1. Pain, Agitation and Delirium (PAD): An Overview of Recent Guidelines
Brenda Pun, RN, MSN, ACNP Vanderbilt University Medical Center

2. Barr J, et al. Crit Care Med. 2013;41:263–306.

3. Pain, Agitation, and Delirium Are Interrelated
Barr J, et al. Crit Care Med. 2013;41:

4. 5 Key Themes 1. Goal = Light sedation 2. Sedative titration method =
Daily Sedative Interruption or
Targeted sedation
3. Avoid/Minimize Benzodiazepines
4. Early Mobility
5. No Med Recommendation for Delirium

7. #1: Light Sedation (rather than deep)

8. PAD Depth of Sedation Recommendations
We recommend that sedative medications be titrated to maintain a light rather than a deep level of sedation in adult ICU patients, unless clinically contraindicated (+1B).
Light Sedation: patient is arousable and able to purposefully follow simple commands
Barr J, et al. Crit Care Med 2013; 41:263–306

9. Early Deep Sedation: Longer Ventilation, Reduced Survival
Multicenter study (N=251)
Deep sedation (RASS -3 to - 5)
76% within 4 hours of MV
68% at 48 hours
Early deep sedation was independent predictor of time to extubation (P<0.001)
Deeply sedated, 7.7 days
Not deeply sedated, 2.4 days
Early deep sedation was also an independent predictor of hospital death and 180-day mortality
Survival
Probability of death at 180 days
Days
Shehabi Y, et al. Am J Respir Crit Care Med. 2012;186:

10. Mental Health and Light vs Deep Sedation
Sedation with midazolam
Light: Ramsay 1-2, intermittent injection
Deep: Ramsay 3-4, continuous infusion
Results
4 weeks after ICU discharge the deep group:
Higher PTSD Scores
Trouble remembering the ICU
Disturbing memories
Patients: adults requiring mechanical ventilation
Treggiari MM, et al. Crit Care Med Sep;37(9):

11. #2: Sedative Titration Method
Daily Sedative Interruption
Light Targeted Titration

12. PAD Titration Recommendations
We recommend either daily sedation interruption or a light target level of sedation be routinely used in mechanically ventilated adult ICU patients (+1B).
Barr J, et al. Crit Care Med 2013; 41:263–306

13. Daily Sedation Interruption
Methods:
Hold sedation infusion until patient awake and then restart at 50% of the prior dose
Results:
Shorter time on the ventilatory
Shorter stay in the ICU
Fewer diagnostic tests to assess changes in mental status
No increase in rate of agitated-related complications or episodes of patient-initiated device removal
No increase in PTSD or cardiac ischemia
Open eyes in response to voice
Use eyes to follow investigator on request
Squeeze hand on request
Stick out tongue on request
Kress JP, et al. N Engl J Med. 2000;342:
Kress, JP, et al. AJRCCM 2003; 168:

14. Wake up and Breathe (ABC) Study
The ABC protocol reduced….
Duration of mechanical ventilation by ~3 days
ICU and hospital length of stay by ~4 days
Duration of coma by ~1 day
32% lower likelihood of dying and a number needed to treat (NNT) of 7 to save a life at 1 year
A: Spontaneous Awakening Trials
B: Spontaneous Breathing Trials
Girard TD, et al. Lancet. 2008;371:

15. Nursing-Implemented Sedation Protocol: Barnes Jewish Pilot
Significant patient characteristics/metrics/outcomes
Protocol
Routine
P value
CIVS†
66 (40)
66 (42)
0.9
Duration CIVS, hrs*
3.5 ± 4
5.6 ± 6.4
0.003
Bolus†
118 (72)
127 (80)
0.14
Reintubated†
14 (8.6)
21 (13)
0.2
Trached†
10 (6.2)
21 (13.2)
0.04
*Data presented in median; †Data presented as n (%)
CIVS: continuous intravenous infusion sedation
P < 0.001
P = 0.13
P = 0.003
Single center, prospective, trial of 332 consecutive ICU patients requiring mechanical ventilation randomized to protocolized sedation (n = 162) or routine care (n = 159) at Barnes Jewish Hospital from 8/97 to 7/98. Protocol used goal orientated sedation to target Ramsey with bolus requirements before initiation of continuous infusion and uptitration of opioids and benzodiazepines.
Brook AD, et al. Crit Care Med. 1999;27(12):

