1Department of Anaesthesia & Intensive Care, Worthing Hospital, Lyndhurst Road, Worthing, West Sussex BN11 2DH, UK. 2Department of Intensive Care Medicine, St Georges Hospital, Blackshaw Road, London SW17 OQT, UK*Corresponding author
This article is accompanied by Editorial I.
Dr R. M. Grounds has performed consultancy work on behalf of Abbott Laboratories. Abbott Laboratories have also contributed towards the St Georges Hospital Special Trustees research fund, which supports the salaries of research fellows in the ICU.
Accepted for publication: May 17, 2001
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Abstract |
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Br J Anaesth 2001; 87; 68490
Keywords: sympathetic nervous system, dexmedetomidine; intensive care, sedation, post-operative; monitoring, cardiopulmonary; anaesthetic techniques, extubation; analgesics, opioid; complications
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Introduction |
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The 2 agonist dexmedetomidine is a new sedative and analgesic agent which has been licensed recently in the USA as ICU sedation for up to 24 h after surgery. Dexmedetomidine provides haemodynamic stability6 and appears to have no clinically important adverse effects on respiration.7 Its sedative properties are unique in that it produces only mild cognitive impairment,8 allowing easy communication between health-care provider and patient in the ICU.6 We therefore compared the sedative and analgesic properties, safety profile, cardiovascular responses, ventilation and extubation characteristics, and patient perceptions of dexmedetomidine with those of the commonly used i.v. sedative agent propofol in the ICU.
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Methods |
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Patients were ventilated mechanically with oxygen-enriched air to attain acceptable blood gases. The sedative infusion was discontinued, in preparation for extubation, when there was no evidence of bleeding and the patient was alert, cardiovascularly stable, normothermic, and with an arterial oxygen tension 10 kPa on an inspired oxygen concentration <40% and had positive end-expiratory pressure <5 cm H2O. Once spontaneous respiration had been established with pressure support <10 cm H2O, a tidal volume of >6 ml kg1, and respiratory rate
10 breaths min1 but <20 breaths min1, extubation was undertaken.11 Extubation time was defined as the time from cessation of sedation infusion to extubation. Heart rate, arterial pressure, central venous pressure and oxygen saturation were monitored continuously. Venous samples were taken for routine haematological (full blood count, coagulation profile) and biochemical (electrolytes, urea, creatinine, liver function, phosphate and calcium) profiles immediately on arrival in the ICU, and then at 24 and 48 h. Cardiovascular and respiratory adverse events were defined as a change in arterial pressure of
40% from baseline, bradycardia <50 beats min1, tachyarrhythmia, and a respiratory rate <8 or >25 breaths min1 after extubation. Patients were given a Hewitt questionnaire3 to complete (see Appendix) 4872 h after discharge from the ICU. The effects of dexmedetomidine on adrenocortical function and endocrine and inflammatory responses were also studied, the results of which are presented separately.12
From previous work,6 7 a sample size of 20 was expected to have a power of 80% to detect a 50% reduction in analgesic requirements and a 20% reduction in heart rate at a significance level of 5%. Data are shown as mean (SD) values unless otherwise stated, and comparisons were made using the unpaired t-test. Medians and interquartile ranges (IQR) are quoted for skewed data, and comparisons were made using the MannWhitney U-test. Haematological and biochemical values and haemodynamics were compared using ANOVA for repeated measures followed by post hoc Bonferroni testing. Values of RSS and BI are shown as median (IQR) and were compared by a two-stage method that used summary measures;13 the area under the curve was calculated for each patient and between-group comparisons were made using the MannWhitney U-test. P<0.05 was accepted as significant. All analysis was carried out using the Statview for Windows software package (version 4.57; Abacus Concepts, Berkeley, CA, USA).
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Results |
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Analgesia
Intraoperative analgesia was equivalent in the two groups (Table 1). Patients receiving propofol infusions required significantly more alfentanil [2.5 (2.22.9) mg h1] than patients receiving dexmedetomidine [0.8 (0.651.2) mg h1] (P=0.004) (Fig. 1).
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Ventilation and extubation
Mechanical ventilation variables and arterial blood gas analysis were similar in the two groups for the first 8 h of intubation and artificial ventilation (Table 2). Significant differences existed in the arterial/inspired oxygen ratio between the two groups at baseline and throughout the study (P=0.003). Mean (range) extubation times were 28 (2050) and 29 (1550) min respectively for the propofol and dexmedetomidine groups (P=0.63). There were no respiratory adverse events after extubation in either group, and no patient required re-intubation.
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Median (IQR) urine output for the study period was 141 (104177) ml h1 for the dexmedetomidine group and 94 (64146) ml h1 for the propofol group (P=0.12).
Mortality
Two patients died in the dexmedetomidine group and one in the propofol group, on days 14, 17 and 35 respectively, after initially recovering well.
Patient experiences (Table 4)
Memory of ICU experiences
The majority of patients receiving dexmedetomidine recorded the length of stay in the ICU accurately, in contrast to those in the propofol group (P=0.023). However, only a few patients in both groups remembered the duration of mechanical ventilation; these five patients experienced discomfort whilst receiving mechanical ventilation, although none recorded any pain.
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Discomforts and anxieties
Noise and difficulty in sleeping were the principal concerns in the propofol group. Discomfort on the ventilator was a major concern in those receiving dexmedetomidine, although it only occurred in three patients.
