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Dexmedetomidine( Precedex )

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• 2008/10/06

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Sedation
Analgesia
Anxiolysis
Amnesia
Hypnosis
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CNS Effects
Sedation
Amnesia
Anxiolysis
Hypnosis
Analgesia
Agent




Opioids1




Benzodiazepines2




Propofol1




Dexmedetomidine3

• Harvey. Am J Crit Care. 1996510, 11.
• Pepperman. Care of the Critically Ill.
  19895197.
• Aantaa et al. Drugs of the Future. 19931849-56.

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Dexmedetomidine

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• Dexmedetomidine ???????a2-adrenergic
  agonist,???????????????
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• 1. Dexmedetomidine?????????,?????????24???
• 2. ???????????(bolus injection)??????????????
• 3. ???????????????,????????????

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Background (I)

• BDZ, acting on GABAA receptors, have been the
  most commonly prescribed medications for
  providing sedation for critically ill patients.
• Lorazepam is currently recommended by the Society
  of Critical Care Medicine (SCCM) for the
  sustained sedation of mechanically ventilated ICU
  patients.

Jacobi J, et al. Crit Care Med. 2002
30(1)119-141. Young C, et al. Crit Care Med.
2000 28(3)854-866.
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Background (II)

• BZD drugs may increase mechanical ventilation
  time and ICU length of stay and potentiate the
  risk of developing acute brain dysfunction, ie,
  delirium and coma.
• BZD drugs may impair the quality of sleep via
  slow-wave sleep suppression.

Kollef MH, et al. Chest. 1998114(2)541-548. Dubo
is MJ, et al. Intensive Care Med.
200127(8)1297-1304. Pandharipande P, et al.
Anesthesiology. 2006104(1)21-26.
Pandharipande P, et al. Crit Care Clin. 2006
22(2)313-327. Bourne RS, et al. Anaesthesia.
200459(4)374-384.
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Background (III)

• BZD drugs activate GABAA receptors, and then
  release deliriogenic neurotransmitters
• Dexmedetomidine induces sedation via different
  central nervous system receptors and may lower
  the risk of acute brain dysfunction.
• Several small trials have found that
  dexmedetomidine attenuates postoperative delirium
  in adults and children

Pandharipande P, et al. Crit Care Clin. 2006
22(2)313-327.
Nelson LE, et al. Anesthesiology. 2003
98(2)428-436.
Maldonado JR, et al. Anesthesiology.
200399A465. Ibacache ME, et al. Anesth Analg.
200498(1)60-63.
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Material and Methods
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Patient

• Inclusion criteria
• adult medical and surgical ICU patients
• requiring mechanical ventilation for longer than
  24 hours.
• Excluded criteria
• any disease that would confound the diagnosis of
  delirium
• previous stroke, cerebral palsy, active seizures
• Childs-Pugh class B or C liver disease
• family or physician refusal, alcohol abuse
• inability to understand English to allow delirium
  evaluations

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Study Drug Administration (I)

• All patients and study personnel were blinded to
  study drug assignment, except for the
  investigational pharmacist.
• FDA permitted the study of dexmedetomidine for
• the longest duration of 120 hours
• the maximal doses of 1.5µg/kg/hr
• We used infusion instead of bolus dosing to
  preserve the blinding and to minimize potential
  adverse effects.
• The study drug infusion to achieve the sedation
  goal set by the patients medical team using the
  RASS.

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Study Drug Administration (II)

• Apparent pain was treated by the nurses with
  intermittent doses of fentanyl based on
  physiological parameters
• If a patient experienced severe agitation that
  had the potential to cause, a propofol bolus was
  allowed

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Primary and Secondary Outcomes

• The primary outcome
• The delirium-free and coma-free days, defined as
  the days alive without delirium or coma.
• The efficacy of the 2 sedation regimens in
  achieving clinically individualized target
  sedation goals.
• The secondary outcomes
• lengths of stay with ventilation, and in the
  hospital
• 28-day mortality rate
• 12-month survival rate.

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Assessing Delirium and Coma

• Delirium was measured until hospital discharge or
  for 12 days using the CAM-ICU.
• Delirium (2/2)
• RASS score gt -3
• a positive CAM-ICU
• Coma
• RASS score of - 4 or -5

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Assessing Efficacy of Sedation

• Sedation level was assessed using the RASS
• Efficacy of the study drug
• the ability to achieve a sedation score within 1
  point of the desired goal sedation level.

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Baseline Characteristics
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Results
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Clinical Outcomes

• Dexmedetomidine group had more days alive without
  delirium or coma
• About 30 fewer patients experienced coma in the
  dexmedetomidine group (63 vs 92 Plt.001).

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• Nonsignificant differences were noted between two
  groups in
• The 28- day mortality (17 vs 27 P.18)
• The ventilator-free days (22 vs 18 P.22).

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Efficacy of Sedation

• Patients sedated with dexmedetomidine spent more
  time at the level of sedation targeted than
  patients sedated with lorazepam.
• There was significant difference in
  administration of analgesic medications
  (fentanyl) during the study.

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• The median administered fentanyl dose was higher
  in the dexmedetomidine group (575 vs 150 µg/day)
• Difference was more notable when patients had
  deeper sedation goals.

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Safety Evaluation

• Higher incidence of sinus bradycardia in the
  dexmedetomidine group .
• Non-significant increase in the incidence of
  atrial fibrillation in the dexmedetomidine group .

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Cost of Care

• The median calculated cost for the study drug in
  the dexmedetomidine group was 4675 and for
  lorazepam was 2335.
• The net costs were balanced between two groups
  with regard to
• overall pharmacy, respiratory care,
• ICU, and hospital costs

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Discussion
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Issues to be discussed in the study

• ( I ) The use of delirium and coma as a primary
  outcome
• The number of days alive without delirium or coma
  as the measurement that demonstrate improvement
  of cognitive status
• Thinking about the best way to construct studies
  to measure brain organ dysfunction.
• (II) Pain management and monitoring
• Dexmedetomidine (as opposed to lorazepam) is
  known to have analgesic qualities.
• Pain was assessed by the nurses, using
  physiological cues.

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Issues to be discussed in the study

• ( III ) The FDA allowing dose of Precedex
• more fentanyl was used in dexmedetomidine
  group
• Patients in dexmedetomidine group spent less time
  delirious and comatose, more capable of
  expressing the need for analgesia
• Fentanyl was used for its sedating properties
• deep sedation goals needs high fentanyl dose in
  the dexmedetomidine group
• Both explanations can be explored by allowing
  higher doses of dexmedetomidine

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Issues to be discussed in the study

• ( V ) FDA stipulated the use duration of
  Precedex
• Patients requiring sedation ? 120 hours were
  treated with lorazepam or midazolam according to
  each ICUs usual protocol.
• This effect of dexmedetomidine may have been
  diluted

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Issues to be discussed in the study

• (VI) Bolus use of Precedex is contraindicated
• This protocol could lead to a higher probability
  of oversedation in the lorazepam group
• The impact of a randomized, double blind
  investigation outweighed the probability of
  oversedation
• Nearly 70 of the times, patients in the
  lorazepam group were at their sedation goal much
  higher than most critical care practices

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Conclusion

• In mechanically ventilated ICU patients managed
  with individualized targeted sedation, the use of
  Predex infusion
• more days alive without delirium or coma
• more time at the targeted level of sedation

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