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Transcript of The Maze Runner - Critical Care Canada · PDF fileDelirium –Pharmacotherapy in 2015...
Delirium ndash Pharmacotherapy in 2015
Lisa Burry BScPharm PharmD
Mount Sinai Hospital
University of Toronto
The Maze Runner
Disclosures
Industry None
Grant Funding from Centre for Collaborative Drug Research (University of Toronto) to support a pilot RCT for 2 doses of melatonin vs placebo for prevention of ICU delirium
Is there a drug for primary prevention of delirium in critically ill
2013 SCCM Recommendations
bull No recommendation for using pharmacologic prevention
(alone or in combination with non-pharmacologic strategies)
in adult ICU patients as no compelling data demonstrate
that this reduces the incidence or duration of delirium in
these patients
bull Do not suggest that antipsychotics be administered to
prevent delirium in adult ICU patients (haloperidol or
atypical)
bull No recommendation for the use of dexmedetomidine
to prevent delirium in adult ICU patients as there is no
compelling evidence regarding its effectiveness in these
patients
Design DB Placebo-controlled RCT (2 sites) to evaluate the efficacy amp safety of IV haloperidol for delirium prevention
Participants ge 65 years admitted to ICU after non-cardiac surgery (457 patients)
Intervention Haloperidol 05 mg IV bolus + 01 mghr infusion x 12 hr vs placebo
Design Beforeafter evaluation of delirium prevention QI project that used prophylactic haloperidol
Participants ICU patients with a predicted risk of delirium ge 50 (PRE-DELIRIC tool) or history of alcohol abuse or dementia
Intervention early initiation of haloperidol 1 mg IV q8h vs historical control amp contemporary group that did not receive haloperidol)
- 05mg based on age organ dysfunction size
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Design DB placebo-controlled RCT to determine efficacy amp safety of haloperidol to prevent delirium
Participants 68 mechanically ventilated patients with ICDSC score lt 4
Intervention haloperidol 1 mg or placebo q6h until either ICDSC gt 4 therapy gt10 days or ICU discharge All managed with paired SAT-SBT
Design DB RCT (2 sites) to assess the effect of dexmedetomidinecompared to morphine-based regimen on prevalence of delirium within 5 days post-op
Participants 306 cardiac surgery patients ge 60 years
Intervention dexmedetomidine infusion vs morphine infusion x 48 h ndash All could receive open label propofol titrated to MAAS 2-4
ndash Dexmedetomidine group could receive morphine
Shehabi Y et al Anethesiology 20091111075-84
Dexmedetomidine patients experienced less systolic hypotension (23 versus 381 P 1113091
0006) required less norepinephrine (P lt 0001) but had more bradycardia (1645 versus
612 P 1113091 0006) than morphine treatment patients
Delirium involves complex pathways
Design Rater amp clinician blinded placebo-controlled RCT (5 sites) to examine whether ramelteon a melatonin agonist is effective for prevention of delirium
Participants 67 patients age 65-89 years newly admitted due to serious medical problem able to take oral medications (24 ICU and 43 ward patients)
Intervention ramelteon 8 mgday (dose approved for sleep) vs placebo qHS x 7 days
relative risk of 009 (95 CI 001-069)
Is there a drug that lsquocuresrsquo delirium in critically ill
bull Cohort = 102 adult intubated medical ICU patients CAM-ICU evaluation before amp after SAT
bull CAM-ICU indicated patients are gt 10 x more likely to have delirium before DIS vs after (P lt 0001)
bull Rapidly reversible sedation-related delirium does not signify the same poor prognosis as persistent deliriumndash Rapidly reversible delirium showed fewer ventilator (Plt0001) ICU
(P=0001) and hospital days (Plt0001) than persistent delirium
ndash Patients rapidly reversible delirium had similar outcomes to those without delirium
Question Does treatment with haloperidol reduce the
duration of delirium in adult ICU patients
Answer There is no published evidence that treatment with
haloperidol reduces the duration of delirium in adult ICU
patients
Question Does treatment with atypical antipsychotics
reduce the duration of delirium in adult ICU patients
Answer Atypical antipsychotics may reduce the duration of
delirium in adult ICU patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
Design Multi centre DB placebo-controlled feasibility RCT
Participants 101 mechanically ventilated medical or surgical patients with delirium
Intervention Haloperidol 5mg po q6h vs ziprasidone 40 mg vs placebo up to
14 days
ndash Titration amp taper off study drug
ndash All other treatments including sedation determined by ICU team
Primary outcome of days alive without delirium or coma
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Disclosures
Industry None
Grant Funding from Centre for Collaborative Drug Research (University of Toronto) to support a pilot RCT for 2 doses of melatonin vs placebo for prevention of ICU delirium
Is there a drug for primary prevention of delirium in critically ill
2013 SCCM Recommendations
bull No recommendation for using pharmacologic prevention
(alone or in combination with non-pharmacologic strategies)
in adult ICU patients as no compelling data demonstrate
that this reduces the incidence or duration of delirium in
these patients
bull Do not suggest that antipsychotics be administered to
prevent delirium in adult ICU patients (haloperidol or
atypical)
bull No recommendation for the use of dexmedetomidine
to prevent delirium in adult ICU patients as there is no
compelling evidence regarding its effectiveness in these
patients
Design DB Placebo-controlled RCT (2 sites) to evaluate the efficacy amp safety of IV haloperidol for delirium prevention
Participants ge 65 years admitted to ICU after non-cardiac surgery (457 patients)
