Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit

Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit R. M. Venn, 1 C. J. Bradshaw, 1 R. Spencer, 2 D. Brealey, 3 E. Caudwell, 3 C. Naughton, 4 A. Vedio, 4 M. Singer, 3 R. Feneck, 4 D. Treacher, 4 S. M. Willatts 2 and R. M. Grounds 1 1 Department of Intensive Care, St George s Hospital, Blackshaw Road, London SW17 0QT, UK 2 Department of Intensive Care, Bristol Royal Infirmary, Marlborough St, Bristol, UK 3 Department of Intensive Care, University College Hospital, Mortimer St, London, UK 4 Department of Intensive Care, St Thomas Hospital, Lambeth Palace Rd, London, UK Summary Dexmedetomidine, a highly selective and potent a 2 -adrenergic agonist, has a potentially useful role as a sedative agent in patients requiring intensive care. As part of a larger European multicentre trial, a total of 119 postoperative cardiac and general surgical patients requiring ventilation and sedation in an intensive care unit were enrolled in four centres in the United Kingdom. One hundred and five patients were randomly allocated to receive either dexmedetomidine or placebo with rescue sedation and analgesia provided by midazolam and morphine, respectively. Compared with the control group, intubated patients receiving dexmedetomidine required 80% less midazolam [mean 4.9 (5.8) mg.kg ¹1.h ¹1 vs. 23.7 (27.5) mg.kg ¹1.h ¹1,p< 0.0001], and 50% less morphine [11.2 (13.4) mg.kg ¹1.h ¹1 vs. 21.5 (19.4) mg.kg ¹1.h ¹1,p ¼ 0.0006]. Cardiovascular effects and adverse events could be predicted from the known properties of alpha-2 agonists. In conclusion, dexmedetomidine is a useful agent for the provision of postoperative analgesia and sedation. Keywords Dexmedetomidine; sedation. Intensive care; postoperative.... Correspondence to: Dr R. M. Grounds Accepted: 28 May 1999 Intubated, mechanically ventilated patients on the intensive care unit (ICU) require sedation and analgesia in order to tolerate the tracheal tube, artificial ventilation and other intensive care procedures such as bronchial suctioning, physiotherapy and catheter placement. Sedation may improve outcome by reducing the stress response and its sequelae to these interventions [1]. However, sedation regimens also have potentially adverse effects which may increase morbidity and prolong the clinical course [2]. Consequently, sedation techniques are changing and new drugs, working at different sites in the central nervous system to traditional agents, have been developed. Dexmedetomidine is a new, highly selective and potent a 2 -adrenoreceptor agonist under investigation as a sedative agent in intensive care patients. As well as offering sedation and anxiolysis, a 2 agonists have analgesic qualities and reduce the stress response to surgery and intensive care procedures [3]. Importantly, at therapeutic doses, dexmedetomidine does not cause any significant respiratory depression [4]. This paper reports the initial experience of this agent for postoperative sedation in four ICUs in the United Kingdom (UK). Methods Patients admitted postoperatively to general or cardiothoracic intensive care units at four teaching hospitals in the UK were enrolled into the study. Patients were aged 18 years or over and were expected to require a minimum of 6 h postoperative sedation and ventilation. Exclusion criteria were patients with serious central nervous system trauma or undergoing neurosurgery, a requirement for neuromuscular blocking agents, epidural or spinal anaesthesia, any contraindications or allergy to any of the trial drugs, gross obesity (over 50% above ideal body weight), admission for a drug overdose, prior enrolment in a trial 1136 1999 Blackwell Science Ltd Amneal Pharmaceuticals LLC Exhibit 1024 Page 1136

