Pharmacoeconomic Consequences Of Analgesia in the Intensive Care Unit (ICU)

• Duration of Time on Mechanical Ventilation (Intent-to-Treat Population) [ Time Frame: Up to 38 days (912 hours) ] [ Designated as safety issue: No ]
  Time from start of mechanical ventilation until actual extubation (the process of removing a tube from the airway).
• Duration of Time on Mechanical Ventilation (Modified-Intent-to-Treat Population) [ Time Frame: Up to 38 days (912 hours) ] [ Designated as safety issue: No ]
  Time from start of mechanical ventilation until actual extubation.
• Duration of Time on Mechanical Ventilation (Per-Protocol Population) [ Time Frame: Up to 38 days (912 hours) ] [ Designated as safety issue: No ]
  Time from start of mechanical ventilation until actual extubation

• Reducing the duration of mechanical ventilation may reduce the length of stay and therefore reduce the costs per patient.
• Duration of time on mechanical ventilation.

• Duration of Time in Intensive Care Unit (ICU) and Potential Stay in ICU (the Time Expected for Extubation, i.e., the Time Between Intubation and Eligibility for Extubation, According to Investigator's Decision) [ Time Frame: Up to 38 days (912 hours) ] [ Designated as safety issue: No ]
  Duration of Intensive Care Unit (ICU) stay and the duration of potential stay in the ICU were measured.
• Duration of Extubation [ Time Frame: up to 38 days (912 hours) ] [ Designated as safety issue: No ]
  Duration of extubation was measured.
• Duration of Weaning [ Time Frame: up to 38 days (912 hours) ] [ Designated as safety issue: No ]
  Duration of weaning (the time from the intubation until the recovery of natural respiratory ability) was measured.
• Duration of Remifentanil Infusion (ITT Population) [ Time Frame: Up to 10 days (240 hours) ] [ Designated as safety issue: No ]
  Data for this measure come from the infusion pump display; the infusion pump infuses medication (analgesics and sedative agents) into the participant's circulatory system.
• Duration of Propofol Infusion (ITT Population) [ Time Frame: up to 10 days (240 hours) ] [ Designated as safety issue: No ]
  Data for this measure come from the infusion pump display; the infusion pump infuses medication (analgesics and sedative agents) into the participant's circulatory system.
• Duration of Sufentanil, Fentanil, and Morphine Infusion (ITT Population) [ Time Frame: up to 10 days (240 hours) ] [ Designated as safety issue: No ]
  Data for this measure come from the infusion pump display; the infusion pump infuses medication (analgesics and sedative agents) into the participant's circulatory system.
• Dose of Remifentanil Administered - Continuous Infusion [ Time Frame: Up to 10 days ] [ Designated as safety issue: No ]
  Data for this measure come from infusion pump display; the infusion pump infuses medication (analgesics and sedative agents) into the participant's circulatory system.
• Doses of Sufentanil and Fentanil Administered - Continuous Infusion [ Time Frame: up to 10 days ] [ Designated as safety issue: No ]
  Data for this measure come from infusion pump display; the infusion pump infuses medication (analgesics and sedative agents) into the participant's circulatory system.
• Dose of Propofol Administered - Continuous Infusion [ Time Frame: Up to 10 days ] [ Designated as safety issue: No ]
  Data for this measure come from infusion pump display; the infusion pump infuses medication (analgesics and sedative agents) into the participant's circulatory system.
• Dose of Morphine Administered - Continuous Infusion [ Time Frame: up to 10 days ] [ Designated as safety issue: No ]
  Data for this measure come from infusion pump display; the infusion pump infuses medication (analgesics and sedative agents) into the participant's circulatory system.
• Total Dose of Propofol Administered - Bolus [ Time Frame: Up to 10 days ] [ Designated as safety issue: No ]
  Data from this measure come from infusion pump display; the infusion pump infuses medication (analgesics and sedative agents) into the participant's circulatory system.
• Total Dose of Fentanil Administered - Bolus [ Time Frame: Up to 10 days ] [ Designated as safety issue: No ]
  Data for this measure come from infusion pump display; the infusion pump infuses medication (analgesics and sedative agents) into the participant's circulatory system.
• Number of Participants Analyzed for Sedation - Agitation Scale (SAS) and Pain Intensity (PI) Scale [ Time Frame: Up to 38 Days ] [ Designated as safety issue: No ]
  Data from participants in the study for which the Sedation-Agitation Scale (SAS) and Pain Intensity (PI) were recorded were analyzed. "Sedation - Agitation" was assessed, using the "Riker Sedation-Agitation Scale" (SAS), by the following 7-point scale: 7, dangerous agitation; 6, very agitated; 5, agitated; 4, calm, cooperative; 3, sedated; 2, very sedated; 1, unarousable. "Pain Intensity" was assessed by the following 6-point Pain Intensity Scale: 1, no pain; 2, mild pain; 3, moderate pain; 4, severe pain; 5 very severe pain; 6, worst possible pain.
• Sedation-Agitation From Screening Through the End of Study [ Time Frame: Up to 38 days ] [ Designated as safety issue: No ]
  "Sedation - Agitation" was assessed, using the "Riker Sedation-Agitation Scale" (SAS), by the following 7-point scale: 7, dangerous agitation; 6, very agitated; 5, agitated; 4, calm, cooperative; 3, sedated; 2, very sedated; 1, unarousable.
• Sedation-Agitation for Day 7 [ Time Frame: Day 7 ] [ Designated as safety issue: No ]
  "Sedation - Agitation" was assessed, using the "Riker Sedation-Agitation Scale" (SAS), by the following 7-point scale: 7, dangerous agitation; 6, very agitated; 5, agitated; 4, calm, cooperative; 3, sedated; 2, very sedated; 1, unarousable.
• Sedation-Agitation From Day 8 to Day 10 [ Time Frame: Days 8, 9, and 10 ] [ Designated as safety issue: No ]
  "Sedation - Agitation" was assessed, using the "Riker Sedation-Agitation Scale" (SAS), by the following 7-point scale: 7, dangerous agitation; 6, very agitated; 5, agitated; 4, calm, cooperative; 3, sedated; 2, very sedated; 1, unarousable.
• Number of Participants Analyzed for BIS (Bispectral Index Scale) [ Time Frame: Up to 38 days ] [ Designated as safety issue: No ]
  Participants in the study for which BIS were evaluated. The BIS monitor provides a single dimensionless number, the BIS value, which ranges from 0 to 100. A BIS value of 0 equals electroencephalogram silence, near 100 is the expected value in a fully awake adult, and between 40 and 60 indicates a level for general anaesthesia.
• Bispectral Index (BIS) [ Time Frame: Screening through End of Study, up to 38 days ] [ Designated as safety issue: No ]
  The BIS monitor provides a single dimensionless number, the BIS value, which ranges from 0 to 100. A BIS value of 0 equals electroencephalogram silence, near 100 is the expected value in a fully awake adult, and between 40 and 60 indicates a level for general anaesthesia.
• Bispectral Index (BIS) for Day 5 [ Time Frame: Day 5 ] [ Designated as safety issue: No ]
  The BIS monitor provides a single dimensionless number, the BIS value, which ranges from 0 to 100. A BIS value of 0 equals electroencephalogram silence, near 100 is the expected value in a fully awake adult, and between 40 and 60 indicates a level for general anaesthesia.
• Bispectral Index (BIS) for Extubation Period and Post-Extubation Period [ Time Frame: up to 38 days ] [ Designated as safety issue: No ]
  The BIS monitor provides a single dimensionless number, the BIS value, which ranges from 0 to 100. A BIS value of 0 equals electroencephalogram silence, near 100 is the expected value in a fully awake adult, and between 40 and 60 indicates a level for general anaesthesia.
• Pain Intensity (PI) [ Time Frame: Up to 38 days ] [ Designated as safety issue: No ]
  "Pain Intensity" was assessed by the following 6-point Pain Intensity Scale: 1, no pain; 2, mild pain; 3, moderate pain; 4, severe pain; 5 very severe pain; 6, worst possible pain.
• Pain Intensity From Day 8 to Day 10 [ Time Frame: Days 8, 9, and 10 ] [ Designated as safety issue: No ]
  "Pain Intensity" was assessed by the following 6-point Pain Intensity Scale: 1, no pain; 2, mild pain; 3, moderate pain; 4, severe pain; 5 very severe pain; 6, worst possible pain.