Intervention Haloperidol 05 mg IV bolus + 01 mghr infusion x 12 hr vs placebo
Design Beforeafter evaluation of delirium prevention QI project that used prophylactic haloperidol
Participants ICU patients with a predicted risk of delirium ge 50 (PRE-DELIRIC tool) or history of alcohol abuse or dementia
Intervention early initiation of haloperidol 1 mg IV q8h vs historical control amp contemporary group that did not receive haloperidol)
- 05mg based on age organ dysfunction size
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Design DB placebo-controlled RCT to determine efficacy amp safety of haloperidol to prevent delirium
Participants 68 mechanically ventilated patients with ICDSC score lt 4
Intervention haloperidol 1 mg or placebo q6h until either ICDSC gt 4 therapy gt10 days or ICU discharge All managed with paired SAT-SBT
Design DB RCT (2 sites) to assess the effect of dexmedetomidinecompared to morphine-based regimen on prevalence of delirium within 5 days post-op
Participants 306 cardiac surgery patients ge 60 years
Intervention dexmedetomidine infusion vs morphine infusion x 48 h ndash All could receive open label propofol titrated to MAAS 2-4
ndash Dexmedetomidine group could receive morphine
Shehabi Y et al Anethesiology 20091111075-84
Dexmedetomidine patients experienced less systolic hypotension (23 versus 381 P 1113091
0006) required less norepinephrine (P lt 0001) but had more bradycardia (1645 versus
612 P 1113091 0006) than morphine treatment patients
Delirium involves complex pathways
Design Rater amp clinician blinded placebo-controlled RCT (5 sites) to examine whether ramelteon a melatonin agonist is effective for prevention of delirium
Participants 67 patients age 65-89 years newly admitted due to serious medical problem able to take oral medications (24 ICU and 43 ward patients)
Intervention ramelteon 8 mgday (dose approved for sleep) vs placebo qHS x 7 days
relative risk of 009 (95 CI 001-069)
Is there a drug that lsquocuresrsquo delirium in critically ill
bull Cohort = 102 adult intubated medical ICU patients CAM-ICU evaluation before amp after SAT
bull CAM-ICU indicated patients are gt 10 x more likely to have delirium before DIS vs after (P lt 0001)
bull Rapidly reversible sedation-related delirium does not signify the same poor prognosis as persistent deliriumndash Rapidly reversible delirium showed fewer ventilator (Plt0001) ICU
(P=0001) and hospital days (Plt0001) than persistent delirium
ndash Patients rapidly reversible delirium had similar outcomes to those without delirium
Question Does treatment with haloperidol reduce the
duration of delirium in adult ICU patients
Answer There is no published evidence that treatment with
haloperidol reduces the duration of delirium in adult ICU
patients
Question Does treatment with atypical antipsychotics
reduce the duration of delirium in adult ICU patients
Answer Atypical antipsychotics may reduce the duration of
delirium in adult ICU patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
Design Multi centre DB placebo-controlled feasibility RCT
Participants 101 mechanically ventilated medical or surgical patients with delirium
Intervention Haloperidol 5mg po q6h vs ziprasidone 40 mg vs placebo up to
14 days
ndash Titration amp taper off study drug
ndash All other treatments including sedation determined by ICU team
Primary outcome of days alive without delirium or coma
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Is there a drug for primary prevention of delirium in critically ill
2013 SCCM Recommendations
bull No recommendation for using pharmacologic prevention
(alone or in combination with non-pharmacologic strategies)
in adult ICU patients as no compelling data demonstrate
that this reduces the incidence or duration of delirium in
these patients
bull Do not suggest that antipsychotics be administered to
prevent delirium in adult ICU patients (haloperidol or
atypical)
bull No recommendation for the use of dexmedetomidine
to prevent delirium in adult ICU patients as there is no
compelling evidence regarding its effectiveness in these
patients
Design DB Placebo-controlled RCT (2 sites) to evaluate the efficacy amp safety of IV haloperidol for delirium prevention
Participants ge 65 years admitted to ICU after non-cardiac surgery (457 patients)
Intervention Haloperidol 05 mg IV bolus + 01 mghr infusion x 12 hr vs placebo
Design Beforeafter evaluation of delirium prevention QI project that used prophylactic haloperidol
Participants ICU patients with a predicted risk of delirium ge 50 (PRE-DELIRIC tool) or history of alcohol abuse or dementia
Intervention early initiation of haloperidol 1 mg IV q8h vs historical control amp contemporary group that did not receive haloperidol)
- 05mg based on age organ dysfunction size
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Design DB placebo-controlled RCT to determine efficacy amp safety of haloperidol to prevent delirium
Participants 68 mechanically ventilated patients with ICDSC score lt 4
Intervention haloperidol 1 mg or placebo q6h until either ICDSC gt 4 therapy gt10 days or ICU discharge All managed with paired SAT-SBT
Design DB RCT (2 sites) to assess the effect of dexmedetomidinecompared to morphine-based regimen on prevalence of delirium within 5 days post-op
Participants 306 cardiac surgery patients ge 60 years
Intervention dexmedetomidine infusion vs morphine infusion x 48 h ndash All could receive open label propofol titrated to MAAS 2-4
ndash Dexmedetomidine group could receive morphine
Shehabi Y et al Anethesiology 20091111075-84
Dexmedetomidine patients experienced less systolic hypotension (23 versus 381 P 1113091
0006) required less norepinephrine (P lt 0001) but had more bradycardia (1645 versus
612 P 1113091 0006) than morphine treatment patients
