.2 mg. A reduction of 50% in total PCS propofol after intranasal dexmedetomidine in the treatment group was considered clinically significant, and this required a sample size of 20 per group to achieve a power of 80% and a type I error of 5%. In order to account for any dropouts, 25 patients were recruited to each study group. Statistical analysis was performed using Statistical Analysis System for Windows Release 9.2 (SAS Institute Inc, Cary, NC, USA). The data were tested for normality before they were summarised and compared. The demographic and operation measurement data were analysed by t-test and chi-square test as appropriate. The operation measures and drug consumptions (propofol and alfentanil) were analysed by Mann–Whitney U-test. The OAA/S scores and vital signs over the periods before, during and after endoscopy were expressed as weighted areas under the curve (AUCw) using the trapezoid rule and analysed by the Mann–Whitney U-test. Incidents of adverse events were analysed by chi-square test or Fisher’s exact test as appropriate. P < 0.05 was considered statistically significant. Data are presented as mean (SD) if normally distributed, with mean difference between the groups and a 95% confidence interval (CI). Data are presented as median [interquartile range] if the distribution was skewed, and analysed by the Mann–Whitney U-test with an independent sample Hodges–Lehmann estimation of the median difference with a constructed 95% CI. Results From January 2009 to April 2010, 50 patients were recruited (25 patients per group) with no
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Fig. 1. Flow diagram of patient recruitment.
dropouts (Fig. 1). The patient characteristics, and sedation and procedural data of both study groups are shown in Tables 1 and 2 respectively. Intranasal dexmedetomidine resulted in a significant reduction in consumption of propofol and alfentanil when sedation was deemed adequate to start the procedure by the patient [mean difference −9.2 mg (95% CI −20.7 to 2.3) of propofol and −22.9 μg (95% CI −51.7 to 5.8) of alfentanil; P = 0.031] and when the procedure was completed [mean difference −13.8 mg (95% CI −27.3 to −0.3) of propofol and −34.5 μg (95% CI −68.2 to −0.7) of alfentanil; P = 0.044], compared with placebo (Table 3). AUCw of OAA/S scores were significantly less in the dexmedetomidine group
Table 1 Patient demographics.
Age (years) Body weight (kg) Sex (M : F %) ASA physical status (I : II %)
Dexmedetomidine group (n = 25)
Placebo group (n = 25)
41.7 ± 11.7 62.5 ± 11.7 48 : 52 96 : 4
43 ± 11.7 57.1 ± 9.0 28 : 72 96 : 4
Values are mean ± SD (95% CI) or percentage. ASA, American Society of Anesthesiologists.
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Table 2 Sedation and procedural data.
Duration of endoscopy (minutes) Duration from intranasal study medication administration to PDS equal or more than 9 (minutes) Proportion of patients achieving PDS equal or more than 9 at first hour after procedure (%)
Dexmedetomidine group (n = 25)
Placebo group (n = 25)
5 [4–6] 105 [95–120] 88
5 [3–5] 100 [93.5–109] 88
Difference
P value
0 (0 to 1) −5 (−15 to 5) 0 (−19.6 to 19.6)
0.161 0.332 1.000
Values are median (interquartile range) or median difference (95% CI) or percentage or percentage difference (95% CI). PDS, post-anaesthetic discharge scores.
Table 3 Additional propofol and alfentanil consumption during upper gastrointestinal endoscopy.
Propofol (mg) Sedation adequate to start the procedure Total Alfentanil (μg) Sedation adequate to start the procedure Total
Dexmedetomidine group (n = 25)
Placebo group (n = 25)
Difference
P value
16.5 ± 22.3 (7.3 to 25.7) 28.6 ± 23.9 (18.8 to 38.5)
25.7 ± 17.9 (18.3 to 33.1) 42.4 ± 23.5 (32.7 to 52.1)
−9.2 (−20.7 to 2.3) −13.8 (−27.3 to −0.3)
0.031*
41.3 ± 55.7 (18.3 to 64.3) 71.6 ± 59.9 (46.9 to 96.3)
64.2 ± 44.8 (45.7 to 82.7) 106.1 ± 58.8 (81.8 to 130.3)
−22.9 (−51.7 to 5.8) −34.5 (−68.2 to −0.7)
0.031*
0.044*
0.044*
Values are mean ± SD (95% CI) or mean difference (95% CI). *Statistically significant at P < 0.05.
Table 4 Observer’s assessment of alertness/sedation OAA/S (scale 1 to 5).
