Anaesthesia, 1999, 54, pages 1136–1142
`................................................................................................................................................................................................................................................
`
`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. Willatts2 and R. M. Grounds1
`
`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 a2-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.kg¹1.h¹1 vs. 23.7 (27.5) mg.kg¹1.h¹1, p < 0.0001], and 50% less
`morphine [11.2 (13.4) mg.kg¹1.h¹1 vs. 21.5 (19.4) mg.kg¹1.h¹1,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 devel-
`oped. Dexmedetomidine is a new, highly selective and
`potent a2-adrenoreceptor agonist under investigation as
`a sedative agent in intensive care patients. As well as
`offering sedation and anxiolysis, a2 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 cardio-
`thoracic 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 anaes-
`thesia, 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
`
`䊚 1999 Blackwell Science Ltd
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1024 – Page 1136
`
`

`
`R. M. Venn et al. (cid:129) Dexmedetomidine for postoperative sedation
`Anaesthesia, 1999, 54, pages 1136–1142
`................................................................................................................................................................................................................................................
`
`with any experimental drug in the last 30 days, uncon-
`trolled 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 dexme-
`detomidine. 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 anal-
`gesia, respectively.
`Both dexmedetomidine and placebo solutions were
`labelled ‘study drug’ and coded for later analysis. Dexme-
`detomidine was supplied in 2-ml ampoules at a concen-
`tration of 100 mg.ml¹1, and diluted with normal saline to
`a concentration of 4 mg.ml¹1. 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.kg¹1 over 10 min followed
`by a maintenance infusion rate of 0.2–0.7 mg.kg¹1.h¹1
`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.kg¹1.h¹1; bolus injections were not permitted.
`The patients were intubated and ventilated with oxygen-
`enriched air to attain acceptable arterial blood gases for a
`minimum of 6 h. They were extubated when clinically
`indicated. Following extubation, the infusion was con-
`tinued 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.kg¹1 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.kg¹1.h¹1).
`
`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 adminis-
`tration of midazolam. A further assessment was made
`at 10 min following each change. Total doses of midazo-
`lam, 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. Tempera-
`ture 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 correc-
`tion. 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 dex-
`medetomidine 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 bleed-
`ing, two had bradycardia with hypotension, one had
`residual neuromuscular blockade and the other was with-
`drawn 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 anal-
`gesia doses (Table 1).
`
`䊚 1999 Blackwell Science Ltd
`
`1137
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1024 – Page 1137
`
`

`
`R. M. Venn et al. (cid:129) Dexmedetomidine for postoperative sedation
`Anaesthesia, 1999, 54, pages 1136–1142
`................................................................................................................................................................................................................................................
`
`Table 1 Patient, anaesthetic and operative
`characteristics in the two groups (mean
`(SD)).
`
`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)).
`
`Age; years
`Weight; kg
`Male: Female
`Duration of intubation; h
`Duration of study drug infusion; h
`Operation time; h
`Intra-operative analgesia in
`morphine equivalents; mg
`Type of surgery
`
`Dexmedetomidine
`(n ¼ 47)
`
`Placebo
`(n ¼ 51)
`
`63.3 (13.7)
`76.3 (16.4)
`2.9: 1
`11.4 (4.9)
`18.2 (4.6)
`4.1 (1.1)
`
`64.2 (12.3)
`75.9 (13.7)
`2.9: 1
`10.8 (5.8)
`16.1 (4.4)
`4.1(1.3)
`
`16.8 (13.4)
`39 cardiac/8 general
`
`17.8 (10.0)
`42 cardiac/9 general
`
`Dexmedetomidine
`(n ¼ 47)
`
`Placebo
`(n ¼ 51)
`
`p-value
`
`Midazolam
`0–6 h (mg.kg¹1)
`whilst intubated
`(mg.kg¹1.h¹1)
`
`Morphine
`0–6 h (mg.kg¹1)
`whilst intubated
`(mg.kg¹1.h¹1)
`whilst extubated
`(mg.kg¹1.h¹1)
`observation period
`(mg.kg¹1.h¹1)
`
`4.3 (5.8)
`4.9 (5.8)
`
`9.1 (9.6)
`11.2 (13.4)
`
`4.8 (11.0)
`
`5.6 (10.6)
`
`18.5 (24.6) × 10¹3
`23.7 (27.5) × 10¹3
`
`< 0.0001
`< 0.0001
`
`15.3 (17.4) × 10¹3
`21.5 (19.4) × 10¹3
`
`5.8 (5.5) × 10¹3
`
`0.0135
`0.0006
`
`0.027
`
`9.7 (17.7) × 10¹3
`
`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.kg¹1.h¹1, p ¼ 0.0001]. The requirement
`for morphine was reduced by half in the dexmedetomi-
`dine group while intubated [11.2 (13.4) vs. 21.5
`(19.4) mg.kg¹1.h¹1, p ¼ 0.0006], and by 17% after extu-
`bation [4.8 (11.0) vs. 5.8 (5.5) mg.kg¹1.h¹1, p ¼ 0.0270]
`(Table 2).
`Those patients (n ¼ 9) on the higher infusion rates of
`dexmedetomidine (0.56–0.7 mg.kg¹1.h¹1) whilst intubated
`as compared with those (n ¼ 4) on the lowest infusion rates
`(0.1–0.25 mg.kg¹1.h¹1) required more midazolam (9.3
`(1.7) vs. 0.58 (0.58) mg.kg¹1.h¹1) and morphine (11.1
`(3.2) vs. 4.3 (2.2) mg.kg¹1.h¹1) (Fig. 1).
`Six of the patients receiving placebo and 17 receiving
`dexmedetomidine required no midazolam while intu-
`bated. 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
`
`䊚 1999 Blackwell Science Ltd
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1024 – Page 1138
`
`

