Delirium Unarousable to Ashley Thompson, Pharm D., BCPS voice - - PDF document

5/9/2015 1

ICU Delirium Controversies & Updates

Ashley Thompson, Pharm D., BCPS Critical Care Pharmacist UCSF Medical Center May 2015

Pun, et al. Chest 2007; 132; 624-636 Ely, et al. JAMA. 2001; 286:2703-2710 Diagnostic and Statistical Manual of Mental Disorders (4th ed.)

Delirium

Arousable to voice Acute mental status change Fluctuating mental status

Altered level

• f

consciousness Inattention Disorganized thinking

COMA

Unarousable to voice

Sedation Analgesia

Scope of the Problem

• Independent predictor of mortality
• ↑ Long term cognitive dysfunction
• ↑ duration of mechanical ventilation,

reintubation rates

• ↑ hospital/ICU length of stay
• ↑ healthcare costs
• Reduced functional status at discharge

Pun, et al. Chest 2007; 132; 624-636 Ely EW, et al. JAMA. 2004; 291(14):1753-1762 AJRCCM 2009 12. 1; 180(11): 1092–1097 Milbrandt et al. Crit Care Med. 2004;32 (4): 955-962 Pandharipande PP. NEJM 2013;369:1306-16. Girard, et al. Crit Care Med 2012; 38:1513-1520

The Bedside Assessment

Intensive Care Med (2009) 35: 1276-1280

Attending = 28% RN = 35%

Crit Care Med 2013; 41:263–306. JAMA 1990;263(8):1097–101. Am J Med 1994;97(3):278–88.

+1B

Validated Screening tool

Delirium is unrecognized in up to 84% of hospitalized adults

Does level of sedation influence CAM- ICU positivity?

…But what I see these days are paralyzed, sedated patients, lying without motion, appearing to be dead, except for the monitors that tell me otherwise…

• Tomas Petty, 1998

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No Sedation

No sedation vs Prop/Midaz (+ SWU) + open label morphine

• Results:
• No sedation is feasible; 18% didn’t tolerate
•  vent days (4 days, P=0.019)*
•  ICU (9 days)/Hospital LOS (24 days)
• mortality (22% vs 38%, P=0.06)
• No difference in PTSD (follow-up study)
• Post-hoc analysis
•  hyperactive delirium

– hypoactive, i.e sedation induced, not measured

•  Acute renal failure

Strom T, et al. Lancet 2010;375:475-80.

Rapidly Reversible, Sedation-related versus Persistent Delirium

• Prospective observational blinded study, Single centered

(N=102)

• Results:
• Patients 10x more likely to be CAM-ICU + before sedation

interruption vs after (P < 0.001)

• Not all “types” of delirium are the same

Patel SB, et al. Am J Respir Crit Care Med 2014; 189: 658-665

Mechanically ventilated, sedated MICU pts DSI Outcome

If CAM-ICU + (followed by (-) after DSI) = rapidly reversible sedation- related delirium If CAM-ICU + = persistent delirium

Rapidly Reversible, Sedation-related versus Persistent Delirium

Patel SB, et al. Am J Respir Crit Care Med 2014; 189: 658-665

Rapidly Reversible, Sedation-related versus Persistent Delirium

Patel SB, et al. Am J Respir Crit Care Med 2014; 189: 658-665

Mortality

Each day of persistent delirium was associated with a 14% ↑risk

• f death by 1 year (P<0.001)

Do Benzodiazepines increase a patients risk

• f developing delirium?

Benzodiazepines & Delirium

Pandharipande, et al. Anesthesiology 2006; 104:21– 6.

Lorazepam was an independent risk factor for daily transition to delirium (OR 1.2 95% CI 1.1-1.4, p=0.003)

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Riker R, et al. JAMA. 2009; 301 (5):489-499.

SEDCOM Trial: Daily prevalence of delirium

COMA associated with duration, NOT daily dose of drug exposure

Factors Predisposing to Coma & Delirium

Skrobik Y, et al. Crit Care Med 2013; 41: 999-1008

Midazolam & delirium

• LOWER levels in patients with delirium vs no delirium

(p=0.001)

• Time to first occurrence of delirium:
• Unrelated to dose or presence of (p=0.4 p=0.3 respectively , cox

analysis)

• Duration of first episode of delirium, not associated with:
• Concomitant administration (p=0.26)
• Cumulative midazolam administration (p=0.96)
• Days in delirium/days in ICU
• Not associated with midazolam doses on delirium days (p=0.25)
• Not associated with cumulative doses (p=0.96)

Factors Predisposing to Coma & Delirium

Skrobik Y, et al. Crit Care Med 2013; 41: 999-1008

Inflammation & Delirium

Factors Predisposing to Coma & Delirium

Skrobik Y, et al. Crit Care Med 2013; 41: 999-1008

Does delirium respond to pharmacological treatment?

“Doctor, she’s not all there. The wit, the comprehension, the concentration…The best way to describe it is mental disorganization, like there is a connection missing or a synapse not firing. It has been 10 months, and I just keep waiting for it to straighten itself out. Is this it?”

• Family testimonial (icudelirium.org)

RCTs for Antipsychotic use in ICU delirium?

• 1. Devlin, et al. (n=36); treatment
• Quetiapine vs haloperidol PRN
• ↓time to first delirium resolution (1 vs 4.5 days)
• ↓ duration of delirium (36 vs 120 hours)
• ↓agitation (6 vs 36 hours)
• ↓PRN haloperidol vs placebo
• 2. MIND (n=101), prophylaxis, no difference
• Prophylactic ziprasidone vs haloperidol vs placebo
• 3. HOPE-ICU (n=142), prophylaxis; no difference
• Prophylactic haloperidol IV ATC vs placebo

Devlin, et al. Crit Care Med 2010; 38 Girad, et al. Crit Care Med; 2010; 38:428-437 Page VJ et al. Lancet Resp Med 2013;1(7):515-23.