AUCw 1 h before endoscopy AUCw during endoscopy AUCw 30 min after endoscopy
Dexmedetomidine group (n = 25)
Placebo group (n = 25)
Difference
P value
4.2 [4.1–4.4] 4 [3.5–4.5] 4.8 [4–5]
4.7 [4.6–5] 4.5 [4–5] 5 [4.8–5]
−0.5 (−0.7 to −0.3) −0.5 (−1 to 0) −0.1 (−0.7 to 0)
< 0.001* 0.024* 0.041*
Values are median [interquartile range] or median difference (95% CI). *Statistically significant at P < 0.05. AUCw, weighted areas under the curve.
than placebo before (median difference of −0.5 with 95% CI −0.7 to −0.3; P < 0.001), during (median difference of −0.5 with 95% CI −1 to 0; P = 0.024) and after (median difference of −0.1 with 95% CI −0.7 to 0; P = 0.041) upper gastrointestinal endoscopy (Table 4). The same proportion of patients (88%) had PDS equal or more
than 9 at the first hour after the procedure (Table 2). Concerning perioperative haemodynamic parameters, AUCw of heart rate (beat/min) was significantly lower in the dexmedetomidine than placebo group before (median difference of −6.7 with 95% CI −11.6 to −1.3; P = 0.015), during
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Fig. 2. Heart rate (HR) and systolic blood pressure (SBP) of patients receiving intranasal dexmedetomidine (dexmedetomidine group, denoted by black round data points ●) and 0.9% saline (placebo group, denoted by white round data points ○) before (induction), during (intraOp) and after (RR) upper gastrointestinal endoscopy. Data shown are mean ± standard deviation (SD). Data points were slightly shifted horizontally to avoid overlapping. *AUCw significantly different between dexmedetomidine and placebo groups.
(median difference of −12.5 with 95% CI −18.5 to −5.5; P = 0.007) and after (median difference of −12.4 with 95% CI −16.7 to −6.6; P < 0.001) the procedure (Fig. 2). AUCw of systolic blood pressure (mmHg) was also significantly lower during surgery (median difference −13.5 with 95% CI −25.5 to −2; P = 0.022) and in PACU (median difference of −11.9 with 95% CI −21.1 to −2.7; P = 0.018) for patients in the dexmedetomidine compared with placebo group (Fig. 2). None of these, however, were clinically significant decreases that required vasopressors or anticholinergic support. Eight patients from the dexmedetomidine group and five from the placebo group had oxygen saturation below 92% (breathing room air) transiently during the procedure, but this difference was not statistically significant. All of patients responded immediately to
oxygen supplementation (O2 3 l/min by nasal cannulae) to restore SpO2 back to above 95%. There was no difference in other common adverse events after the procedure including headache, dizziness and nausea. No difference was found between the two groups with regard to patient satisfaction.
Discussion We demonstrated that patients given intranasal dexmedetomidine with PCS propofol and alfentanil experienced significantly deeper perioperative sedation with significantly less consumption of additional sedatives. They were also less likely to have tachycardia or hypertension. No delay in recovery or increase in side effects was seen, Acta Anaesthesiologica Scandinavica 59 (2015) 215–223
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although there was no difference in satisfaction about sedation. There are few reports regarding the efficacy of dexmedetomidine for sedation in endoscopic procedures with conflicting results. One study found it inferior to a midazolam and pethidine combination and to fentanyl alone.16 However, another found dexmedetomidine was similar to midazolam in efficacy but superior with regard to retching, side effects and endoscopist satisfaction.17 Dexmedetomidine alone was not as effective as propofol combined with fentanyl for providing sedation during endoscopic retrograde cholangiopancreatography (ERCP).18 However, using dexmedetomidine in a multimodal manner may allow lower doses of each component drug and, potentially, side effects similar to the way it is used during general anaesthesia.19 The antisialagogue effect may also be an advantage in improving the efficacy of topical lignocaine, similar to during fibreoptic intubation.20 Intranasal administration is convenient, effective and non-invasive. Medications can access the systemic circulation via the blood vessels of the subepithelium in the nasal cavity and avoid hepatic first-pass metabolism.21 The pharmacokinetic and pharmacodynamics of intranasal dexmedetomidine have been evaluated in volunteers,22 and the onset of clinical sedation occurs around 30–45 min after administration. Consequently, we gave intranasal dexmedetomidine 1 h before the procedure, and 1.5 μg/kg in healthy volunteers provides clinical sedation for more than 180 min.23 In this study, 1.5 μg/kg was used because upper gastrointestinal endoscopy was stimulating and deeper sedation was desirable while attempting to minimise the cardiovascular and respiratory depression seen with propofol/ alfentanil. No visible signs of local mucosal irritation, inflammation, bleeding or ulceration were noticed in common with our other studies. Propofol has been used successfully in PCS sedation in endoscopy.24–26 However, propofol, often administered with an opioid, increases the incidence of oversedation and respiratory depression.27,28 Therefore, reduction in consumption of PCS propofol and alfentanil was potentially desirable to reduce side effects and improve safety. The bolus dose of PCS propofol and alfentanil in this study was lower than that used by Mazanikov et al. in ERCP.29 We had no incidents