Delirium involves complex pathways
Design Rater amp clinician blinded placebo-controlled RCT (5 sites) to examine whether ramelteon a melatonin agonist is effective for prevention of delirium
Participants 67 patients age 65-89 years newly admitted due to serious medical problem able to take oral medications (24 ICU and 43 ward patients)
Intervention ramelteon 8 mgday (dose approved for sleep) vs placebo qHS x 7 days
relative risk of 009 (95 CI 001-069)
Is there a drug that lsquocuresrsquo delirium in critically ill
bull Cohort = 102 adult intubated medical ICU patients CAM-ICU evaluation before amp after SAT
bull CAM-ICU indicated patients are gt 10 x more likely to have delirium before DIS vs after (P lt 0001)
bull Rapidly reversible sedation-related delirium does not signify the same poor prognosis as persistent deliriumndash Rapidly reversible delirium showed fewer ventilator (Plt0001) ICU
(P=0001) and hospital days (Plt0001) than persistent delirium
ndash Patients rapidly reversible delirium had similar outcomes to those without delirium
Question Does treatment with haloperidol reduce the
duration of delirium in adult ICU patients
Answer There is no published evidence that treatment with
haloperidol reduces the duration of delirium in adult ICU
patients
Question Does treatment with atypical antipsychotics
reduce the duration of delirium in adult ICU patients
Answer Atypical antipsychotics may reduce the duration of
delirium in adult ICU patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
Design Multi centre DB placebo-controlled feasibility RCT
Participants 101 mechanically ventilated medical or surgical patients with delirium
Intervention Haloperidol 5mg po q6h vs ziprasidone 40 mg vs placebo up to
14 days
ndash Titration amp taper off study drug
ndash All other treatments including sedation determined by ICU team
Primary outcome of days alive without delirium or coma
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
2013 SCCM Recommendations
bull No recommendation for using pharmacologic prevention
(alone or in combination with non-pharmacologic strategies)
in adult ICU patients as no compelling data demonstrate
that this reduces the incidence or duration of delirium in
these patients
bull Do not suggest that antipsychotics be administered to
prevent delirium in adult ICU patients (haloperidol or
atypical)
bull No recommendation for the use of dexmedetomidine
to prevent delirium in adult ICU patients as there is no
compelling evidence regarding its effectiveness in these
patients
Design DB Placebo-controlled RCT (2 sites) to evaluate the efficacy amp safety of IV haloperidol for delirium prevention
Participants ge 65 years admitted to ICU after non-cardiac surgery (457 patients)
Intervention Haloperidol 05 mg IV bolus + 01 mghr infusion x 12 hr vs placebo
Design Beforeafter evaluation of delirium prevention QI project that used prophylactic haloperidol
Participants ICU patients with a predicted risk of delirium ge 50 (PRE-DELIRIC tool) or history of alcohol abuse or dementia
Intervention early initiation of haloperidol 1 mg IV q8h vs historical control amp contemporary group that did not receive haloperidol)
- 05mg based on age organ dysfunction size
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Design DB placebo-controlled RCT to determine efficacy amp safety of haloperidol to prevent delirium
Participants 68 mechanically ventilated patients with ICDSC score lt 4
Intervention haloperidol 1 mg or placebo q6h until either ICDSC gt 4 therapy gt10 days or ICU discharge All managed with paired SAT-SBT
Design DB RCT (2 sites) to assess the effect of dexmedetomidinecompared to morphine-based regimen on prevalence of delirium within 5 days post-op
Participants 306 cardiac surgery patients ge 60 years
Intervention dexmedetomidine infusion vs morphine infusion x 48 h ndash All could receive open label propofol titrated to MAAS 2-4
ndash Dexmedetomidine group could receive morphine
Shehabi Y et al Anethesiology 20091111075-84
Dexmedetomidine patients experienced less systolic hypotension (23 versus 381 P 1113091
0006) required less norepinephrine (P lt 0001) but had more bradycardia (1645 versus
612 P 1113091 0006) than morphine treatment patients
Delirium involves complex pathways
Design Rater amp clinician blinded placebo-controlled RCT (5 sites) to examine whether ramelteon a melatonin agonist is effective for prevention of delirium
Participants 67 patients age 65-89 years newly admitted due to serious medical problem able to take oral medications (24 ICU and 43 ward patients)
Intervention ramelteon 8 mgday (dose approved for sleep) vs placebo qHS x 7 days
relative risk of 009 (95 CI 001-069)
Is there a drug that lsquocuresrsquo delirium in critically ill
bull Cohort = 102 adult intubated medical ICU patients CAM-ICU evaluation before amp after SAT
bull CAM-ICU indicated patients are gt 10 x more likely to have delirium before DIS vs after (P lt 0001)
bull Rapidly reversible sedation-related delirium does not signify the same poor prognosis as persistent deliriumndash Rapidly reversible delirium showed fewer ventilator (Plt0001) ICU
(P=0001) and hospital days (Plt0001) than persistent delirium
ndash Patients rapidly reversible delirium had similar outcomes to those without delirium
Question Does treatment with haloperidol reduce the
duration of delirium in adult ICU patients
Answer There is no published evidence that treatment with
haloperidol reduces the duration of delirium in adult ICU
patients
Question Does treatment with atypical antipsychotics
reduce the duration of delirium in adult ICU patients
Answer Atypical antipsychotics may reduce the duration of
delirium in adult ICU patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
Design Multi centre DB placebo-controlled feasibility RCT