16. Pharmacist Enforced Adherence to an ICU Sedation Guideline
Significant patient characteristics/metrics/outcomes
RPh
Control
P value
Alcohol/drug overdose†
15 (19.2)
6 (7.7)
0.03
Lorazepam equivalents/vent day, mg*
65.2 ± 114.1
74.8 ± 76.1
0.54
Fentanyl equivalents/vent day, mcg*
102.5 ± 328
400 ± 1026
0.02
*Data presented in mean ; †Data presented as n (%)
P = 0.002
P =
102.5 ± 328
Single center trial of 156 adult MICU patients requiring mechanical ventilation before (n = 78) and after (n = 78) implementation of RPh enforced guideline sedation management at Boston Medical Center. Guideline addressed use of agent selection, goal oriented therapy, and dose limitation strategies.
Marshall J, et al. Crit Care Med. 2008;36(2):

17. #3: Avoid/Minimize Benzodiazepine use

18. PAD Choice of Sedative Recommendations
We suggest that analgesia-first sedation be used in mechanically ventilated adult ICU patients (+2B).
We suggest that sedation strategies using nonbenzodiazepine sedatives (either propofol or dexmedetomidine) may be preferred over sedation with benzodiazepines (either midazolam or lorazepam) to improve clinical outcomes in mechanically ventilated adult ICU patients (+2B).
We suggest that in adult ICU patients with delirium unrelated to alcohol or benzodiazepine withdrawal, continuous IV infusions of dexmedetomidine rather than benzodiazepine infusions be administered for sedation to reduce the duration of delirium in these patients (+2B).
Barr J, et al. Crit Care Med 2013; 41:263–306

19. Analgosedation Analgesia Sedation vs. Hypnotic Sedation
Analgesic first sedation + supplement with hypnotic sedative
Treats pain + provides sedation
Remifentanil
Fentanyl
Morphine
Not appropriate for drug or alcohol withdrawal
Park G, et al. Br J Anaesth. 2007;98:76-82.
Rozendaal FW, et al. Intensive Care Med. 2009;35:

20. Analgosedation Study Results
Patients receiving analgosedation had
More days without ventilation (13.8 vs 9.6 days, P = 0.02)
Shorter stay in ICU (HR 1.86, P = 0.03)
Shorter stay in hospital (HR 3.57, P = 0.004)
More agitated delirium (N = 11, 20% vs N = 4, 7%, P = 0.04)
No differences found in
Accidental extubations
Need for CT or MRI
Ventilator-associated pneumonia
Strøm T, et al. Lancet. 2010;375:

21. PAD Choice of Sedative Recommendations
We suggest that analgesia-first sedation be used in mechanically ventilated adult ICU patients (+2B).
We suggest that sedation strategies using nonbenzodiazepine sedatives (either propofol or dexmedetomidine) may be preferred over sedation with benzodiazepines (either midazolam or lorazepam) to improve clinical outcomes in mechanically ventilated adult ICU patients (+2B).
We suggest that in adult ICU patients with delirium unrelated to alcohol or benzodiazepine withdrawal, continuous IV infusions of dexmedetomidine rather than benzodiazepine infusions be administered for sedation to reduce the duration of delirium in these patients (+2B).
Barr J, et al. Crit Care Med 2013; 41:263–306

22. Propofol vs. Benzodiazepines
Randomized Trial
ICU
Comparator
Superior
Ronan et al.1995
Surgical
Midazolam
Propofol
Chamorro et al. 1996
General
Hsiao et al. 1996
Equivalent
Kress et al. 1996
Medical
Barrientos-Vega et al. 1997
Searle et al. 1997
Cardiac
Weinbroum et al. 1997
Both
Sanchez-Izquierdo-Riera JA, et al. 1998
Trauma
Hall et al. 2001
Mixed
Carson et al. 2006
Lorazepam
Outcomes improved by propofol: sedation quality, ventilator synchrony, time to awakening, variability of awakening, time to extubation from discontinuation of sedation, overall time to extubation, ventilator days, ICU LOS among survivors, costs of sedation

23. Dexmedetomidine vs Benzodiazepines
Trials with better outcomes with Dex
Population
Outcome Improved
  Pandharipande et al/2007
Mixed ICU
More accurate sedation, more delirium/coma-free days
  Riker et al/2009
Lower prevalence of delirium, earlier extubation
  Ruokonen et al/2009
Shorter duration of mechanical ventilation
  Maldonado et al/2009
Cardiac surgery
Lower incidence and duration of delirium
  Esmaoglu et al/2009
Eclampsia
Shorter ICU length of stay
  Dasta et al/2010
Lower ICU costs
  Jakob et al/2012
General ICU
Lighter sedation, fewer ventilation days
Relatively consistent answer:
more accurate sedation, more days without Delirium or coma, shorter duration of MV support and ICU stay
Trials with better outcomes with Benzo’s = None
Ely EW, et al. Chest. 2012;142(2);