of significant respiratory depression, as opposed to 11% of patients in theirs.29 This may be because we used smaller PCS doses and had overall lower sedative consumption in our study. The addition of intranasal dexmedetomidine provided deeper sedation (lower OAA/S scores) with less requirement for additional sedatives in this study. Its administration before the procedure may also help to alleviate pre-procedural anxiety. Although dexmedetomidine has a synergistic interaction with propofol, based on the results of PDS scores in this study, the recovery in psychomotor function was not delayed when compared with placebo and PCS propofol/alfentanil alone. Such administration, therefore, is suitable for upper gastrointestinal endoscopy and in the day surgery setting. Being an α2 agonist, apart from the sedative and analgesic effects, a modest reduction in heart rate and blood pressure is usual.30 This was also apparent in this study, but no patient required intervention for bradycardia or hypotension. It is important to emphasise that, generally, this is not a clinical concern, and this reduction in catecholamine release and stress response may, in fact, be beneficial, particularly in patients with underlying cardiovascular disease. Jalonen et al. showed that dexmedetomidine reduced sympathetic tone and haemodynamic responses to surgery.31 Its cardioprotection was also supported in a metaanalysis.32 In our previous study, patients using PCS propofol in third molar surgery experienced more dizziness post-operatively compared with using a combination of intranasal dexmedetomidine and PCS propofol;11 however, there was no significant difference between the two groups in common side effects including dizziness in this study. Addition of intranasal dexmedetomidine before the procedure, with the use of PCS propofol and alfentanil, appeared not to increase side effects while providing deeper sedation. However, this study may not be powered enough to show this difference. Most patients in both groups were satisfied with their sedation. Thus, intranasal dexmedetomidine or placebo, with PCS propofol and alfentanil, appears to be equally acceptable to patients, although, again, our study may not be sufficiently powered to detect small differences in patient satisfaction. This could only be truly evaluated with
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a crossover comparison. In fact, it may also not be easy to detect the true difference in satisfaction in a clinical study because patients are often reluctant to criticise their treatment after surgery.33 There are some limitations to our study. Firstly, most of the patients receiving intranasal dexmedetomidine still needed to use PCS. Only a mean reduction in total propofol consumption by 13.8 mg at the completion of the procedure in the dexmedetomidine group was found, which was short of the target of a 50% reduction in total propofol consumption (from our pilot data of 41.3 ± 23.2 mg) used for sample size calculation. This could be overcome by setting stricter statistical requirements (i.e. a power of 90% and a type I error of 1%) and should be considered in future studies. However, with the 25 subjects included in each group in the study, a statistically significant reduction in total propofol consumption was still seen nevertheless. Intranasal dexmedetomidine, therefore, is potentially a useful sedative adjuvant, rather than a strong sedative for sole use. Secondly, as upper gastrointestinal endoscopy is a short procedure, whether our results can be applied to more prolonged and complicated procedures requires further work. Thirdly, patients have to receive it 45–60 min before the procedure due to its delayed clinical onset. Its use, therefore, may not be feasible in centres where the procedure waiting time is short. In conclusion, intranasal dexmedetomidine with PCS propofol and alfentanil appears to confer deeper perioperative clinical sedation, with significantly less use of additional sedatives during upper gastrointestinal endoscopy.
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Acknowledgements We would like to thank the staff of the endoscopy room at Queen Mary Hospital, Hong Kong for their help for the study.
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24. Lee DW, Chan AC, Sze TS, Ko CW, Poon CM, Chan KC, Sin KS, Chung SC. Patient-controlled sedation versus intravenous sedation for colonoscopy in elderly patients: a prospective randomized controlled trial. Gastrointest Endosc 2002; 56: 629–32. 25. Roseveare C, Seavell C, Patel P, Criswell J, Kimble J, Jones C, Shepherd H. Patient-controlled sedation and analgesia, using propofol and alfentanil, during colonoscopy: a prospective randomized controlled trial. Endoscopy 1998; 30: 768–73. 26. Kulling D, Fantin AC, Biro P, Bauerfeind P, Fried M. Safer colonoscopy with patient-controlled analgesia and sedation with propofol and alfentanil. Gastrointest Endosc 2001; 54: 1–7. 27. Metzner J, Posner KL, Domino KB. The risk and safety of anesthesia at remote locations: the US closed claims analysis. Curr Opin Anaesthesiol 2009; 22: 502–8. 28. Metzner J, Domino KB. Risks of anesthesia or sedation outside the operating room: the role of the anesthesia care provider. Curr Opin Anaesthesiol 2010; 23: 523–31. 29. Mazanikov M, Udd M, Kylänpää L, Mustonen H, Lindström O, Halttunen J, Färkkilä M, Pöyhiä R. Patient-controlled sedation for ERCP: a randomized double-blind comparison of alfentanil and remifentanil. Endoscopy 2012; 44: 487–92. 30. Bloor BC, Ward DS, Belleville JP, Maze M. Effects of intravenous dexmedetomidine in humans. II. Hemodynamic changes. Anesthesiology 1992; 77: 1134–42. 31. Jalonen J, Hynynen M, Kuitunen A, Heikkila H, Perttila J, Salmenpera M, Valtonen M, Aantaa R, Kallio A. Dexmedetomidine as an anesthetic adjunct in coronary artery bypass grafting. Anesthesiology 1997; 86: 331–45. 32. Biccard BM, Goga S, de Beurs J. Dexmedetomidine and cardiac protection for non-cardiac surgery: a meta-analysis of randomised controlled trials. Anaesthesia 2008; 63: 4–14. 33. Chumbley GM, Hall GM, Salmon P. Patient-controlled analgesia: an assessment by 200 patients. Anaesthesia 1998; 53: 216–21.
