dexmedetomidine for sedation during elective awake fiberoptic intubation: a multicenter trial

Dexmedetomidine for Sedation Dexmedetomidine for Sedation During Elective Awake During Elective Awake

Fiberoptic Intubation: A Fiberoptic Intubation: A Multicenter TrialMulticenter Trial

Sergio D Bergese, Keith Candiotti, Andrew Sergio D Bergese, Keith Candiotti, Andrew Zura, Paula M Bokesch and Alex Y BekkerZura, Paula M Bokesch and Alex Y Bekker

Presented at the American Society Presented at the American Society of Anesthesiologists (ASA) 2008 Annual of Anesthesiologists (ASA) 2008 Annual

Meeting. October 18–22, 2008, Orlando, FL.Meeting. October 18–22, 2008, Orlando, FL.

BackgroundBackground

An awake fiberoptic intubation (AFOI) is indicated for An awake fiberoptic intubation (AFOI) is indicated for patients with an anticipated difficult airway due to their patients with an anticipated difficult airway due to their anatomy, airway trauma, morbid obesity, or unstable anatomy, airway trauma, morbid obesity, or unstable cervical spine injuriescervical spine injuries

Benzodiazepines, combined with opioids, are commonly Benzodiazepines, combined with opioids, are commonly used during AFOIused during AFOI– However, these agents can cause respiratory depression, in However, these agents can cause respiratory depression, in

addition to addition to the desired sedation, increasing the risk for hypoxemia and the desired sedation, increasing the risk for hypoxemia and aspirationaspiration

There is an unmet need for a primary sedative that There is an unmet need for a primary sedative that provides adequate sedation during AFOI while provides adequate sedation during AFOI while maintaining a patent maintaining a patent airway and patient responsivenessairway and patient responsiveness

Bergese S.D., et. al. American Society of Anesthesiologists (ASA) Bergese S.D., et. al. American Society of Anesthesiologists (ASA) 2008 Annual Meeting. October 18–22, 2008, Orlando, FL.2008 Annual Meeting. October 18–22, 2008, Orlando, FL.

BackgroundBackground

A number of case reports and retrospective studies have A number of case reports and retrospective studies have demonstrated the success of using dexmedetomidine demonstrated the success of using dexmedetomidine (DEX) (DEX) for AFOIfor AFOI

However, there has not been a prospective, doubleblind, However, there has not been a prospective, doubleblind, multicenter clinical trial in this population to datemulticenter clinical trial in this population to date

This phase III multicenter study evaluated the safety and This phase III multicenter study evaluated the safety and efficacy of DEX compared with placebo (PBO) in the efficacy of DEX compared with placebo (PBO) in the sedation of nonintubated patients with anticipated sedation of nonintubated patients with anticipated difficult to intubate airways who were undergoing AFOI difficult to intubate airways who were undergoing AFOI prior to a surgical or diagnostic procedureprior to a surgical or diagnostic procedure


PurposePurpose

This phase III multicenter study evaluated the safety and This phase III multicenter study evaluated the safety and efficacy of DEX compared with placebo (PBO) in the efficacy of DEX compared with placebo (PBO) in the sedation sedation of nonintubated patients with anticipated difficult to of nonintubated patients with anticipated difficult to intubate airways who were undergoing AFOI prior to a intubate airways who were undergoing AFOI prior to a surgical or diagnostic proceduresurgical or diagnostic procedure


MethodsMethods

A phase III, randomized, double-blind placebo-controlled A phase III, randomized, double-blind placebo-controlled study was conducted at 17 US sites with institutional study was conducted at 17 US sites with institutional approval and informed written patient consentapproval and informed written patient consent

Patients ≥ 18 years old scheduled for an elective AFOI Patients ≥ 18 years old scheduled for an elective AFOI due to due to an anticipated difficult airway and who had an American an anticipated difficult airway and who had an American Society of Anesthesiologists physical status classification Society of Anesthesiologists physical status classification score of I-IV were includedscore of I-IV were included


MethodsMethods

Patients received DEX 1 mcg/kg loading dose over 10 min Patients received DEX 1 mcg/kg loading dose over 10 min followed by a 0.7 mcg/kg/hr maintenance infusion or PBO followed by a 0.7 mcg/kg/hr maintenance infusion or PBO with an equal loading and maintenance dose of normal with an equal loading and maintenance dose of normal salinesaline