`
`R. M. Venn et al. (cid:129) Dexmedetomidine for postoperative sedation
`Anaesthesia, 1999, 54, pages 1136–1142
`................................................................................................................................................................................................................................................
`
`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.kg¹1.h¹1 and, after extubation, 0.146 (0.08)
`mg.kg¹1.h¹1 (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 dexmedeto-
`midine 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.min¹1, p ¼ 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 dexmedetomi-
`dine. Thereafter,
`these differences
`in blood pressure
`diminished but those patients receiving dexmedetomidine
`continued to have significantly lower heart rates at around
`75 beat.min¹1. This was well demonstrated for the period
`4 h before and after extubation (75 (5.6) vs. 91 (6.5)
`beat.min¹1, < 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.min¹1, p ¼ 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 dexmede-
`tomidine group) but none of these deaths was considered
`attributable to the study drug. Ten patients who received
`dexmedetomidine and nine receiving placebo had clini-
`cally significant ECG changes – all these patients had
`undergone cardiac surgery (Table 3).
`Eighteen of the 66 patients receiving dexmedetomidine
`experienced significant hypotension (mean arterial pres-
`sure < 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.min¹1). 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 hyper-
`tension was sustained in the placebo group (between
`10 min and 4 h).
`
`䊚 1999 Blackwell Science Ltd
`
`1139
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1024 – Page 1139
`
`

`
`R. M. Venn et al. (cid:129) Dexmedetomidine for postoperative sedation
`Anaesthesia, 1999, 54, pages 1136–1142
`................................................................................................................................................................................................................................................
`
`Table 3 Adverse events excluding hypotension and/or brady-
`cardia.
`
`Event
`
`Dexmedetomidine
`(n ¼ 66)
`
`Placebo
`(n ¼ 53)
`
`Death
`Loading dose hypertension
`Atrial fibrillation/tachyarrythmias
`Postoperative bleeding
`Stroke
`Angina
`Myocardial infarction
`Nausea and vomiting
`Flashing lights
`ECG changes
`
`1
`6
`8
`6
`0
`1
`0
`16
`2
`10
`
`3
`5
`5
`6
`3
`1
`2
`5
`0
`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 a2 agonist
`with an affinity eight times that of clonidine for the
`adrenoceptor (a2 : a1 ratio 1600 : 1) [3]. a2 adrenoceptors
`can be found in the central nervous system, peripheral
`nerves and autonomic ganglia at presynaptic and post-
`synaptic sites. Stimulation of presynaptic a2 receptors
`located in sympathetic nerve endings inhibits the release
`of noradrenaline. Activation of postsynaptic receptors by
`a2 agonists in the CNS leads to inhibition of sympathetic
`activity, decreases in blood pressure and heart rate, and
`sedation, while binding of agonists to a2 adrenoceptors
`in the spinal cord produces analgesia [3]. Peripheral a2
`receptors in blood vessels mediate vascular smooth muscle
`contraction and a rapid injection of a potent a2 agonist can
`result in transient hypertension [6]. Dexmedetomidine is
`rapidly and extensively distributed to tissues with a distri-
`bution 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 concen-
`trations 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 require-
`ments between postoperative patients receiving dexmede-
`tomidine 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 anaes-
`thesia. 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
`
`䊚 1999 Blackwell Science Ltd
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1024 – Page 1140
`
`