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Intranasal dexmedetomidine in combination with patient-controlled sedation during upper gastrointestinal endoscopy: a randomised trial C. W. Cheung1, Q. Qiu1, J. Liu2, K. M. Chu3 and M. G. Irwin1 1
Department of Anaesthesiology, The University of Hong Kong, Hong Kong Department of Anesthesiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China 3 Department of Surgery, The University of Hong Kong, Hong Kong 2
Correspondence C. W. Cheung, Department of Anaesthesiology, The University of Hong Kong, Room 424, Block K, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong E-mail: [email protected] Conflicts of interest None. Funding This study was supported by the departmental fund, Department of Anaesthesiology, the University of Hong Kong. Submitted 1 November 2014; accepted 11 November 2014; submission 21 August 2014. Citation Cheung CW, Qiu Q, Liu J, Chu KM, Irwin MG. Intranasal dexmedetomidine in combination with patient controlled sedation during upper gastrointestinal endoscopy – a randomised trial. Acta Anaesthesiologica Scandinavica 2014 doi: 10.1111/aas.12445
Background: Sedation using intranasal dexmedetomidine is a convenient and well-tolerated technique. This study evaluated the sedative efficacy of intranasal dexmedetomidine in combination with patient-controlled sedation (PCS) for upper gastrointestinal endoscopy. Methods: In this double-blind, randomised, controlled trial, 50 patients received either intranasal dexmedetomidine 1.5 μg/kg (dexmedetomidine group) or intranasal saline (placebo group) 1 h before the procedure. PCS with propofol and alfentanil was provided for rescue sedation. Additional sedative consumption, perioperative sedation scores using Observer’s Assessment of Alertness/ Sedation (OAA/S) scale, recovery, vital signs, adverse events and patient satisfaction were assessed. Results: Total consumption of PCS propofol and alfentanil was significantly less in the dexmedetomidine than placebo group with a mean difference of −13.8 mg propofol (95% confidence interval −27.3 to −0.3) and −34.5 μg alfentanil (95% confidence interval −68.2 to −0.7) at the completion of the procedure (P = 0.044). Weighted areas under the curve (AUCw) of OAA/S scores were significantly lower in the dexmedetomidine group before, during and after procedures (P < 0.001, P = 0.024 and P = 0.041 respectively). AUCw of heart rate and systolic blood pressure were also significantly lower during the procedure (P = 0.007 and P = 0.022 respectively) with dexmedetomidine. There was no difference in recovery, side effects or satisfaction. Conclusion: Intranasal dexmedetomidine with PCS propofol and alfentanil confers deeper perioperative clinical sedation with significantly less use of additional sedatives during upper gastrointestinal endoscopy.
Editorial comment: what this article tells us Intranasal dexmedetomidine 1.5 μg/kg 1 h before upper gastrointestinal endoscopy was associated with a significant reduction in the need for propofol and alfentanil using patient-controlled sedation. The level of sedation was deeper with dexmedetomidine.