R. M. Venn et al. Dexmedetomidine for postoperative sedation with any experimental drug in the last 30 days, uncontrolled diabetes and excessive bleeding which would be likely to require re-operation. Ethics committee approval was gained at each participating hospital and informed consent was obtained pre-operatively from each patient. Anaesthetic technique prior to entry into the ICU was left to the individual anaesthetist, the only constraint being that benzodiazepines were not used as sole anaesthetic agent. If remifentanil was used for intra-operative analgesia, morphine was given prior to leaving the operating theatre. The first four patients at each centre could be enrolled into an open label study to gain familiarity with dexmedetomidine. Data from these patients were included in the safety analysis. Subsequent patients were then entered into a randomised, double-blind, placebo-controlled trial on entry into the ICU. They received either placebo or dexmedetomidine, with midazolam and morphine used as clinically indicated for rescue sedation and analgesia, respectively. Both dexmedetomidine and placebo solutions were labelled study drug and coded for later analysis. Dexmedetomidine was supplied in 2-ml ampoules at a concentration of 100 mg.ml ¹1, and diluted with normal saline to a concentration of 4 mg.ml ¹1. Placebo solution (normal saline) was supplied and prepared in a similar fashion. Patients were randomly allocated on entry into the ICU to receive either dexmedetomidine or placebo, which was commenced within 1 h of arrival on the unit. The patients received a loading dose of 1 mg.kg ¹1 over 10 min followed by a maintenance infusion rate of 0.2 0.7 mg.kg ¹1.h ¹1 into a peripheral or central vein. The sedation level of the patient was measured using the Ramsay Sedation Score [5] (Appendix A) and patients were maintained at a Ramsay sedation score greater than 2 whilst intubated. The infusion rate could be increased if this was not achieved or reduced if Ramsay sedation score 6 was reached. The protocol stipulated a maximum infusion rate of 0.7 mg.kg ¹1.h ¹1 ; bolus injections were not permitted. The patients were intubated and ventilated with oxygenenriched air to attain acceptable arterial blood gases for a minimum of 6 h. They were extubated when clinically indicated. Following extubation, the infusion was continued for a further 6 h and adjusted to achieve a Ramsay sedation score of more than 1. Sedation with the trial drug could be continued up to a total maximum duration of infusion of 24 h. If patients still required sedation and ventilation after 24 h, they were switched to the usual regimen used on each individual ICU. If adequate sedation was not achieved at the maximum study drug infusion rate, 0.02 mg.kg ¹1 midazolam boluses could be given intravenously. If more than three such boluses were required within 1 h, a midazolam infusion could be commenced (range 0.01 0.2 mg.kg ¹1.h ¹1 ). Morphine could be administered for pain relief in 2-mg intravenous boluses as required, but not by continuous infusion. After extubation, paracetamol and morphine could be used as analgesic agents. Ramsay sedation scores were recorded hourly and prior to every infusion rate change, or prior to administration of midazolam. A further assessment was made at 10 min following each change. Total doses of midazolam, morphine and the study drug administered were recorded. Heart rate, arterial blood pressure, central venous blood pressure, respiratory rate and oxygen saturation were monitored continuously and recorded hourly for the duration of the study period and then at three-hourly intervals for 24 h after the infusion had ended. Temperature and arterial blood gases were recorded at regular intervals and a 12-lead electrocardiogram taken before and after the study infusion. Results are presented as mean (standard deviation (SD)). Analysis of variance for repeated measures was performed on haemodynamic parameters, with compensation for multiple post hoc comparisons using the Bonferroni correction. Intergroup statistical analyses were performed using the Mann Whitney U-test. Statistical significance was considered at p < 0.05. Results Of the 119 patients recruited into the UK study, 14 patients entered the open-labelled study to receive dexmedetomidine and 105 patients were recruited into the double-blind randomised study. Seven