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

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

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

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

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

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

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

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

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

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

relative risk of 009 (95 CI 001-069)

Is there a drug that lsquocuresrsquo delirium in critically ill

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

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