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Discomfort is common during upper gastrointestinal endoscopy, and although it is usually a short procedure, concomitant sedation is frequently used to facilitate examination, reduce fear, anxiety, pain, discomfort and cardiovascular stress. The combination of an opioid and a benzodiazepine is probably the most popular choice globally,1 but this combination also increases the risk of respiratory depression. Propofol has been increasingly used due to its fast onset and offset with deeper sedation, but it has a narrow therapeutic index.2 Dexmedetomidine is a highly selective α2adrenoceptor agonist with sedative and analgesic effects.3 Its desirable properties include decreased requirements for other anaesthetics,4 analgesia and opioid sparing,5 a diminished sympathetic response to stress6 and possible cardioprotection.7 Unlike other sedative medications, it does not produce respiratory depression and appears to not have detrimental effects on post-procedural cognition.8,9 Intranasal administration has been pioneered in our department and is a convenient and well-tolerated technique that results in a fairly predictable and rapid onset in both adults and children.10,11 A limited number of clinical studies have explored the use of intranasal dexmedetomidine in sedation for surgery and clinical procedures.11,12 However, to date, no study has been conducted to explore the clinical use of intranasal dexmedetomidine for sedation in upper gastrointestinal endoscopy, the purpose of this study. Consumption of additional sedatives was used as a measure of efficacy. We hypothesised that total consumption of patient-controlled sedation (PCS) propofol at the completion of the procedure would be significantly less for patients receiving intranasal dexmedetomidine. Perioperative sedation scores, recovery, vital signs, side effects resulting from the use of sedative and analgesic medications, and patient satisfaction were also evaluated. Methods The protocol of this double-blind, randomised, controlled trial was approved by our local Institutional Review Board on 19 July 2008: reference number UW07-212 (Room 901, Administrative Block, Queen Mary Hospital, Hong Kong). It was also registered at ClinicalTrials.gov: registration number NCT01887184. Patients who were scheduled for upper gastrointestinal endoscopy were
recruited by the investigators after being admitted into the day ward of the hospital. The nature of the study was explained and written consent was obtained from all participants. Eligibility included American Society of Anesthesiologists physical status I to III and age between 18 and 60 years. Exclusion criteria included clinical history or electrocardiographic evidence of heart block, ischaemic heart disease, asthma, sleep apnoea syndrome, BMI > 35 kg/m2, impaired liver (preoperative serum albumin level less than 30 g/l) or renal function (creatinine > 120 μmol/l) or known renal or hepatic disease, alcohol consumption in excess of 28 units per week, pregnancy, patient refusal, known psychiatric illness, chronic sedative use, and regular use of or known allergy to dexmedetomidine, propofol and opioids. Patients were randomly allocated to receive either dexmedetomidine (dexmedetomidine group) or 0.9% saline (placebo group) intranasally 1 h before upper gastrointestinal endoscopy. A computer-generated random sequence was used for drug allocation, and this was prepared by a statistician who was unaware of the clinical nature of the study. The patients did not receive any premedication. Explanation was given with respect to PCS with propofol and alfentanil being provided as required. Patients were told that they could press the button of the PCS machine until they felt relaxed enough before the procedure. During the procedure, PCS was also used if the patient felt a need for further relaxation or if discomfort was experienced. Study medications were prepared according to the generated random sequence by an anaesthesiologist who did not know the nature of the study. The prepared study medications were then given to a research assistant, which were then passed onto another anaesthesiologist responsible for the sedation of the patients in the endoscopy room. Both the investigators and the subjects were blinded to the study medications. Moreover, both preparations were clear solutions; therefore, patients, medical and nursing staff, and data collection staff were all blind to the allocated drug. Patients were sent to a room beside the endoscopy suite about 1 h before the procedure. Sedation scores using Observer Assessment of Alertness/ Sedation (OAA/S) scale and heart rate, blood pressure, SpO2 and respiratory rate (S/5 Anaesthesia Monitor, Datex-Ohmeda, WI, USA) were Acta Anaesthesiologica Scandinavica 59 (2015) 215–223