• Health:
• Length of stay in ICU
• Time of weaning
• Requirement of opioid and conc. sedative agents
• Time from start of extubation process.
• Efficacy and safety outcomes.

This study will be a multicentre randomized, open-label, phase IIIb study. This study will evaluate two different techniques of sedation: an analgesia based regimen with remifentanil versus a conventional sedation based regimen using propofol in subjects that require mechanical ventilation for at least 2 days in the ICU. The conventional sedation based regimen will consist of propofol combined with an opioid according to routine clinical practice (morphine, fentanyl, sufentanil or other as required) . The analgesia based regimen will consist of remifentanil, with propofol added on if required.

• Drug: Remifentanil
  analgesia in medical and post-surgical Intensive Care Unit subjects requiring mechanical ventilation
• Drug: Propofol
  conventional sedation in medical and post-surgical Intensive Care Unit subjects requiring mechanical

• Experimental: Remifentanil
  remifentanil
  Intervention: Drug: Remifentanil
• Active Comparator: Propofol
  Propofol infusion
  Intervention: Drug: Propofol

Inclusion Criteria:

• Medical and post-surgical patients admitted to ICU and requiring mechanical ventilation.
• Intubated subjects expected to require mechanical ventilation for longer than 48 hours after starting the study drug.
• Subjects requiring both analgesia and sedation with a regimen comprising a hypnotic agent and an opioid.

Exclusion Criteria:

• Diagnosis: cardiopulmonary resuscitation (CPR) in the previous 24 hours or expecting to require major surgery within the next three days
• Subject who, in the judgement of the investigator, has a life expectancy of 2 days or refrained or refuses full life support, which would limit the care provided

• Concurrent medications:

  • Requires or is likely to require neuromuscular blocking agents by continuous infusion to facilitate mechanical ventilation
  • Has or is likely to receive an epidural block during the treatment period