of these 105 patients received less than 4 h study drug infusion as three returned to the operating theatre because of bleeding, two had bradycardia with hypotension, one had residual neuromuscular blockade and the other was withdrawn from the study at the surgeon s request because of operative complications. Details from these seven patients, plus those from the 14 patients entered into the open labelled study, were used only in the safety analysis. None of the patients in the open-labelled study were withdrawn because of complications. Of the 98 patients with complete data, 47 received dexmedetomidine (35 male, 12 female), and 51 received placebo (38 male, 13 female). Eighty-one patients (83%) underwent cardiac surgery requiring cardiopulmonary bypass, 39 of whom received dexmedetomidine. The remaining 17 patients underwent general, orthopaedic, head & neck, oncological or vascular surgery, of whom eight received dexmedetomidine. No differences were found between the groups with respect to age, sex, weight, height, operation time and intra-operative analgesia doses (Table 1). 1999 Blackwell Science Ltd 1137 Amneal Pharmaceuticals LLC Exhibit 1024 Page 1137

R. M. Venn et al. Dexmedetomidine for postoperative sedation Anaesthesia, 1999, 54, pages 1136 1142 Table 1 Patient, anaesthetic and operative characteristics in the two groups (mean (SD)). Dexmedetomidine Placebo (n ¼ 47) (n ¼ 51) Age; years 63.3 (13.7) 64.2 (12.3) Weight; kg 76.3 (16.4) 75.9 (13.7) Male: Female 2.9: 1 2.9: 1 Duration of intubation; h 11.4 (4.9) 10.8 (5.8) Duration of study drug infusion; h 18.2 (4.6) 16.1 (4.4) Operation time; h 4.1 (1.1) 4.1(1.3) Intra-operative analgesia in morphine equivalents; mg 16.8 (13.4) 17.8 (10.0) Type of surgery 39 cardiac/8 general 42 cardiac/9 general Table 2 Midazolam requirements for the first 6 h of study and whilst intubated, followed by morphine requirements for the first 6 h, whilst intubated, whilst extubated and during observation period (mean (SD)). Dexmedetomidine Placebo (n ¼ 47) (n ¼ 51) p-value Midazolam 0 6h (mg.kg ¹1 ) 4.3 (5.8) 18.5 (24.6) 10 ¹3 < 0.0001 whilst intubated 4.9 (5.8) 23.7 (27.5) 10 ¹3 < 0.0001 Morphine 0 6h (mg.kg ¹1 ) 9.1 (9.6) 15.3 (17.4) 10 ¹3 0.0135 whilst intubated 11.2 (13.4) 21.5 (19.4) 10 ¹3 0.0006 whilst extubated 4.8 (11.0) 5.8 (5.5) 10 ¹3 0.027 observation period 5.6 (10.6) 9.7 (17.7) 10 ¹3 ns There were no overall differences in the distribution of Ramsay sedation scores between the dexmedetomidine and placebo groups while intubated. However, intubated patients receiving dexmedetomidine required significantly less midazolam than those receiving placebo [4.9 (5.9) vs. 23.7 (27.5) mg.kg ¹1.h ¹1,p¼ 0.0001]. The requirement for morphine was reduced by half in the dexmedetomidine group while intubated [11.2 (13.4) vs. 21.5 (19.4) mg.kg ¹1.h ¹1,p¼ 0.0006], and by 17% after extubation [4.8 (11.0) vs. 5.8 (5.5) mg.kg ¹1.h ¹1,p¼ 0.0270] (Table 2). Those patients (n ¼ 9) on the higher infusion rates of dexmedetomidine (0.56 0.7 mg.kg ¹1.h ¹1 )whilstintubated as compared with those (n ¼ 4) on the lowest infusion rates (0.1 0.25 mg.kg ¹1.h ¹1 ) required more midazolam (9.3 (1.7) vs. 0.58 (0.58) mg.kg ¹1.h ¹1 ) and morphine (11.1 (3.2) vs. 4.3 (2.2) mg.kg ¹1.h ¹1 ) (Fig. 1). Six of the patients receiving placebo and 17 receiving dexmedetomidine required no midazolam while intubated. In addition, two on placebo and six receiving dexmedetomidine required no analgesia. All were cardiac surgical patients with no significant differences in their intra-operative analgesia, age or pathology. In general surgical patients, the placebo group required six times as much midazolam in the first 6 h compared with the dexmedetomidine group (p ¼ 0.02). Overall, morphine requirements in general surgical patients were twice those of cardiac surgical patients, irrespective of the method of sedation. Figure 1 Requirements for rescue sedation and analgesia at differing dexmedetomidine infusion rates. (B) Midazolam; (A) morphine. 1138 1999 Blackwell Science Ltd Amneal Pharmaceuticals LLC Exhibit 1024 Page 1138