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recorded at baseline and every 5 min thereafter. OAA/S scale was developed to measure the level of alertness in subjects who are sedated on a 1–5 scale, with 5 being most alert.13 A blinded research assistant was responsible for data collection. Either placebo (0.015 ml/kg, placebo group) or undiluted dexmedetomidine 0.015 ml/kg (1.5 μg/kg, Precedex, Hospira Inc., Lake Forest, IL, USA; 100 mcg/ml, dexmedetomidine group) was administered intranasally 1 h before the procedure. After baseline testing, an investigator administered the study preparation divided in two equal volumes to each naris with the patient in a semi-recumbent position and the head of the bed elevated at a 20- to 40-degree angle. OAA/S scale was assessed every 15 min after the study drug administration while vital sign measurements were recorded every 5 min. Patients were then transferred to the procedure room for upper gastrointestinal endoscopy. Before the procedure started, three sprays of 10% lignocaine were administered to the oropharynx. Patients were given the handset of a patientcontrolled analgesia (PCA) pump (Graseby 3300 Syringe Pump, Smiths Medical, London, UK). On pressing the button, they would receive a bolus dose of 0.5 ml which contained 4.8 mg of propofol and 12 μg of alfentanil mixed together.14 Lockout time was set at zero. However, as the PCA pump was programmed to deliver a bolus dose of 0.5 ml at 200 ml/h on the patient’s demand and the pump took 9 s to deliver the bolus, the effective lockout time was around 9 s. Sedation was deemed adequate to start the procedure if the patients subjectively felt relaxed. OAA/S and vital signs were monitored every 5 min during the endoscopy. If oxygen desaturation developed (SpO2 < 92%), oxygen 3 l/min was administered via a nasal cannula. PCS propofol and alfentanil were terminated and disconnected from the patient when the endoscope was completely removed. After the procedure, patients were transferred to the post-anaesthetic care unit (PACU) beside the endoscopy room where monitoring of OAA/S and vital signs continued every 5 min for 30 min before discharge back to the day ward. Recovery was assessed as fitness for discharge using the post-anaesthetic discharge (PAD) scoring system that is commonly used in ambulatory surgery.15 It was assessed from 1 h post-
operation until the PAD score was equal to or more than 9. Side effects resulting from the use of sedative and analgesic medications were recorded. Satisfaction of sedation was graded by patients using Numerical Rating Scale (zero being least satisfied and 10 being most satisfied). Our primary outcome measure was total consumption of PCS propofol at procedure completion, which was used as a measure of sedative efficacy. A pilot study at our centre found that the total mean ± standard deviation (SD) propofol consumption using PCS propofol and alfentanil for upper gastrointestinal endoscopy was 41.3 ± 23.2 mg. A reduction of 50% in total PCS propofol after intranasal dexmedetomidine in the treatment group was considered clinically significant, and this required a sample size of 20 per group to achieve a power of 80% and a type I error of 5%. In order to account for any dropouts, 25 patients were recruited to each study group. Statistical analysis was performed using Statistical Analysis System for Windows Release 9.2 (SAS Institute Inc, Cary, NC, USA). The data were tested for normality before they were summarised and compared. The demographic and operation measurement data were analysed by t-test and chi-square test as appropriate. The operation measures and drug consumptions (propofol and alfentanil) were analysed by Mann–Whitney U-test. The OAA/S scores and vital signs over the periods before, during and after endoscopy were expressed as weighted areas under the curve (AUCw) using the trapezoid rule and analysed by the Mann–Whitney U-test. Incidents of adverse events were analysed by chi-square test or Fisher’s exact test as appropriate. P < 0.05 was considered statistically significant. Data are presented as mean (SD) if normally distributed, with mean difference between the groups and a 95% confidence interval (CI). Data are presented as median [interquartile range] if the distribution was skewed, and analysed by the Mann–Whitney U-test with an independent sample Hodges–Lehmann estimation of the median difference with a constructed 95% CI. Results From January 2009 to April 2010, 50 patients were recruited (25 patients per group) with no
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Fig. 1. Flow diagram of patient recruitment.
dropouts (Fig. 1). The patient characteristics, and sedation and procedural data of both study groups are shown in Tables 1 and 2 respectively. Intranasal dexmedetomidine resulted in a significant reduction in consumption of propofol and alfentanil when sedation was deemed adequate to start the procedure by the patient [mean difference −9.2 mg (95% CI −20.7 to 2.3) of propofol and −22.9 μg (95% CI −51.7 to 5.8) of alfentanil; P = 0.031] and when the procedure was completed [mean difference −13.8 mg (95% CI −27.3 to −0.3) of propofol and −34.5 μg (95% CI −68.2 to −0.7) of alfentanil; P = 0.044], compared with placebo (Table 3). AUCw of OAA/S scores were significantly less in the dexmedetomidine group
Table 1 Patient demographics.
Age (years) Body weight (kg) Sex (M : F %) ASA physical status (I : II %)
Dexmedetomidine group (n = 25)
Placebo group (n = 25)
41.7 ± 11.7 62.5 ± 11.7 48 : 52 96 : 4
43 ± 11.7 57.1 ± 9.0 28 : 72 96 : 4
Values are mean ± SD (95% CI) or percentage. ASA, American Society of Anesthesiologists.
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Table 2 Sedation and procedural data.
Duration of endoscopy (minutes) Duration from intranasal study medication administration to PDS equal or more than 9 (minutes) Proportion of patients achieving PDS equal or more than 9 at first hour after procedure (%)
Dexmedetomidine group (n = 25)
Placebo group (n = 25)
5 [4–6] 105 [95–120] 88
5 [3–5] 100 [93.5–109] 88
Difference
P value
0 (0 to 1) −5 (−15 to 5) 0 (−19.6 to 19.6)
0.161 0.332 1.000
Values are median (interquartile range) or median difference (95% CI) or percentage or percentage difference (95% CI). PDS, post-anaesthetic discharge scores.
Table 3 Additional propofol and alfentanil consumption during upper gastrointestinal endoscopy.