Participants 101 mechanically ventilated medical or surgical patients with delirium
Intervention Haloperidol 5mg po q6h vs ziprasidone 40 mg vs placebo up to
14 days
ndash Titration amp taper off study drug
ndash All other treatments including sedation determined by ICU team
Primary outcome of days alive without delirium or coma
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Design DB Placebo-controlled RCT (2 sites) to evaluate the efficacy amp safety of IV haloperidol for delirium prevention
Participants ge 65 years admitted to ICU after non-cardiac surgery (457 patients)
Intervention Haloperidol 05 mg IV bolus + 01 mghr infusion x 12 hr vs placebo
Design Beforeafter evaluation of delirium prevention QI project that used prophylactic haloperidol
Participants ICU patients with a predicted risk of delirium ge 50 (PRE-DELIRIC tool) or history of alcohol abuse or dementia
Intervention early initiation of haloperidol 1 mg IV q8h vs historical control amp contemporary group that did not receive haloperidol)
- 05mg based on age organ dysfunction size
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Design DB placebo-controlled RCT to determine efficacy amp safety of haloperidol to prevent delirium
Participants 68 mechanically ventilated patients with ICDSC score lt 4
Intervention haloperidol 1 mg or placebo q6h until either ICDSC gt 4 therapy gt10 days or ICU discharge All managed with paired SAT-SBT
Design DB RCT (2 sites) to assess the effect of dexmedetomidinecompared to morphine-based regimen on prevalence of delirium within 5 days post-op
Participants 306 cardiac surgery patients ge 60 years
Intervention dexmedetomidine infusion vs morphine infusion x 48 h ndash All could receive open label propofol titrated to MAAS 2-4
ndash Dexmedetomidine group could receive morphine
Shehabi Y et al Anethesiology 20091111075-84
Dexmedetomidine patients experienced less systolic hypotension (23 versus 381 P 1113091
0006) required less norepinephrine (P lt 0001) but had more bradycardia (1645 versus
612 P 1113091 0006) than morphine treatment patients
Delirium involves complex pathways
Design Rater amp clinician blinded placebo-controlled RCT (5 sites) to examine whether ramelteon a melatonin agonist is effective for prevention of delirium
Participants 67 patients age 65-89 years newly admitted due to serious medical problem able to take oral medications (24 ICU and 43 ward patients)
Intervention ramelteon 8 mgday (dose approved for sleep) vs placebo qHS x 7 days
relative risk of 009 (95 CI 001-069)
Is there a drug that lsquocuresrsquo delirium in critically ill
bull Cohort = 102 adult intubated medical ICU patients CAM-ICU evaluation before amp after SAT
bull CAM-ICU indicated patients are gt 10 x more likely to have delirium before DIS vs after (P lt 0001)
bull Rapidly reversible sedation-related delirium does not signify the same poor prognosis as persistent deliriumndash Rapidly reversible delirium showed fewer ventilator (Plt0001) ICU
(P=0001) and hospital days (Plt0001) than persistent delirium
ndash Patients rapidly reversible delirium had similar outcomes to those without delirium
Question Does treatment with haloperidol reduce the
duration of delirium in adult ICU patients
Answer There is no published evidence that treatment with
haloperidol reduces the duration of delirium in adult ICU
patients
Question Does treatment with atypical antipsychotics
reduce the duration of delirium in adult ICU patients
Answer Atypical antipsychotics may reduce the duration of
delirium in adult ICU patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
Design Multi centre DB placebo-controlled feasibility RCT
Participants 101 mechanically ventilated medical or surgical patients with delirium
Intervention Haloperidol 5mg po q6h vs ziprasidone 40 mg vs placebo up to
14 days
ndash Titration amp taper off study drug
ndash All other treatments including sedation determined by ICU team
Primary outcome of days alive without delirium or coma
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Design Beforeafter evaluation of delirium prevention QI project that used prophylactic haloperidol
Participants ICU patients with a predicted risk of delirium ge 50 (PRE-DELIRIC tool) or history of alcohol abuse or dementia
Intervention early initiation of haloperidol 1 mg IV q8h vs historical control amp contemporary group that did not receive haloperidol)
- 05mg based on age organ dysfunction size
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Design DB placebo-controlled RCT to determine efficacy amp safety of haloperidol to prevent delirium
Participants 68 mechanically ventilated patients with ICDSC score lt 4
Intervention haloperidol 1 mg or placebo q6h until either ICDSC gt 4 therapy gt10 days or ICU discharge All managed with paired SAT-SBT
Design DB RCT (2 sites) to assess the effect of dexmedetomidinecompared to morphine-based regimen on prevalence of delirium within 5 days post-op
Participants 306 cardiac surgery patients ge 60 years
Intervention dexmedetomidine infusion vs morphine infusion x 48 h ndash All could receive open label propofol titrated to MAAS 2-4
ndash Dexmedetomidine group could receive morphine
Shehabi Y et al Anethesiology 20091111075-84
Dexmedetomidine patients experienced less systolic hypotension (23 versus 381 P 1113091
0006) required less norepinephrine (P lt 0001) but had more bradycardia (1645 versus
612 P 1113091 0006) than morphine treatment patients
Delirium involves complex pathways
Design Rater amp clinician blinded placebo-controlled RCT (5 sites) to examine whether ramelteon a melatonin agonist is effective for prevention of delirium
Participants 67 patients age 65-89 years newly admitted due to serious medical problem able to take oral medications (24 ICU and 43 ward patients)