R. M. Venn et al. Dexmedetomidine for postoperative sedation There were no significant differences in the duration of intubation (11.4 (4.9) h vs. 10.8 (5.8) h), nor the duration of weaning (3.4 (3.2) h vs. 3.1 (3.0) h) between the dexmedetomidine and placebo groups, respectively. The mean duration of infusion in the dexmedetomidine group was 18.2 h (range 0.17 29 h). The mean infusion rate of dexmedetomidine during intubation was 0.345 (0.15) mg.kg ¹1.h ¹1 and, after extubation, 0.146 (0.08) mg.kg ¹1.h ¹1 (n ¼ 43 as four patients remained intubated for > 24 h). There were no significant differences in respiratory rates nor arterial oxygen saturations between the dexmedetomidine and placebo groups. Insufficient arterial blood gas samples were collected to provide evaluable data on oxygen and carbon dioxide tensions. In the general surgical subgroup, those receiving dexmedetomidine had lower, albeit nonsignificant, respiratory rates (14 (4.7) vs. 21 (7.2) breath.min ¹1,p¼ 0.08) at 2 h after extubation, with 2% higher pulse oximetry readings (98.1 (0.8) vs. 96 (1.9), p ¼ 0.0136). No differences were seen between the cardiac patient subgroups. During the first hour of study drug infusion, systolic and diastolic arterial blood pressures, and heart rates were significantly lower in patients receiving dexmedetomidine. Thereafter, these differences in blood pressure diminished but those patients receiving dexmedetomidine continued to have significantly lower heart rates at around 75 beat.min ¹1. This was well demonstrated for the period 4 h before and after extubation (75 (5.6) vs. 91 (6.5) beat.min ¹1, < 0.0001] (Fig. 2). Over this same period, the mean systolic and diastolic arterial pressures in the dexmedetomidine group were consistently slightly lower than placebo by 6 mmhg and 5 mmhg, respectively (both p ¼ 0.05), with a reduction in the variability of the systolic pressures (p ¼ 0.05). No significant differences were seen in central venous pressures. General surgical patients showed more pronounced cardiovascular differences with a 9-mmHg reduction in diastolic arterial pressure in the dexmedetomidine group (57 (7) vs. 66 (8) mmhg, p ¼ 0.03) and significant tachycardia in the placebo group (78 (6) vs. 101 (9) beat.min ¹1,p¼ 0.02) in the period around extubation (Fig. 3). Safety was examined in all 119 patients recruited, 66 of whom received dexmedetomidine. There were four deaths (three in the placebo group, one in the dexmedetomidine group) but none of these deaths was considered attributable to the study drug. Ten patients who received dexmedetomidine and nine receiving placebo had clinically significant ECG changes all these patients had undergone cardiac surgery (Table 3). Eighteen of the 66 patients receiving dexmedetomidine experienced significant hypotension (mean arterial pressure < 60 mmhg or > 30% fall from preinfusion values) Figure 2 Cardiovascular profiles of all patients (n ¼ 98) for 0 6 h and extubation 4 h. Mean (SD) arterial pressures and heart rates for the two groups. (B) Dexmedetomidine; (A) placebo. or bradycardia (< 50 beat.min ¹1 ). In 11 patients, this occurred during the loading dose period. This resulted in a temporary interruption of the infusion in three patients and withdrawal from the study in a further three. There was no difference in the use of vasoactive drugs between groups (Table 4). Loading dose hypertension was reported as an adverse event in six patients receiving dexmedetomidine and five patients on placebo. In the dexmedetomidine group, this was a transient event (less than 10 min) but hypertension was sustained in the placebo group (between 10 min and 4 h). 1999 Blackwell Science Ltd 1139 Amneal Pharmaceuticals LLC Exhibit 1024 Page 1139