Propofol (mg) Sedation adequate to start the procedure Total Alfentanil (μg) Sedation adequate to start the procedure Total
Dexmedetomidine group (n = 25)
Placebo group (n = 25)
Difference
P value
16.5 ± 22.3 (7.3 to 25.7) 28.6 ± 23.9 (18.8 to 38.5)
25.7 ± 17.9 (18.3 to 33.1) 42.4 ± 23.5 (32.7 to 52.1)
−9.2 (−20.7 to 2.3) −13.8 (−27.3 to −0.3)
0.031*
41.3 ± 55.7 (18.3 to 64.3) 71.6 ± 59.9 (46.9 to 96.3)
64.2 ± 44.8 (45.7 to 82.7) 106.1 ± 58.8 (81.8 to 130.3)
−22.9 (−51.7 to 5.8) −34.5 (−68.2 to −0.7)
0.031*
0.044*
0.044*
Values are mean ± SD (95% CI) or mean difference (95% CI). *Statistically significant at P < 0.05.
Table 4 Observer’s assessment of alertness/sedation OAA/S (scale 1 to 5).
AUCw 1 h before endoscopy AUCw during endoscopy AUCw 30 min after endoscopy
Dexmedetomidine group (n = 25)
Placebo group (n = 25)
Difference
P value
4.2 [4.1–4.4] 4 [3.5–4.5] 4.8 [4–5]
4.7 [4.6–5] 4.5 [4–5] 5 [4.8–5]
−0.5 (−0.7 to −0.3) −0.5 (−1 to 0) −0.1 (−0.7 to 0)
< 0.001* 0.024* 0.041*
Values are median [interquartile range] or median difference (95% CI). *Statistically significant at P < 0.05. AUCw, weighted areas under the curve.
than placebo before (median difference of −0.5 with 95% CI −0.7 to −0.3; P < 0.001), during (median difference of −0.5 with 95% CI −1 to 0; P = 0.024) and after (median difference of −0.1 with 95% CI −0.7 to 0; P = 0.041) upper gastrointestinal endoscopy (Table 4). The same proportion of patients (88%) had PDS equal or more
than 9 at the first hour after the procedure (Table 2). Concerning perioperative haemodynamic parameters, AUCw of heart rate (beat/min) was significantly lower in the dexmedetomidine than placebo group before (median difference of −6.7 with 95% CI −11.6 to −1.3; P = 0.015), during
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Fig. 2. Heart rate (HR) and systolic blood pressure (SBP) of patients receiving intranasal dexmedetomidine (dexmedetomidine group, denoted by black round data points ●) and 0.9% saline (placebo group, denoted by white round data points ○) before (induction), during (intraOp) and after (RR) upper gastrointestinal endoscopy. Data shown are mean ± standard deviation (SD). Data points were slightly shifted horizontally to avoid overlapping. *AUCw significantly different between dexmedetomidine and placebo groups.
(median difference of −12.5 with 95% CI −18.5 to −5.5; P = 0.007) and after (median difference of −12.4 with 95% CI −16.7 to −6.6; P < 0.001) the procedure (Fig. 2). AUCw of systolic blood pressure (mmHg) was also significantly lower during surgery (median difference −13.5 with 95% CI −25.5 to −2; P = 0.022) and in PACU (median difference of −11.9 with 95% CI −21.1 to −2.7; P = 0.018) for patients in the dexmedetomidine compared with placebo group (Fig. 2). None of these, however, were clinically significant decreases that required vasopressors or anticholinergic support. Eight patients from the dexmedetomidine group and five from the placebo group had oxygen saturation below 92% (breathing room air) transiently during the procedure, but this difference was not statistically significant. All of patients responded immediately to
oxygen supplementation (O2 3 l/min by nasal cannulae) to restore SpO2 back to above 95%. There was no difference in other common adverse events after the procedure including headache, dizziness and nausea. No difference was found between the two groups with regard to patient satisfaction.