Intervention ramelteon 8 mgday (dose approved for sleep) vs placebo qHS x 7 days
relative risk of 009 (95 CI 001-069)
Is there a drug that lsquocuresrsquo delirium in critically ill
bull Cohort = 102 adult intubated medical ICU patients CAM-ICU evaluation before amp after SAT
bull CAM-ICU indicated patients are gt 10 x more likely to have delirium before DIS vs after (P lt 0001)
bull Rapidly reversible sedation-related delirium does not signify the same poor prognosis as persistent deliriumndash Rapidly reversible delirium showed fewer ventilator (Plt0001) ICU
(P=0001) and hospital days (Plt0001) than persistent delirium
ndash Patients rapidly reversible delirium had similar outcomes to those without delirium
Question Does treatment with haloperidol reduce the
duration of delirium in adult ICU patients
Answer There is no published evidence that treatment with
haloperidol reduces the duration of delirium in adult ICU
patients
Question Does treatment with atypical antipsychotics
reduce the duration of delirium in adult ICU patients
Answer Atypical antipsychotics may reduce the duration of
delirium in adult ICU patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
Design Multi centre DB placebo-controlled feasibility RCT
Participants 101 mechanically ventilated medical or surgical patients with delirium
Intervention Haloperidol 5mg po q6h vs ziprasidone 40 mg vs placebo up to
14 days
ndash Titration amp taper off study drug
ndash All other treatments including sedation determined by ICU team
Primary outcome of days alive without delirium or coma
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Design DB placebo-controlled RCT to determine efficacy amp safety of haloperidol to prevent delirium
Participants 68 mechanically ventilated patients with ICDSC score lt 4
Intervention haloperidol 1 mg or placebo q6h until either ICDSC gt 4 therapy gt10 days or ICU discharge All managed with paired SAT-SBT
Design DB RCT (2 sites) to assess the effect of dexmedetomidinecompared to morphine-based regimen on prevalence of delirium within 5 days post-op
Participants 306 cardiac surgery patients ge 60 years
Intervention dexmedetomidine infusion vs morphine infusion x 48 h ndash All could receive open label propofol titrated to MAAS 2-4
ndash Dexmedetomidine group could receive morphine
Shehabi Y et al Anethesiology 20091111075-84
Dexmedetomidine patients experienced less systolic hypotension (23 versus 381 P 1113091
0006) required less norepinephrine (P lt 0001) but had more bradycardia (1645 versus
612 P 1113091 0006) than morphine treatment patients
Delirium involves complex pathways
Design Rater amp clinician blinded placebo-controlled RCT (5 sites) to examine whether ramelteon a melatonin agonist is effective for prevention of delirium
Participants 67 patients age 65-89 years newly admitted due to serious medical problem able to take oral medications (24 ICU and 43 ward patients)
Intervention ramelteon 8 mgday (dose approved for sleep) vs placebo qHS x 7 days
relative risk of 009 (95 CI 001-069)
Is there a drug that lsquocuresrsquo delirium in critically ill
bull Cohort = 102 adult intubated medical ICU patients CAM-ICU evaluation before amp after SAT
bull CAM-ICU indicated patients are gt 10 x more likely to have delirium before DIS vs after (P lt 0001)
bull Rapidly reversible sedation-related delirium does not signify the same poor prognosis as persistent deliriumndash Rapidly reversible delirium showed fewer ventilator (Plt0001) ICU
(P=0001) and hospital days (Plt0001) than persistent delirium
ndash Patients rapidly reversible delirium had similar outcomes to those without delirium
Question Does treatment with haloperidol reduce the
duration of delirium in adult ICU patients
Answer There is no published evidence that treatment with
haloperidol reduces the duration of delirium in adult ICU
patients
Question Does treatment with atypical antipsychotics
reduce the duration of delirium in adult ICU patients
Answer Atypical antipsychotics may reduce the duration of
delirium in adult ICU patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
Design Multi centre DB placebo-controlled feasibility RCT
Participants 101 mechanically ventilated medical or surgical patients with delirium
Intervention Haloperidol 5mg po q6h vs ziprasidone 40 mg vs placebo up to
14 days
ndash Titration amp taper off study drug
ndash All other treatments including sedation determined by ICU team
Primary outcome of days alive without delirium or coma
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Design DB RCT (2 sites) to assess the effect of dexmedetomidinecompared to morphine-based regimen on prevalence of delirium within 5 days post-op
Participants 306 cardiac surgery patients ge 60 years
Intervention dexmedetomidine infusion vs morphine infusion x 48 h ndash All could receive open label propofol titrated to MAAS 2-4
ndash Dexmedetomidine group could receive morphine
Shehabi Y et al Anethesiology 20091111075-84
Dexmedetomidine patients experienced less systolic hypotension (23 versus 381 P 1113091
0006) required less norepinephrine (P lt 0001) but had more bradycardia (1645 versus
612 P 1113091 0006) than morphine treatment patients
Delirium involves complex pathways
Design Rater amp clinician blinded placebo-controlled RCT (5 sites) to examine whether ramelteon a melatonin agonist is effective for prevention of delirium
Participants 67 patients age 65-89 years newly admitted due to serious medical problem able to take oral medications (24 ICU and 43 ward patients)
Intervention ramelteon 8 mgday (dose approved for sleep) vs placebo qHS x 7 days
relative risk of 009 (95 CI 001-069)
Is there a drug that lsquocuresrsquo delirium in critically ill
bull Cohort = 102 adult intubated medical ICU patients CAM-ICU evaluation before amp after SAT
