Transcript Results - Tier1 Group

Dexmedetomidine for Sedation
During Elective Awake Fiberoptic
Intubation: A Multicenter Trial
Sergio D Bergese, Keith Candiotti, Andrew Zura,
Paula M Bokesch and Alex Y Bekker
Presented at the American Society
of Anesthesiologists (ASA) 2008 Annual Meeting.
October 18–22, 2008, Orlando, FL.
Background
 An awake fiberoptic intubation (AFOI) is indicated for patients
with an anticipated difficult airway due to their anatomy, airway
trauma, morbid obesity, or unstable cervical spine injuries
 Benzodiazepines, combined with opioids, are commonly used
during AFOI
– However, these agents can cause respiratory depression, in addition to
the desired sedation, increasing the risk for hypoxemia and aspiration
 There is an unmet need for a primary sedative that provides
adequate sedation during AFOI while maintaining a patent
airway and patient responsiveness
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Background
 A number of case reports and retrospective studies have
demonstrated the success of using dexmedetomidine (DEX)
for AFOI
 However, there has not been a prospective, doubleblind,
multicenter clinical trial in this population to date
 This phase III multicenter study evaluated the safety and efficacy
of DEX compared with placebo (PBO) in the sedation of
nonintubated patients with anticipated difficult to intubate airways
who were undergoing AFOI prior to a surgical or diagnostic
procedure
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Purpose
 This phase III multicenter study evaluated the safety and
efficacy of DEX compared with placebo (PBO) in the sedation
of nonintubated patients with anticipated difficult to intubate
airways who were undergoing AFOI prior to a surgical or
diagnostic procedure
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Methods
 A phase III, randomized, double-blind placebo-controlled study
was conducted at 17 US sites with institutional approval and
informed written patient consent
 Patients ≥ 18 years old scheduled for an elective AFOI due to
an anticipated difficult airway and who had an American Society
of Anesthesiologists physical status classification score of I-IV
were included
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Methods
 Patients received DEX 1 mcg/kg loading dose over 10 min
followed by a 0.7 mcg/kg/hr maintenance infusion or PBO
with an equal loading and maintenance dose of normal saline
 After topical anesthesia (lidocaine) and a Ramsay Sedation Scale
(RSS) score ≥ 2 was achieved, nasal or oral intubation using
a flexible fiberoptic bronchoscope was performed
 Following successful intubation, the drug infusion was
discontinued, general anesthesia was induced, and scheduled
procedure proceeded
 Midazolam (MDZ) was administered at any time as rescue
medication at increments of 0.5 mg up to 0.2 mg/kg for patients
with a RSS score of 1 until target RSS score of ≥ 2
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Methods
 All patients’ vital signs were continuously monitored and baseline
RSS scores were documented
 The primary endpoint was the percentage of patients requiring
rescue midazolam (MDZ) to achieve and/or maintain a target
sedation level (Ramsay Sedation Scale [RSS] score ≥ 2)
throughout the infusion
 Secondary endpoints included anesthesiologists’ and patients’
satisfaction assessments
– Immediately following the procedure, anesthesiologists responded
to questions about the intubation using a Visual Analog Scale
– At the end of the 24-hour follow up, patients were assessed for AFOI
satisfaction (recall of intubation, discomfort, and satisfaction)
 All statistical analyses were 2-sided, and P values ≤ 0.05
were considered significant
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Methods
 Safety was assessed by adverse events, protocol prespecified
laboratory tests, vital signs, cardiac monitoring and concomitant
medications
 Hemodynamic stability was evaluated using a composite endpoint
of the time a patient’s systolic blood pressure (SBP) and/or heart
rate (HR) was outside of the hemodynamically stable range
– A score = 2 means both SBP and HR were outside of the stable range,
while a score = 0 means neither SBP nor HR were outside of the stable
range at anytime during the infusion
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Methods
 Major exclusions:
– Use of an a-2 agonist or antagonist within 14 days of study entry
– Use of an opioid administered orally or intravenously within 1 hour
or intramuscularly within 4 hours of study drug administration
– Presence of central nervous system disease with an anticipated increased
intracranial pressure or cerebrospinal fluid leak or acute alcoholic intoxication
– Uncontrolled seizure disorder and/or psychiatric illness
– History of acute unstable angina
–
–
–
–
Laboratory-confirmed acute myocardial infarction within the past 6 weeks
Heart rate < 50 beats per minute
Systolic blood pressure (SBP) < 90 mm Hg
Complete heart block unless the patient had a pacemaker
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Results
 A total of 105 patients (DEX = 55; PBO = 50) were included
in the intent-to-treat and safety analyses
 Of the 55 patients in the DEX group, 49 (89.1%) completed the
study drug infusion and were intubated; of the 50 patients in the
PBO group, 46 (92%) completed study drug infusion and were
intubated
 No demographic differences were noted between groups
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Methods: Patient Demographics and
Baseline Characteristics of Interest
Variable
DEX (n = 55)
PBO (n = 50)
52.6 ± 14.1 (21-78)
51.9 ± 15.3 (19-77)
33 (60.0)
36 (72.0)
93.5 ± 29.8
94.5 ± 23.9
I
6 (10.9)
4 (8.0)
II
11 (20.0)
18 (36.0)
III
26 (47.3)
16 (32.0)
IV
12 (21.8)
12 (24.0)
Cardiovascular disease, n (%)
22 (40.0)
11 (22.0)
Diabetes, n (%)
14 (26.0)
9 (18.0)
Use of any cardiovascular medication
22 (40.0)
13 (26.0)
18 (32.7)
7 (14.0)
Mean age ± SD (range), y
Male, n (%)
Mean weight ± SD, kg
Mallampati classification, n (%)
Beta-blockers
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Results
 Significantly fewer patients in the DEX group required rescue
MDZ to achieve and/or maintain sedation compared with the
PBO group
– 47.3% vs. 86.0%, P < 0.001
 The total mean supplemental MDZ dose required was significantly
lower in DEX-treated patients than in PBO-treated patients
– 1.07 mg v. 2.85 mg, P < 0.001
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Results: Rescue Midazolam (MDZ)
Administration and Dose
Did Not Require MDZ
Required MDZ
100
90
14%
53%
Patients (%)
80
86%
70
60
50
40
47%*
30
20
10
0
Mean MDZ
Dose
1.07 mg*
Mean MDZ
Dose
1.07 mg*
Dexmedetomidine
(n=55)
Placebo
(n=50)
*P<0.001 vs. placebo.