After topical anesthesia (lidocaine) and a Ramsay After topical anesthesia (lidocaine) and a Ramsay Sedation Scale (RSS) score ≥ 2 was achieved, nasal or Sedation Scale (RSS) score ≥ 2 was achieved, nasal or oral intubation using oral intubation using a flexible fiberoptic bronchoscope was performeda flexible fiberoptic bronchoscope was performed

Following successful intubation, the drug infusion was Following successful intubation, the drug infusion was discontinued, general anesthesia was induced, and discontinued, general anesthesia was induced, and scheduled procedure proceededscheduled procedure proceeded

Midazolam (MDZ) was administered at any time as rescue Midazolam (MDZ) was administered at any time as rescue medication at increments of 0.5 mg up to 0.2 mg/kg for 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 ≥ patients with a RSS score of 1 until target RSS score of ≥ 22


MethodsMethods

All patients’ vital signs were continuously monitored and All patients’ vital signs were continuously monitored and baseline RSS scores were documentedbaseline RSS scores were documented

The primary endpoint was the percentage of patients The primary endpoint was the percentage of patients requiring rescue midazolam (MDZ) to achieve and/or requiring rescue midazolam (MDZ) to achieve and/or maintain a target sedation level (Ramsay Sedation Scale maintain a target sedation level (Ramsay Sedation Scale [RSS] score ≥ 2) throughout the infusion[RSS] score ≥ 2) throughout the infusion

Secondary endpoints included anesthesiologists’ and Secondary endpoints included anesthesiologists’ and patients’ satisfaction assessmentspatients’ satisfaction assessments– Immediately following the procedure, anesthesiologists responded Immediately following the procedure, anesthesiologists responded

to questions about the intubation using a Visual Analog Scaleto questions about the intubation using a Visual Analog Scale– At the end of the 24-hour follow up, patients were assessed for AFOI At the end of the 24-hour follow up, patients were assessed for AFOI

satisfaction (recall of intubation, discomfort, and satisfaction)satisfaction (recall of intubation, discomfort, and satisfaction)

All statistical analyses were 2-sided, and P values ≤ 0.05 All statistical analyses were 2-sided, and P values ≤ 0.05 were considered significantwere considered significant


MethodsMethods

Safety was assessed by adverse events, protocol Safety was assessed by adverse events, protocol prespecified laboratory tests, vital signs, cardiac prespecified laboratory tests, vital signs, cardiac monitoring and concomitant medicationsmonitoring and concomitant medications

Hemodynamic stability was evaluated using a composite Hemodynamic stability was evaluated using a composite endpoint of the time a patient’s systolic blood pressure endpoint of the time a patient’s systolic blood pressure (SBP) and/or heart rate (HR) was outside of the (SBP) and/or heart rate (HR) was outside of the hemodynamically stable rangehemodynamically stable range– A score = 2 means both SBP and HR were outside of the stable A score = 2 means both SBP and HR were outside of the stable

range, range, while a score = 0 means neither SBP nor HR were outside of the while a score = 0 means neither SBP nor HR were outside of the stable range at anytime during the infusionstable range at anytime during the infusion


MethodsMethods

Major exclusions:Major exclusions:– Use of an a-2 agonist or antagonist within 14 days of study entryUse of an a-2 agonist or antagonist within 14 days of study entry– Use of an opioid administered orally or intravenously within 1 hour Use of an opioid administered orally or intravenously within 1 hour

or intramuscularly within 4 hours of study drug administrationor intramuscularly within 4 hours of study drug administration– Presence of central nervous system disease with an anticipated Presence of central nervous system disease with an anticipated

increased intracranial pressure or cerebrospinal fluid leak or acute increased intracranial pressure or cerebrospinal fluid leak or acute alcoholic intoxicationalcoholic intoxication