bull CAM-ICU indicated patients are gt 10 x more likely to have delirium before DIS vs after (P lt 0001)
bull Rapidly reversible sedation-related delirium does not signify the same poor prognosis as persistent deliriumndash Rapidly reversible delirium showed fewer ventilator (Plt0001) ICU
(P=0001) and hospital days (Plt0001) than persistent delirium
ndash Patients rapidly reversible delirium had similar outcomes to those without delirium
Question Does treatment with haloperidol reduce the
duration of delirium in adult ICU patients
Answer There is no published evidence that treatment with
haloperidol reduces the duration of delirium in adult ICU
patients
Question Does treatment with atypical antipsychotics
reduce the duration of delirium in adult ICU patients
Answer Atypical antipsychotics may reduce the duration of
delirium in adult ICU patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
Design Multi centre DB placebo-controlled feasibility RCT
Participants 101 mechanically ventilated medical or surgical patients with delirium
Intervention Haloperidol 5mg po q6h vs ziprasidone 40 mg vs placebo up to
14 days
ndash Titration amp taper off study drug
ndash All other treatments including sedation determined by ICU team
Primary outcome of days alive without delirium or coma
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Shehabi Y et al Anethesiology 20091111075-84
Dexmedetomidine patients experienced less systolic hypotension (23 versus 381 P 1113091
0006) required less norepinephrine (P lt 0001) but had more bradycardia (1645 versus
612 P 1113091 0006) than morphine treatment patients
Delirium involves complex pathways
Design Rater amp clinician blinded placebo-controlled RCT (5 sites) to examine whether ramelteon a melatonin agonist is effective for prevention of delirium
Participants 67 patients age 65-89 years newly admitted due to serious medical problem able to take oral medications (24 ICU and 43 ward patients)
Intervention ramelteon 8 mgday (dose approved for sleep) vs placebo qHS x 7 days
relative risk of 009 (95 CI 001-069)
Is there a drug that lsquocuresrsquo delirium in critically ill
bull Cohort = 102 adult intubated medical ICU patients CAM-ICU evaluation before amp after SAT
bull CAM-ICU indicated patients are gt 10 x more likely to have delirium before DIS vs after (P lt 0001)
bull Rapidly reversible sedation-related delirium does not signify the same poor prognosis as persistent deliriumndash Rapidly reversible delirium showed fewer ventilator (Plt0001) ICU
(P=0001) and hospital days (Plt0001) than persistent delirium
ndash Patients rapidly reversible delirium had similar outcomes to those without delirium
Question Does treatment with haloperidol reduce the
duration of delirium in adult ICU patients
Answer There is no published evidence that treatment with
haloperidol reduces the duration of delirium in adult ICU
patients
Question Does treatment with atypical antipsychotics
reduce the duration of delirium in adult ICU patients
Answer Atypical antipsychotics may reduce the duration of
delirium in adult ICU patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
Design Multi centre DB placebo-controlled feasibility RCT
Participants 101 mechanically ventilated medical or surgical patients with delirium
Intervention Haloperidol 5mg po q6h vs ziprasidone 40 mg vs placebo up to
14 days
ndash Titration amp taper off study drug
ndash All other treatments including sedation determined by ICU team
Primary outcome of days alive without delirium or coma
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Delirium involves complex pathways
Design Rater amp clinician blinded placebo-controlled RCT (5 sites) to examine whether ramelteon a melatonin agonist is effective for prevention of delirium
Participants 67 patients age 65-89 years newly admitted due to serious medical problem able to take oral medications (24 ICU and 43 ward patients)
Intervention ramelteon 8 mgday (dose approved for sleep) vs placebo qHS x 7 days
relative risk of 009 (95 CI 001-069)
Is there a drug that lsquocuresrsquo delirium in critically ill
bull Cohort = 102 adult intubated medical ICU patients CAM-ICU evaluation before amp after SAT
bull CAM-ICU indicated patients are gt 10 x more likely to have delirium before DIS vs after (P lt 0001)
bull Rapidly reversible sedation-related delirium does not signify the same poor prognosis as persistent deliriumndash Rapidly reversible delirium showed fewer ventilator (Plt0001) ICU
(P=0001) and hospital days (Plt0001) than persistent delirium
ndash Patients rapidly reversible delirium had similar outcomes to those without delirium
Question Does treatment with haloperidol reduce the
duration of delirium in adult ICU patients
Answer There is no published evidence that treatment with
haloperidol reduces the duration of delirium in adult ICU
patients
Question Does treatment with atypical antipsychotics
reduce the duration of delirium in adult ICU patients
Answer Atypical antipsychotics may reduce the duration of
delirium in adult ICU patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
Design Multi centre DB placebo-controlled feasibility RCT
Participants 101 mechanically ventilated medical or surgical patients with delirium
Intervention Haloperidol 5mg po q6h vs ziprasidone 40 mg vs placebo up to
14 days
ndash Titration amp taper off study drug
ndash All other treatments including sedation determined by ICU team
Primary outcome of days alive without delirium or coma
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Design Rater amp clinician blinded placebo-controlled RCT (5 sites) to examine whether ramelteon a melatonin agonist is effective for prevention of delirium
Participants 67 patients age 65-89 years newly admitted due to serious medical problem able to take oral medications (24 ICU and 43 ward patients)