Discussion We demonstrated that patients given intranasal dexmedetomidine with PCS propofol and alfentanil experienced significantly deeper perioperative sedation with significantly less consumption of additional sedatives. They were also less likely to have tachycardia or hypertension. No delay in recovery or increase in side effects was seen, Acta Anaesthesiologica Scandinavica 59 (2015) 215–223
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although there was no difference in satisfaction about sedation. There are few reports regarding the efficacy of dexmedetomidine for sedation in endoscopic procedures with conflicting results. One study found it inferior to a midazolam and pethidine combination and to fentanyl alone.16 However, another found dexmedetomidine was similar to midazolam in efficacy but superior with regard to retching, side effects and endoscopist satisfaction.17 Dexmedetomidine alone was not as effective as propofol combined with fentanyl for providing sedation during endoscopic retrograde cholangiopancreatography (ERCP).18 However, using dexmedetomidine in a multimodal manner may allow lower doses of each component drug and, potentially, side effects similar to the way it is used during general anaesthesia.19 The antisialagogue effect may also be an advantage in improving the efficacy of topical lignocaine, similar to during fibreoptic intubation.20 Intranasal administration is convenient, effective and non-invasive. Medications can access the systemic circulation via the blood vessels of the subepithelium in the nasal cavity and avoid hepatic first-pass metabolism.21 The pharmacokinetic and pharmacodynamics of intranasal dexmedetomidine have been evaluated in volunteers,22 and the onset of clinical sedation occurs around 30–45 min after administration. Consequently, we gave intranasal dexmedetomidine 1 h before the procedure, and 1.5 μg/kg in healthy volunteers provides clinical sedation for more than 180 min.23 In this study, 1.5 μg/kg was used because upper gastrointestinal endoscopy was stimulating and deeper sedation was desirable while attempting to minimise the cardiovascular and respiratory depression seen with propofol/ alfentanil. No visible signs of local mucosal irritation, inflammation, bleeding or ulceration were noticed in common with our other studies. Propofol has been used successfully in PCS sedation in endoscopy.24–26 However, propofol, often administered with an opioid, increases the incidence of oversedation and respiratory depression.27,28 Therefore, reduction in consumption of PCS propofol and alfentanil was potentially desirable to reduce side effects and improve safety. The bolus dose of PCS propofol and alfentanil in this study was lower than that used by Mazanikov et al. in ERCP.29 We had no incidents
of significant respiratory depression, as opposed to 11% of patients in theirs.29 This may be because we used smaller PCS doses and had overall lower sedative consumption in our study. The addition of intranasal dexmedetomidine provided deeper sedation (lower OAA/S scores) with less requirement for additional sedatives in this study. Its administration before the procedure may also help to alleviate pre-procedural anxiety. Although dexmedetomidine has a synergistic interaction with propofol, based on the results of PDS scores in this study, the recovery in psychomotor function was not delayed when compared with placebo and PCS propofol/alfentanil alone. Such administration, therefore, is suitable for upper gastrointestinal endoscopy and in the day surgery setting. Being an α2 agonist, apart from the sedative and analgesic effects, a modest reduction in heart rate and blood pressure is usual.30 This was also apparent in this study, but no patient required intervention for bradycardia or hypotension. It is important to emphasise that, generally, this is not a clinical concern, and this reduction in catecholamine release and stress response may, in fact, be beneficial, particularly in patients with underlying cardiovascular disease. Jalonen et al. showed that dexmedetomidine reduced sympathetic tone and haemodynamic responses to surgery.31 Its cardioprotection was also supported in a metaanalysis.32 In our previous study, patients using PCS propofol in third molar surgery experienced more dizziness post-operatively compared with using a combination of intranasal dexmedetomidine and PCS propofol;11 however, there was no significant difference between the two groups in common side effects including dizziness in this study. Addition of intranasal dexmedetomidine before the procedure, with the use of PCS propofol and alfentanil, appeared not to increase side effects while providing deeper sedation. However, this study may not be powered enough to show this difference. Most patients in both groups were satisfied with their sedation. Thus, intranasal dexmedetomidine or placebo, with PCS propofol and alfentanil, appears to be equally acceptable to patients, although, again, our study may not be sufficiently powered to detect small differences in patient satisfaction. This could only be truly evaluated with
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a crossover comparison. In fact, it may also not be easy to detect the true difference in satisfaction in a clinical study because patients are often reluctant to criticise their treatment after surgery.33 There are some limitations to our study. Firstly, most of the patients receiving intranasal dexmedetomidine still needed to use PCS. Only a mean reduction in total propofol consumption by 13.8 mg at the completion of the procedure in the dexmedetomidine group was found, which was short of the target of a 50% reduction in total propofol consumption (from our pilot data of 41.3 ± 23.2 mg) used for sample size calculation. This could be overcome by setting stricter statistical requirements (i.e. a power of 90% and a type I error of 1%) and should be considered in future studies. However, with the 25 subjects included in each group in the study, a statistically significant reduction in total propofol consumption was still seen nevertheless. Intranasal dexmedetomidine, therefore, is potentially a useful sedative adjuvant, rather than a strong sedative for sole use. Secondly, as upper gastrointestinal endoscopy is a short procedure, whether our results can be applied to more prolonged and complicated procedures requires further work. Thirdly, patients have to receive it 45–60 min before the procedure due to its delayed clinical onset. Its use, therefore, may not be feasible in centres where the procedure waiting time is short. In conclusion, intranasal dexmedetomidine with PCS propofol and alfentanil appears to confer deeper perioperative clinical sedation, with significantly less use of additional sedatives during upper gastrointestinal endoscopy.
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Acknowledgements We would like to thank the staff of the endoscopy room at Queen Mary Hospital, Hong Kong for their help for the study.
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