– Uncontrolled seizure disorder and/or psychiatric illnessUncontrolled seizure disorder and/or psychiatric illness– History of acute unstable anginaHistory of acute unstable angina– Laboratory-confirmed acute myocardial infarction within the past 6 Laboratory-confirmed acute myocardial infarction within the past 6

weeksweeks– Heart rate < 50 beats per minuteHeart rate < 50 beats per minute– Systolic blood pressure (SBP) < 90 mm HgSystolic blood pressure (SBP) < 90 mm Hg– Complete heart block unless the patient had a pacemakerComplete heart block unless the patient had a pacemaker


ResultsResults

A total of 105 patients (DEX = 55; PBO = 50) were A total of 105 patients (DEX = 55; PBO = 50) were included included in the intent-to-treat and safety analysesin the intent-to-treat and safety analyses

Of the 55 patients in the DEX group, 49 (89.1%) Of the 55 patients in the DEX group, 49 (89.1%) completed the study drug infusion and were intubated; of completed the study drug infusion and were intubated; of the 50 patients in the PBO group, 46 (92%) completed the 50 patients in the PBO group, 46 (92%) completed study drug infusion and were intubatedstudy drug infusion and were intubated

No demographic differences were noted between groupsNo demographic differences were noted between groups


Methods: Patient Demographics and Baseline Characteristics of InterestMethods: Patient Demographics and Baseline Characteristics of Interest


Variable DEX (n = 55) PBO (n = 50)

Mean age ± SD (range), y 52.6 ± 14.1 (21-78)

51.9 ± 15.3 (19-77)

Male, n (%) 33 (60.0) 36 (72.0)

Mean weight ± SD, kg 93.5 ± 29.8 94.5 ± 23.9

Mallampati classification, n (%)

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)

Beta-blockers 18 (32.7) 7 (14.0)

ResultsResults

Significantly fewer patients in the DEX group required Significantly fewer patients in the DEX group required rescue rescue MDZ to achieve and/or maintain sedation compared with MDZ to achieve and/or maintain sedation compared with the the PBO groupPBO group– 47.3% vs. 86.0%, P < 0.00147.3% vs. 86.0%, P < 0.001

The total mean supplemental MDZ dose required was The total mean supplemental MDZ dose required was significantly lower in DEX-treated patients than in PBO-significantly lower in DEX-treated patients than in PBO-treated patientstreated patients– 1.07 mg v. 2.85 mg, P < 0.0011.07 mg v. 2.85 mg, P < 0.001


Results: Rescue Midazolam (MDZ) Administration and DoseResults: Rescue Midazolam (MDZ) Administration and Dose

**PP<0.001 vs. placebo.<0.001 vs. placebo.Bergese S.D., et. al. American Society of Anesthesiologists (ASA) Bergese S.D., et. al. American Society of Anesthesiologists (ASA)

2008 Annual Meeting. October 18–22, 2008, Orlando, FL.2008 Annual Meeting. October 18–22, 2008, Orlando, FL.

100

90

80

70

60

50

40

30

20

10

0

Pat

ien

ts (

%)

Dexmedetomidine (n=55)

Placebo (n=50)

Did Not Require MDZ Required MDZ

Mean MDZDose

1.07 mg*

47%*

53%

Mean MDZDose

1.07 mg*

86%

14%

ResultsResults

No patients in the DEX group required additional No patients in the DEX group required additional medication medication other than MDZ to achieve targeted RSSother than MDZ to achieve targeted RSS

Four PBO patients required supplemental fentanyl or Four PBO patients required supplemental fentanyl or propofol propofol to maintain RSS ≥ 2to maintain RSS ≥ 2

Among patients with the most difficult airways, Among patients with the most difficult airways, Mallampati classification IV, significantly more patients in Mallampati classification IV, significantly more patients in the PBO group required rescue MDZ than in the DEX the PBO group required rescue MDZ than in the DEX groupgroup

Mean RSS scores assessed 15 minutes after starting Mean RSS scores assessed 15 minutes after starting study study drug infusion were significantly higher with DEX versus drug infusion were significantly higher with DEX versus PBOPBO


ResultsResults

Hemodynamic changes after study drug infusion were Hemodynamic changes after study drug infusion were similar similar in pattern to those during study drug infusionin pattern to those during study drug infusion