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Results
 No patients in the DEX group required additional medication
other than MDZ to achieve targeted RSS
 Four PBO patients required supplemental fentanyl or propofol
to maintain RSS ≥ 2
 Among patients with the most difficult airways, Mallampati
classification IV, significantly more patients in the PBO group
required rescue MDZ than in the DEX group
 Mean RSS scores assessed 15 minutes after starting study
drug infusion were significantly higher with DEX versus PBO
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Results
 Hemodynamic changes after study drug infusion were similar
in pattern to those during study drug infusion
 Hemodynamic stability composite endpoints were similar between
the DEX-treated and the PBO-treated groups (0.12 and 0.14,
respectively; P = 0.671)
– Seven DEX-treated patients (12.7%) and 4 PBO-treated patients (8.0%)
received medication to treat blood pressure
– the difference was not clinically or statistically significance (P = 0.5316)
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Results: Mean Hemodynamic Changes Versus
Baseline During Study Drug Infusion Period
DEX
PBO
Mean (SD)
Baseline
Study Drug Infusion
Baseline
Study Drug Infusion
SBP, mmHg
144.2 (23.6)
136.2 (23.4)*
132.2 (19.2)
140.4 (17.8)
DBP, mmHg
80.5 (14.4)
77.6 (12.1)†
77.4 (12.2)
78.2 (11.1)
MAP, mmHg
101.73 (16.0)
97.17 (14.6)*
95.66 (13.1)
98.96 (11.6)
77.2 (12.5)
73.3 (12.3)*
76.6 (14.6)
81.6 (15.5)
HR, bpm
*P < 0.001 for change from baseline vs placebo (based on one-way analysis of variance).
†P = 0.034 for change from baseline vs placebo (based on one-way analysis of variance).
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Results
 No significant differences were noted in the percentage of
adverse events experienced by the 2 groups
– Treatment-related adverse events were reported by 29.1% and 18% of DEX
and PBO patients, respectively (P = 0.252)
– The percentage of patients in the DEX group (16.4%) experiencing protocoldefined respiratory depression was similar to the PBO-treated group (14.0%)
 Cardiovascular adverse events:
– DEX was well tolerated in patients also receiving a betablocker with only
one patient experiencing protocol-defined bradycardia
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Results: Cardiovascular Adverse Events
During Study Drug Infusion
Number of Patients (%)
DEX (n = 55)
PBO (n = 55)
P Value*
Hypotension
15 (27.3)
3 (6.0)
0.0042
Hypertension
13 (23.6)
14 (28.0)
0.6591
Tachycardia
4 (7.3)
12 (24.0)
0.0277
Bradycardia
4 (7.3)
0
0.1195
Protocol-defined hypotension: SBP < 80 mm Hg, DBP < 50 mm Hg, or SBP decreased ≤ 30% below baseline values.
Protocol-defined hypertension: SBP > 180 mm Hg, DBP > 100 mm Hg, or SBP increased ≥ 30% higher than baseline values.
Protocol-defined tachycardia: HR > 120 bpm or increased ≥ 30% higher than baseline values.
Protocol-defined bradycardia: HR < 40 bpm or decreased ≤ 30% below baseline values.
*P values derived from Fisher exact test.
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Results
 The anesthesiologists rated both groups similarly in ease of
intubation, hemodynamic stability, and patient cooperation
 The majority of patients in both groups did not recall feeling
anxiety or pain during the AFOI and were highly satisfied with
the procedure
– 47.1% of DEX patients and 53.2% of PBO patients did not feel anxious
– 64.7% of DEX patients and 61.7% of PBO patients did not feel pain
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.
Discussion
 DEX was efficacious as a primary sedative in patients with
high-risk airways undergoing AFOI
 DEX was well tolerated and attenuated the stress response
without airway compromise in this high-risk population
 There was significantly less hypertension and tachycardia with
Dex vs placebo (86% received midazolam)
Bergese S.D., et. al. American Society of Anesthesiologists (ASA)
2008 Annual Meeting. October 18–22, 2008, Orlando, FL.