Intervention ramelteon 8 mgday (dose approved for sleep) vs placebo qHS x 7 days
relative risk of 009 (95 CI 001-069)
Is there a drug that lsquocuresrsquo delirium in critically ill
bull Cohort = 102 adult intubated medical ICU patients CAM-ICU evaluation before amp after SAT
bull CAM-ICU indicated patients are gt 10 x more likely to have delirium before DIS vs after (P lt 0001)
bull Rapidly reversible sedation-related delirium does not signify the same poor prognosis as persistent deliriumndash Rapidly reversible delirium showed fewer ventilator (Plt0001) ICU
(P=0001) and hospital days (Plt0001) than persistent delirium
ndash Patients rapidly reversible delirium had similar outcomes to those without delirium
Question Does treatment with haloperidol reduce the
duration of delirium in adult ICU patients
Answer There is no published evidence that treatment with
haloperidol reduces the duration of delirium in adult ICU
patients
Question Does treatment with atypical antipsychotics
reduce the duration of delirium in adult ICU patients
Answer Atypical antipsychotics may reduce the duration of
delirium in adult ICU patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
Design Multi centre DB placebo-controlled feasibility RCT
Participants 101 mechanically ventilated medical or surgical patients with delirium
Intervention Haloperidol 5mg po q6h vs ziprasidone 40 mg vs placebo up to
14 days
ndash Titration amp taper off study drug
ndash All other treatments including sedation determined by ICU team
Primary outcome of days alive without delirium or coma
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
relative risk of 009 (95 CI 001-069)
Is there a drug that lsquocuresrsquo delirium in critically ill
bull Cohort = 102 adult intubated medical ICU patients CAM-ICU evaluation before amp after SAT
bull CAM-ICU indicated patients are gt 10 x more likely to have delirium before DIS vs after (P lt 0001)
bull Rapidly reversible sedation-related delirium does not signify the same poor prognosis as persistent deliriumndash Rapidly reversible delirium showed fewer ventilator (Plt0001) ICU
(P=0001) and hospital days (Plt0001) than persistent delirium
ndash Patients rapidly reversible delirium had similar outcomes to those without delirium
Question Does treatment with haloperidol reduce the
duration of delirium in adult ICU patients
Answer There is no published evidence that treatment with
haloperidol reduces the duration of delirium in adult ICU
patients
Question Does treatment with atypical antipsychotics
reduce the duration of delirium in adult ICU patients
Answer Atypical antipsychotics may reduce the duration of
delirium in adult ICU patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
Design Multi centre DB placebo-controlled feasibility RCT
Participants 101 mechanically ventilated medical or surgical patients with delirium
Intervention Haloperidol 5mg po q6h vs ziprasidone 40 mg vs placebo up to
14 days
ndash Titration amp taper off study drug
ndash All other treatments including sedation determined by ICU team
Primary outcome of days alive without delirium or coma
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Is there a drug that lsquocuresrsquo delirium in critically ill
bull Cohort = 102 adult intubated medical ICU patients CAM-ICU evaluation before amp after SAT
bull CAM-ICU indicated patients are gt 10 x more likely to have delirium before DIS vs after (P lt 0001)
bull Rapidly reversible sedation-related delirium does not signify the same poor prognosis as persistent deliriumndash Rapidly reversible delirium showed fewer ventilator (Plt0001) ICU
(P=0001) and hospital days (Plt0001) than persistent delirium
ndash Patients rapidly reversible delirium had similar outcomes to those without delirium
Question Does treatment with haloperidol reduce the
duration of delirium in adult ICU patients
Answer There is no published evidence that treatment with
haloperidol reduces the duration of delirium in adult ICU
patients
Question Does treatment with atypical antipsychotics
reduce the duration of delirium in adult ICU patients
Answer Atypical antipsychotics may reduce the duration of
delirium in adult ICU patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
Design Multi centre DB placebo-controlled feasibility RCT
Participants 101 mechanically ventilated medical or surgical patients with delirium
Intervention Haloperidol 5mg po q6h vs ziprasidone 40 mg vs placebo up to
14 days
ndash Titration amp taper off study drug
ndash All other treatments including sedation determined by ICU team
Primary outcome of days alive without delirium or coma
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
bull Cohort = 102 adult intubated medical ICU patients CAM-ICU evaluation before amp after SAT
bull CAM-ICU indicated patients are gt 10 x more likely to have delirium before DIS vs after (P lt 0001)
bull Rapidly reversible sedation-related delirium does not signify the same poor prognosis as persistent deliriumndash Rapidly reversible delirium showed fewer ventilator (Plt0001) ICU
(P=0001) and hospital days (Plt0001) than persistent delirium
ndash Patients rapidly reversible delirium had similar outcomes to those without delirium
Question Does treatment with haloperidol reduce the
duration of delirium in adult ICU patients
Answer There is no published evidence that treatment with
haloperidol reduces the duration of delirium in adult ICU
patients
Question Does treatment with atypical antipsychotics
reduce the duration of delirium in adult ICU patients
Answer Atypical antipsychotics may reduce the duration of
delirium in adult ICU patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
Design Multi centre DB placebo-controlled feasibility RCT
Participants 101 mechanically ventilated medical or surgical patients with delirium