`
`R. M. Venn et al. (cid:129) Dexmedetomidine for postoperative sedation
`Anaesthesia, 1999, 54, pages 1136–1142
`................................................................................................................................................................................................................................................
`
`Table 4 Cardiovascular adverse events in 18/66 patients receiving dexmedetomidine.
`
`Arterial pressure
`(mmHg)
`
`Heart rate
`(beat.min¹1)
`
`Outcome and treatment
`
`Loading dose events
`Hypotension
`Bradycardia
`Hypotension
`Hypotension
`Hypotension
`Hypotension
`Hypotension
`Hypotension
`Hypotension
`Bradycardia
`Hypotension
`Events at other times
`Bradycardia after 3 h of infusion
`Bradycardia, repeated episodes
`Hypotension & bradycardia after 11 h
`Hypotension after 1 h
`Bradycardia, after 4 h
`Bradycardia, repeated episodes
`Bradycardia after 2 h of infusion
`
`75/40
`
`56/35
`70/41
`84/44
`73/35
`95/56
`65/29
`77/40
`79/40
`81/56
`
`68/30
`60/30
`75/54
`85/47
`76/44
`
`45
`
`50
`45
`52
`
`45
`40–45
`48
`
`44
`40–42
`55
`
`Infusion stopped after 10 min
`Paced after 30 min and infusion stopped
`Infusion interrupted for 10 min
`Infusion interrupted for 42 min, restarted at reduced rate
`Resolved in 10 min with fluids & reduced infusion rate
`Resolved with fluids after 10 min
`Resolved with fluids within 30 min
`Paced after 20 min of infusion for 15 h
`Paced after 1 h of infusion for 7 h
`Paced after 10 min of infusion for 12 h
`Resolved with fluids within 10 min
`
`Atropine, inotropes & infusion stopped
`Atropine & inotropes, infusion stopped after 20 h
`Infusion interrupted for 2 h, fluids given
`Hypotension resolved with fluids within 1 h
`Resolved with fluids within 1 h of infusion
`Resolved after 2 h, fluids only
`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 brady-
`cardia) 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 a2 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.kg¹1.h¹1 dexmedetomi-
`dine) if the patient ‘lightened’ and required additional
`sedation. This may have accounted for some of the mida-
`zolam dosing used in the dexmedetomidine group. The
`maximum dexmedetomidine infusion rate was predeter-
`mined from Phase II clinical trials and was clearly insuffi-
`in some patients (n ¼ 9). Patients receiving the
`cient
`maximum infusion rate required considerably more mida-
`zolam 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. Cardio-
`vascular 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, sig-
`nificant 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 a2 receptors
`causing inhibition of sympathetic activity or augmentation
`of parasympathetic activity. Although dexmedetomidine
`is potentially a hypertensive agent by its peripheral a2
`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 anti-
`emetic was higher in patients receiving dexmedetomidine;
`this was contrary to previous findings in women under-
`going 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 tachy-
`cardia (p ¼ 0.04) and less tachypnoea (p ¼ 0.08) at extuba-
`tion 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
`
`䊚 1999 Blackwell Science Ltd
`
`1141
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`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1024 – Page 1141
`
`

`
`R. M. Venn et al. (cid:129) 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 commu-
`nication 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 manage-
`ment 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. Dexmedetomi-
`dine at the doses used may lack the amnesic properties of
`midazolam and this warrants further investigation.
`The study has shown that dexmedetomidine signifi-
`cantly 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
`
`䊚 1999 Blackwell Science Ltd
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1024 – Page 1142