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Discussion |
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It is difficult to quantify the cooperation and ease of management seen with patients sedated with dexmedetomidine in the ICU, which presumably reflects only mild cognitive impairment. This may explain the ease and speed of extubation after dexmedetomidine infusions. Although extubation times were similar in the groups, a longer extubation time would have been predicted with dexmedetomidine from volunteer pharmacokinetic data,1416 as the elimination half-life of propofol17 is approximately three times shorter (3060 min for propofol vs 100150 min for dexmedetomidine). In fact, dexmedetomidine can be continued safely over the extubation period.7 According to our results, the sample size in this study had an 80% power of detecting a 40% difference in extubation times between the two groups (-value 0.05). It is also important to note that species-specific hypoxia,7 seen particularly in sheep given dexmedetomidine, does not occur in humans (Table 2).
The haemodynamics of dexmedetomidine is predictable from the pharmacology of 2 adrenoceptor agonists, and has been confirmed from previous studies in volunteers,18 19 patients under anaesthesia20 21 and, more recently, ICU patients.6 Great interest exists in the comparative difference in cardiovascular responses between dexmedetomidine and other sedative agents. Vasodilatation, which manifests itself as a reduction in arterial pressure, is a feature of sedation with both propofol11 22 23 and dexmedetomidine.6 In this study, equipotent sedative doses of these agents, infused in patients with similar central venous filling pressures, resulted in equivalent mild reductions in arterial pressures. The numerous adverse cardiovascular events seen previously with the loading infusion of dexmedetomidine6 were not seen in this study. This was achieved by reducing the dexmedetomidine dose during the loading infusion. However, the significantly lower heart rates seen with dexmedetomidine in comparison with patients receiving propofol may lower the risk of ischaemic events during the stressful ICU episode, in particular over the extubation period. Previous studies have shown sustained higher heart rates (mean 90 beats min1) similar to those in this study for patients receiving propofol in the ICU.11 22 23
No differences in measured biochemical and haematological variables were seen between the groups. A few within-group differences were seen (and would be expected) after extensive surgery. The median urine output was greater for patients receiving dexmedetomidine, although this was not statistically significant. Previous experimental data have shown that 2 adrenoceptor agonists promote diuresis and natriuresis. The mechanisms proposed include inhibition of antidiuretic hormone24 and/or atrial natriuretic peptide release.25 However, the small increase in urea and creatinine seen in this study do not support any renal protective effects of dexmedetomidine.
The median BIS values of patients receiving either dexmedetomidine or propofol infusions in this study suggest a low incidence of recall.10 Although many patients who received dexmedetomidine were able to record their total length of ICU stay accurately, far fewer could recall the duration of mechanical ventilation, presumably because of the use of sedative agents. It may be that any amnesic actions of dexmedetomidine disappear rapidly after discontinuation of the infusion. However, in both groups a few patients were able to remember the period during which they were mechanically ventilated and sedated, and it would therefore be prudent not to use dexmedetomidine alone in patients who are also receiving neuromuscular block agents.
A modified Hewitt questionnaire was used in this study as it has been used by several researchers3 26 27 to determine patients recollections, anxieties and discomforts within a few days of their ICU stay. Although patients appeared calm and cooperative to the clinician whilst sedated with dexmedetomidine, this may not reflect their perception of this time in the ICU. Reassuringly, all patients who received dexmedetomidine described their ICU stay as pleasant and were not resentful of any awareness. Sleep, anxiety concerning the ventilator, pain and noise featured prominently in both groups as the major discomforts and anxieties whilst in the ICU, and this again parallels previous studies.35 Interestingly, lack of sleep appeared to be less of a problem in patients receiving dexmedetomidine, and it may be that pharmacological sleep with dexmedetomidine resembles normal physiological sleep. This is relevant because deprivation may correlate with the development of ICU psychosis.28
In conclusion, dexmedetomidine appears to be a safe and acceptable ICU sedative agent when both the clinicians and patients perspectives are considered. Depth of sedation is similar to that given by propofol and the extubation time is equally rapid, despite the longer elimination half-life of dexmedetomidine. The cardiovascular response of patients sedated with dexmedetomidine is similar to that of patients sedated with equipotent doses of propofol, except that those receiving dexmedetomidine do not increase their heart rate. These properties, combined with the analgesic qualities and lack of respiratory depression seen with dexmedetomidine, have advantages for patients at risk from myocardial ischaemia.
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Appendix |
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1 How long do you think you were in intensive care?
Hours
Days
No idea
2 How long do you think you were on the breathing machine in intensive care?
Hours
Days
No idea
Never
3 When on the breathing machine did you feel
Pain
Discomfort
4 Which of the following descriptions best describes the nursing staff?
Efficient and sympathetic
Efficient but not always thoughtful enough
Too attentive
Too distant
Unable to remember
5 Which of the following descriptions best describes the doctors?
Efficient and considerate
Efficient but did not explain things enough
Too disturbing and discussed too many worrying medical details in front of you
Not around enough when you felt you needed treatment or explanations
Unable to remember
6 Do you think your relatives or friends
were allowed to see you enough?
Yes
No
received adequate explanation about your progress?
Yes
No
7 Did any/some/all of the following aspects of intensive care upset you a lot?
Physiotherapy
Suction down breathing tubes
Handling and movement of various tubes
Amount of noise
Alarms
Conversations in the ITU (medical or non-medical)
Amount of machinery
Difficulty in resting or sleeping
If you circled this aspect of care, was the difficulty due to any or all of the following?
Pain, discomfort, noise, light, anxiety
Pain
Being on the breathing machine
Fear of insertion of lines and tubes
Fear of machine failure
Being washed
Any other worriesplease state
8 Were you pleased to leave intensive care and return to your ward?
Yes
No
9 What are your overall feelings about intensive care?
Pleasant
Unpleasant
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References |
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