Intervention Haloperidol 5mg po q6h vs ziprasidone 40 mg vs placebo up to
14 days
ndash Titration amp taper off study drug
ndash All other treatments including sedation determined by ICU team
Primary outcome of days alive without delirium or coma
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Question Does treatment with haloperidol reduce the
duration of delirium in adult ICU patients
Answer There is no published evidence that treatment with
haloperidol reduces the duration of delirium in adult ICU
patients
Question Does treatment with atypical antipsychotics
reduce the duration of delirium in adult ICU patients
Answer Atypical antipsychotics may reduce the duration of
delirium in adult ICU patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
Design Multi centre DB placebo-controlled feasibility RCT
Participants 101 mechanically ventilated medical or surgical patients with delirium
Intervention Haloperidol 5mg po q6h vs ziprasidone 40 mg vs placebo up to
14 days
ndash Titration amp taper off study drug
ndash All other treatments including sedation determined by ICU team
Primary outcome of days alive without delirium or coma
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Design Multi centre DB placebo-controlled feasibility RCT
Participants 101 mechanically ventilated medical or surgical patients with delirium
Intervention Haloperidol 5mg po q6h vs ziprasidone 40 mg vs placebo up to
14 days
ndash Titration amp taper off study drug
ndash All other treatments including sedation determined by ICU team
Primary outcome of days alive without delirium or coma
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Haloperidol N = 35
ZiprasidoneN = 30
PlaceboN = 36
P
Deliriumcoma-free days in 1st 21 days 140 150 125 066
Delirium days 4 4 4 093
Resolution of delirium on study drug 69 77 58 028
Coma days 2 2 2 090
Ventilator-free days 78 120 125 025
ICU Length of stay days 117 96 73 070
AkathisiaQTc prolongation gt 500 ms
296
2017
198
060031
We awaitMIND USA STUDY results
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Design Single centre DB placebo-controlled RCT
Patients 142 adult needing MV lt 72 hrs of admission regardless of delirium or coma status
Intervention haloperidol 25mg IV q8h or placebo x 14 days
ndash Fentanyl + propofol infusions titrated to RASS -1 to 0
ndash WeaningSBT standardized physiotherapy step-wise program
ndash Acute agitation reversible causes investigated by bedside team PRN haloperidol 10 mg24 hours
Primary outcome delirium-free amp coma-free days in 1st 14 days post-randomization
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
HOPE-ICU RCT OUTCOMES
Haloperidol (N = 71)
Placebo (N = 70)
P
Alive delirium-free amp coma-free days in 1st 14 days 5 6 053
Days in delirium in 1st 14 days 5 5 099
Days in coma in 1st 14 days 0 05 099
Ventilator-free days in 1st 28 days 21 17 088
Mortality at 28 days 282 271
Length of ICU stay days 95 9 047
Page VJ et al Lancet Respir Dis Aug 21 2013
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Intervention Control Population Outcomes
Olanzapine PO 5 mg daily (n = 28)
haloperidol PO 25 mg q8h(n = 45)
SICU gt MICU
Delirium +
- No difference in delirium index scores day 5- No difference in benzodiazepine use
Quetiapine 50 mg PO q12h + titration (max 200 mg)(n = 18)
Placebo(n = 18)
MICU gt SICU
Delirium +
-Time to 1st resolution quetiapine 10 vs 45 days placebo p = 0001
ATYPICAL ANTIPSYCHOTIC RCTs
Skrobik Y Int Care Med 200430444-449Devlin J Crit Care Med 201038(2)419-427
ADRs
13 mildEPS in haloperidol group
0 EPS
No diff in QTc
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Question For mechanically ventilated adult ICU
patients with delirium who require continuous IV
infusions of sedative medications is dexmedetomidine
preferred over benzodiazepines to reduce the duration
of delirium
Answer We suggest that in adult ICU patients with
delirium which is not related to withdrawal continuous IV
infusions dexmedetomidine rather than benzodiazepine
infusions be administered for sedation in order to reduce
the duration of delirium in these patients
Barr J et al Crit Care Med 2013 41 263-306
2013 SCCM Recommendations
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
SEDCOM
JAMA
2009
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
In 2015hellip
bull There is insufficient evidence that a drug can be used for primary prevention of delirium in critically ill patients
bull There is no evidence treatment of delirium with haloperidol reduces duration of delirium Atypical antipsychotics may reduce duration
bull Reserve drug intervention for patients in distress due to agitation or psychotic symptoms
bull If warranted attempt monotherapy amp the lowest effective dose Re-evaluate need for therapy frequently
bull Pharmacotherapy options will be clearer with greater understanding of pathophysiology and completion of ongoing trials
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
lburrymtsinaionca
ldquoNever be content to sit on the sidelines when there is so much work to be done on the fieldrdquo
- Susan Gale
Find a drug to prevent amp treat delirium in the
critically ill
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Extra slides
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
MIND USA STUDY
Patients requiring either MV NPPV or in shock who are CAM-ICU+
N=876 patients at n=14 USA centers
Haloperidol
up to 10mg IV q12hZiprasidone
up to 20mg IV q12h
Placebo
10ml IV q12h
Treated until delirium has resolved x 48 hours or to 14 days
(whichever occurs first) and followed for 1 year
Period spent delirium-free and coma-free 14 days after randomization
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press
Al-Qadheeb N Skrobik Y Schumaker G Pacheco M Roberts R Ruthazer R Devlin J Crit Care Med 2015 in press