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Antipsychotics: FDA Black box warning dose dependent  risk of death in elderly with dementia (60-70%)

Huybrechts KF et al. BMJ 2012; 344: e977 Wang P et al. Neng J Med 2005;353:2335-41

ADRS associated with antipsychotic use in ICU Delirium Treatment

Hale GM et al. J Pharmacy Practice 2015

No antipsychotic (%), 38 Antipsychotic

(%), 62

ADRS = 18% ADRS associated with antipsychotic use in ICU Delirium Treatment

Hale GM et al. J Pharmacy Practice 2015

10 20 30 40 50 60 ADR

QTc drowsiness tachycardia drug-induced fever neutropenia

Risk Factor for developing ADRs APACHE II Score (p=0.038)

%

Transitioning Out of the Unit?

• Retrospective cohort study (N=59)
• Antipsychotics initiated for ICU delirium:
• 47% continued antipsychotic on ICU

discharge

• 71.4% were continued as an outpatient
• Long-term impact?

Jasiak KD, et al. J Pharm Pract 2013;26(3):253-6.

Statins & Delirium during Critical Illness: ICU statin use & Delirium

Morandi AM. Et al. Crit Care Med 2014; 42: 1899-1909

Statin use associated with reduced Delirium (p < 0.01)

Septic Not Septic

Statins & Delirium during Critical Illness: Prehospital statin users

Morandi AM. Et al. Crit Care Med 2014; 42: 1899-1909

5/9/2015 5 Corticosteroids & Delirium in Patients with Acute Lung Injury

• Multisite, Prospective, cohort study (N=330 MV pts

with ALI)

Schreiber MP et al. Crit Care Med 2014; 42: 1480-1486

Summary: Delirium & Drugs

• Discontinue/minimize deliriogenic medications
• Choose appropriate sedation
• Role of Antipsychotics?
• Lack of compelling evidence
• Risk of side effects
• Consider continuing preadmission statin
• Need RCT to confirm

Sleep, Exercise & Delirium

• 50% of ICU sleep occurs during daytime hours
• Opioids, Benzodiazepines disrupt REM sleep
• Nocturnal [melatonin] in ICU pts negatively

correlated with illness of severity

• Bellapart. BJA 108 (4): 572-80 (2012)

Bourne RS et al. Crit Care 2008, 12:R52 Huang et al. Trials 2014, 15:327

Sleep in the ICU & Delirium

• Ramelteon 8mg or placebo at 2100 + prn hydroxyzine

Hatta K, et al. JAMA Psychiatry. 2014; 71 (4): 397-403

Preventative Effects of Ramelteon on Delirium

Placebo Ramelteon Significance All delirium 32% 3% P=0.003, RR 0.09 (95% CT 0.01-0.69) No history delirium 30% 0% P=0.001 Time to delirium (Kaplan-Meier) 5.74 days 6.94 days No significant differences between the groups in any sleep differences

• Multifaceted QI intervention John Hopkins MICU

Kamdar et al. Crit Care Med 2013; 41: 800-809

Bundled approach to sleep & ICU Delirium

Stage 0: Baseline

Stage 1: Environmental interventions Stage 2: Non-pharm sleep aids Stage 3: Pharmacologic guideline

Baseline Sleep QI Significance Delirium/Coma free 43% 48% P=0.04 Incident delirium/Coma 69% 49% P=0.001 ND: mortality, ICU/Hospital LOS, neurocognitive tests, perceived sleep quality

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Early Rehabilitation & Delirium

• Progressive mobility algorithm beginning ~1.5

days post-intubation

• Primary endpoint:
• Independent functional status at discharge (59% v.

35%, p=0.02)

• Results:
• Shorter duration of ICU delirium (2 vs. 4 days,

p=0.03) with similar sedative administration/SAT

Schweickert WD, et al. Lancet 2009;373:1874-82

ICU Liberation is as easy as…

Critical Care 2010, 14:157 Curr Opin CritCare 2011,17:43–49

• Awake & breathing coordination (DSI,

+1B)

AB

• Choice of sedative (nonBZD, +2B)

C

• Delirium monitoring & management

(+1B)

D

• Early mobility (+1B)

E

• Family involvement

F

The RCTs of the ABCs…

• A: Kress JP, et al. N Engl J Med 2000; 342: 1471-7
• A&B: Girard ED et al. Lancet 2008; 371: 126-34

AB

• Pandharipande PP et al. JAMA 2007; 298: 2644-53
• Riker R. et al, JAMA 2009; 301: 489-499
• Strom T, et al. Lancet 2010; 375: 475-480

C

• Spronk PE intensive Care Med. 2009; 35:1276-1280
• Pun, et al. Chest 2007; 132; 624-636

D

• Schweickert et al. Lancet 2009; 373: 1874-82

E

• ABCDE bundle Implementation: Single center,

pre/post study (n= 296)

•  delirium
• Prevalence (62% vs 49%, p=0.02)
• Days (33.3% vs 50%, p=0.003)
• ↑ventilator free days (21 vs 24 days, p=0.04)
• mobilization (66% vs 48%, p=0.002)

Balas MC et al. Crit Care Med 2014; 42:1024–1036 Balas MC et al. Crit Care Med 2013; 41:S116–S127

ABCDE: Is it that easy?

Thank you

Ashley.Thompson@ucsf.edu

ICU Delirium Controversies & Updates

Ashley Thompson, Pharm D., BCPS Critical Care Pharmacist UCSF Medical Center May 2015