Hemodynamic stability composite endpoints were similar Hemodynamic stability composite endpoints were similar between the DEX-treated and the PBO-treated groups between the DEX-treated and the PBO-treated groups (0.12 and 0.14, respectively; P = 0.671)(0.12 and 0.14, respectively; P = 0.671)– Seven DEX-treated patients (12.7%) and 4 PBO-treated patients Seven DEX-treated patients (12.7%) and 4 PBO-treated patients

(8.0%) received medication to treat blood pressure(8.0%) received medication to treat blood pressure– the difference was not clinically or statistically significance (P = the difference was not clinically or statistically significance (P =

0.5316)0.5316)


Results: Mean Hemodynamic Changes Versus Baseline During Study Drug Infusion Period

Results: Mean Hemodynamic Changes Versus Baseline During Study Drug Infusion Period

*P < 0.001 for change from baseline vs placebo (based on one-way analysis of variance).*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).P = 0.034 for change from baseline vs placebo (based on one-way analysis of variance).


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)

HR, bpm 77.2 (12.5) 73.3 (12.3)* 76.6 (14.6) 81.6 (15.5)

ResultsResults

No significant differences were noted in the percentage of No significant differences were noted in the percentage of adverse events experienced by the 2 groupsadverse events experienced by the 2 groups– Treatment-related adverse events were reported by 29.1% and Treatment-related adverse events were reported by 29.1% and

18% of DEX and PBO patients, respectively (P = 0.252)18% of DEX and PBO patients, respectively (P = 0.252)– The percentage of patients in the DEX group (16.4%) experiencing The percentage of patients in the DEX group (16.4%) experiencing

protocol-defined respiratory depression was similar to the PBO-protocol-defined respiratory depression was similar to the PBO-treated group (14.0%)treated group (14.0%)

Cardiovascular adverse events:Cardiovascular adverse events:– DEX was well tolerated in patients also receiving a betablocker with DEX was well tolerated in patients also receiving a betablocker with

only only one patient experiencing protocol-defined bradycardiaone patient experiencing protocol-defined bradycardia


Results: Cardiovascular Adverse Events During Study Drug InfusionResults: Cardiovascular Adverse Events During Study Drug Infusion

Protocol-defined hypotension: SBP < 80 mm Hg, DBP < 50 mm Hg, or SBP decreased ≤ 30% below baseline values.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 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 tachycardia: HR > 120 bpm or increased ≥ 30% higher than baseline values.Protocol-defined bradycardia: HR < 40 bpm or decreased ≤ 30% below baseline values.Protocol-defined bradycardia: HR < 40 bpm or decreased ≤ 30% below baseline values.

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

*P values derived from Fisher exact test.*P values derived from Fisher exact test.Bergese S.D., et. al. American Society of Anesthesiologists (ASA) Bergese S.D., et. al. American Society of Anesthesiologists (ASA)

2008 Annual Meeting. October 18–22, 2008, Orlando, FL.2008 Annual Meeting. October 18–22, 2008, Orlando, FL.

ResultsResults

The anesthesiologists rated both groups similarly in ease The anesthesiologists rated both groups similarly in ease of intubation, hemodynamic stability, and patient of intubation, hemodynamic stability, and patient cooperationcooperation

The majority of patients in both groups did not recall The majority of patients in both groups did not recall feeling anxiety or pain during the AFOI and were highly feeling anxiety or pain during the AFOI and were highly satisfied with satisfied with the procedurethe procedure– 47.1% of DEX patients and 53.2% of PBO patients did not feel 47.1% of DEX patients and 53.2% of PBO patients did not feel

anxiousanxious– 64.7% of DEX patients and 61.7% of PBO patients did not feel pain64.7% of DEX patients and 61.7% of PBO patients did not feel pain


DiscussionDiscussion

DEX was efficacious as a primary sedative in patients DEX was efficacious as a primary sedative in patients with with high-risk airways undergoing AFOIhigh-risk airways undergoing AFOI

DEX was well tolerated and attenuated the stress DEX was well tolerated and attenuated the stress response without airway compromise in this high-risk response without airway compromise in this high-risk populationpopulation

There was significantly less hypertension and tachycardia There was significantly less hypertension and tachycardia with Dex vs placebo (86% received midazolam)with Dex vs placebo (86% received midazolam)


dexmedetomidine for sedation during elective awake fiberoptic intubation: a multicenter trial

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