R. M. Venn et al. Dexmedetomidine for postoperative sedation Anaesthesia, 1999, 54, pages 1136 1142 Table 3 Adverse events excluding hypotension and/or bradycardia. Event Dexmedetomidine Placebo (n ¼ 66) (n ¼ 53) Death 1 3 Loading dose hypertension 6 5 Atrial fibrillation/tachyarrythmias 8 5 Postoperative bleeding 6 6 Stroke 0 3 Angina 1 1 Myocardial infarction 0 2 Nausea and vomiting 16 5 Flashing lights 2 0 ECG changes 10 9 Discussion Dexmedetomidine is the dextro-stereoisomer and active ingredient of medetomidine, an agent used for many years in veterinary anaesthesia. It is a highly selective a 2 agonist with an affinity eight times that of clonidine for the adrenoceptor (a 2 : a 1 ratio 1600 : 1) [3]. a 2 adrenoceptors can be found in the central nervous system, peripheral nerves and autonomic ganglia at presynaptic and postsynaptic sites. Stimulation of presynaptic a 2 receptors located in sympathetic nerve endings inhibits the release of noradrenaline. Activation of postsynaptic receptors by a 2 agonists in the CNS leads to inhibition of sympathetic activity, decreases in blood pressure and heart rate, and sedation, while binding of agonists to a 2 adrenoceptors in the spinal cord produces analgesia [3]. Peripheral a 2 receptors in blood vessels mediate vascular smooth muscle contraction and a rapid injection of a potent a 2 agonist can result in transient hypertension [6]. Dexmedetomidine is rapidly and extensively distributed to tissues with a distribution half-life of 5 min and elimination half-life of 2 3 h. It is extensively metabolised by phase one and phase two reactions in the liver and both urinary and faecal excretion are involved in elimination of dexmedetomidine and its metabolites (Personal communication. Abbott Laboratories, Abbott Park, IL, USA). Although dexmedetomidine inhibits cytochrome P450 metabolism in the laboratory, clinically relevant drug interactions at the plasma concentrations found in humans are not expected [7]. Unlike etomidate, dexmedetomidine has negligible effects on adrenal steroidogenesis in dogs [8]. The principal end-points of the study were to see if there were any differences in midazolam and morphine requirements between postoperative patients receiving dexmedetomidine and placebo. This was clearly demonstrated by an 80% reduction in midazolam and a 50% reduction in morphine requirements. While intubated, 36% of patients Figure 3 General surgical patients cardiovascular profile (n ¼ 17) for 0 6 h and extubation 4 h. Mean (SD) arterial pressures and heart rates for the two groups. (B) Dexmedetomidine; (A) placebo. on dexmedetomidine and 11% on placebo required no midazolam. The placebo-controlled nature of the protocol ultimately meant that the initial method of sedation differed between patients receiving dexmedetomidine and placebo. The dexmedetomidine group received a loading dose followed by an infusion of the sedative agent, whereas the placebo group received a loading dose followed by an infusion of placebo and so initially remained sedated under the influence of their intra-operative anaesthesia. On waking, they received midazolam boluses, sometimes followed by an infusion. Consequently, this made interpretation of the results difficult, especially during the first hour of the study, due to the less fluent 1140 1999 Blackwell Science Ltd Amneal Pharmaceuticals LLC Exhibit 1024 Page 1140

R. M. Venn et al. Dexmedetomidine for postoperative sedation Table 4 Cardiovascular adverse events in 18/66 patients receiving dexmedetomidine. Arterial pressure Heart rate (mmhg) (beat.min ¹1 ) Outcome and treatment Loading dose events Hypotension 75/40 Infusion stopped after 10 min Bradycardia 45 Paced after 30 min and infusion stopped Hypotension 56/35 Infusion interrupted for 10 min Hypotension 70/41 Infusion interrupted for 42 min, restarted at reduced rate Hypotension 84/44 Resolved in 10 min with fluids & reduced infusion rate Hypotension 73/35 Resolved with fluids after 10 min Hypotension 95/56 Resolved with fluids within 30 min Hypotension 65/29 50 Paced after 20 min of infusion for 15 h Hypotension 77/40 45 Paced after 1 h of infusion for 7 h Bradycardia 79/40 52 Paced after 10 min of infusion for 12 h Hypotension 81/56 Resolved with fluids within 10 min Events at other times Bradycardia after 3 h of infusion 68/30 45 Atropine, inotropes & infusion stopped Bradycardia, repeated episodes 60/30 40 45 Atropine & inotropes, infusion stopped after 20 h Hypotension & bradycardia after 11 h 75/54 48 Infusion interrupted for 2 h, fluids given Hypotension after 1 h 85/47 Hypotension resolved with fluids within 1 h Bradycardia, after 4 h 76/44 44 Resolved with fluids within 1 h of infusion Bradycardia, repeated episodes 40 42 Resolved after 2 h, fluids only Bradycardia after 2 h of infusion 55 Resolved after 1 h, no treatment required sedation received by the placebo group. This may have accounted for the higher initial arterial blood pressures seen in the placebo group. The majority of adverse events (hypotension and bradycardia) occurred early in the study period as a result of the loading dose of dexmedetomidine; these were not a feature in the placebo group. This was predictable from the known properties of a 2 agonists and might have been avoided by omitting the loading dose and commencing the infusion while in the operating theatre. The protocol allowed neither boluses of study drug nor exceeding the maximum infusion rate (0.7 mg.kg ¹1.h ¹1 dexmedetomidine) if the patient lightened and required additional sedation. This may have accounted for some of the midazolam dosing used in the dexmedetomidine group. The maximum dexmedetomidine infusion rate was predetermined from Phase II clinical trials and was clearly insufficient in some patients (n ¼ 9). Patients receiving the maximum infusion rate required considerably more midazolam and, of interest, morphine requirements did not mirror midazolam, perhaps demonstrating that there is an analgesic ceiling-effect to dexmedetomidine. Future studies need to address these issues. The delay mentioned above in achieving an initial fluency of sedation may also have contributed to the cardiovascular differences seen between the groups. Cardiovascular data relating to the 4-h period before and after extubation are likely to be more representative of the differences between the groups. During this period, significant reductions were seen in heart rate, and systolic and diastolic arterial pressures in the dexmedetomidine group, resulting in a lower rate pressure product and, potentially, less ischaemic events due to reduced oxygen demand [9]. An obvious advantage of dexmedetomidine, in contrast to other sedation agents used to blunt cardiovascular responses in the peri-extubation period, is the reported lack of respiratory depression [10]. The hypotension and bradycardia occurring during the loading dose phase of the dexmedetomidine was only seen in cardiac patients. This is probably directly attributable to stimulation of the central postsynaptic a 2 receptors causing inhibition of sympathetic activity or augmentation of parasympathetic activity. Although dexmedetomidine is potentially a hypertensive agent by its peripheral a 2 vasoconstricting effect on vascular smooth muscle, no differences were seen between the two groups. Previous studies in healthy volunteers suggest this to be a transient event with overall dominance of the central effects [6]. The incidence of nausea and vomiting requiring an antiemetic was higher in patients receiving dexmedetomidine; this was contrary to previous findings in women undergoing minor gynaecological surgery [11]. The anxiolytic properties of dexmedetomidine were clearly demonstrated by the general surgical patients who were free from the effects of cardiac anaesthesia and bypass. This group had better pulse oximetry saturations (p ¼ 0.04), less tachycardia (p ¼ 0.04) and less tachypnoea (p ¼ 0.08)at extubation and up to 4 h afterwards. Although an increase in oxygen saturation of only 2% may not seem clinically significant, in combination with a lower respiratory rate 1999 Blackwell Science Ltd 1141 Amneal Pharmaceuticals LLC Exhibit 1024 Page 1141

R. M. Venn et al. Dexmedetomidine for postoperative sedation Anaesthesia, 1999, 54, pages 1136 1142 (up to 33% lower), and a lower heart rate (up to 25%), this does have significant implications for potential reductions in fatigue and myocardial ischaemia, recognised hazards at the stressful time around extubation. The study was performed as part of a larger European Phase III trial and allowed up to four patients in each centre to be entered into an open label study so that medical staff could experience the unique nature of sedation with dexmedetomidine. Patients are calmly and easily roused from sleep to allow excellent communication and co-operation while intubated and ventilated, and then similarly quickly return to sleep. Complex tasks, such as communication by pen and paper, are possible. Nursing staff and patient questionnaires, although limited, revealed no significant differences in the ease of management of the patient, or the patient s memory of their time on intensive care. However, a small number of patients who received dexmedetomidine resented their increased level of awareness while on the ICU and found the whole experience very stressful, despite the apparent ease with which they were managed by ICU staff. Dexmedetomidine at the doses used may lack the amnesic properties of midazolam and this warrants further investigation. The study has shown that dexmedetomidine significantly reduces the requirements for rescue sedation and analgesia in a placebo-controlled trial in postoperative patients for up to 24 h. Its sedative properties differ from traditional agents with patients being more easily roused. Further trials are needed for direct comparisons to be made with traditional sedation agents, to establish its suitability in nonsurgical patients and for long-term use. Declaration This study was supported by Abbott Laboratories. Dr R. M. Grounds performs consultancy work on their behalf. The results of this study were presented in part at the 19th International Symposium on Intensive Care and Emergency Medicine, Brussels, 1999. References 1 Beattie WS, Buckley DN, Forrest JB. Epidural morphine reduces the risk of postoperative myocardial ischaemia in patients with cardiac risk factors. Canadian Journal of Anaesthesia 1993; 40: 532 41. 2 Prielipp RC, Coursin DB, Wood KE, Murray MJ. Complications associated with sedative and neuromuscular blocking drugs in critically ill patients. Critical Care Clinics 1995; 11: 983 1003. 3 Hayashi Y, Maze M. Alpha-2 adrenoceptor agonists and anaesthesia. British Journal of Anaesthesia 1993; 71: 108 18. 4 Belleville JP, Ward DS, Bloor BC, et al. Ventilatory effects of dexmedetomidine in humans. Anesthesiology 1990; 73: A1167. 5 Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxolone alphadolone. British Medical Journal 1974; II: 656 9. 6 Bloor BC, Ward DS, Belleville JP, Maze M. Sedative and hemodynamic effects of dexmedetomidine in humans. Anesthesiology 1990; 73: A411. 7 Dyck JB, Maze M, Shafer SL. The pharmacokinetics of dexmedetomidine in adults. Anesthesiology 1991; 75: A310. 8 Maze M, Virtanen R, Daunt D, Banks SJ, Stover EP, Feldman D. Effects of dexmedetomidine, a novel imidazole sedative-anesthetic agent, on adrenal steroidogenesis: in vivo and in vitro studies. Anesthesia and Analgesia 1991; 73: 204 8. 9 Low JM. Haemodynamic monitoring. In: Oh TE, ed. Intensive Care Manual, 3rd edn. London: Butterworths, 1991: 583. 10 Conti J, Smith D. Haemodynamic responses to extubation after cardiac surgery with and without continued sedation. British Journal of Anaesthesia 1998; 80: 834 6. 11 Aantaa R, Kanto J, Scheinin M, Kallio A, Scheinin H. Dexmedetomidine an alpha 2 adrenoceptor agonist, reduces anaesthetic requirements for patients undergoing minor gynaecological surgery. Anesthesiology 1990; 73: 230 5. Appendix A Level 1 Level 2 Level 3 Level 4 Level 5 Level 6 Patient awake, anxious and agitated or restless, or both Patient awake, co-operative, orientated, and tranquil Patient awake, responds to commands only Patient asleep, brisk response to light glabellar tap or loud auditory stimulus Patient asleep, sluggish response to light glabellar tap or loud auditory stimulus Patient asleep, no response to light glabellar tap or loud auditory stimulus 1142 1999 Blackwell Science Ltd Amneal Pharmaceuticals LLC Exhibit 1024 Page 1142