24. #4: Early Mobility

25. Early Mobility in the ICU
Early exercise = progressive mobility
Study design: paired SAT/SBT protocol with PT/OT from earliest days of mechanical ventilation
Wake Up, Breathe, and Move
Schweickert WD, et al. Lancet. 2009;373:

26. Early Mobility Study Results:
Return to independent functional status at d/c (59% vs 35%)
Decrease in ICU and Hosp Delirium (2 vs 4 days)
Decrease in time on Vent
6/10 back to independent functional status vs 4/10. For every 10 patients 2 more were back to baseline.
Schweickert WD, et al. Lancet. 2009;373:

27. #5: No medication recommendation for the treatment of delirium

28. During the ICU/Hospital Stay After Hospital Discharge
Delirium Risks
Increased mortality
Longer intubation time
Average 10 additional days in hospital
Higher costs of care
During the ICU/Hospital Stay
Increased mortality
Development of dementia
Long-term cognitive impairment
Requirement for care in chronic care facility
Decreased functional status at 6 months
After Hospital Discharge 28

29. PAD Treatment of Delirium Recommendations
There is no published evidence that treatment with haloperidol reduces the duration of delirium in adult ICU patients (No Evidence).
Atypical antipsychotics may reduce the duration of delirium in adult ICU patients (C).
We do not recommend administering rivastigmine to reduce the duration of delirium in ICU patients (–1B).
Barr J, et al. Crit Care Med 2013; 41:263–306

30. The MIND Study Design: Randomized and double-blind
Haloperidol
Ziprasidone
Placebo
n = 35
n = 32
n = 36
Design:
Randomized and double-blind
Multisite (6 centers), 103 MV patients
PO/IM delivery of study drug
Results:
No difference in any outcome
No difference in any side effect
To demonstrate the feasibility of a double-blind, placebo-controlled, randomized trial of antipsychotics in mechanically ventilated ICU patients
To test the hypothesis that antipsychotics are efficacious and safe for the prevention and treatment of ICU delirium
Girard TD, et al. Crit Care Med. 2010;38(2):

31. PAD Treatment of Delirium Recommendations
There is no published evidence that treatment with haloperidol reduces the duration of delirium in adult ICU patients (No Evidence).
Atypical antipsychotics may reduce the duration of delirium in adult ICU patients (C).
We do not recommend administering rivastigmine to reduce the duration of delirium in ICU patients (–1B).
Barr J, et al. Crit Care Med 2013; 41:263–306

32. Delirium + Haloperidol PRN
Quetiapine vs. Placebo
Delirium + Haloperidol PRN
Quetiapine (n = 18)
Placebo (n = 18)
Design:
Randomized, double-blind, placebo-controlled
Multisite (3 centers), 36 ICU patients
PO delivery of study drug
Results:
Faster delirium resolution & Less agitation
Greater rate of transfer to home or rehabilitation
Titrated in response to Haldol dosing q50mg intervals every 12 hrs.
IV prn Haldol 1-10,mg up to q2hrs no other antipsychotics or continuous infusions allowed.
10 day treatment
Dosing info From article:
The study drug was continued until one of
the following occurred: (1) the subject was
deemed by the attending intensivist, based on
their clinical judgment, to no longer demonstrate
signs of delirium and, therefore, to no
longer require scheduled therapy with an antipsychotic
agent; (2) 10 days of therapy had
elapsed; (3) ICU discharge occurred; or (4) an
adverse event potentially attributable to the
study drug occurred that warranted discontinuation
of the study drug. Allowing the attending
intensivist to discontinue study drug once
the subject no longer had signs of delirium
was consistent with existing clinical practice
in our institutions. In situations in which 10
days of therapy was reached or the subject was
ready to transfer out of the ICU while still
receiving study drug, the subject’s treatment
assignment was revealed to the attending intensivist
(but not the study team) to help determine
the best course of therapy (which could include
continued therapy with quetiapine).
Limitations: patient safety (3, 41, 44, 48, 49).
A number of potential limitations of
our study must be considered when evaluating
the results. Although adequate to
demonstrate a difference in our primary
outcome, our sample size was not large
enough to reliably detect differences in
any of the efficacy or safety outcomes. In
addition, the multiple analyses that were
completed may have contributed to an
inflated type 1 error. Therefore, our investigation
should be considered a pilot
study. The rigorous study inclusion criteria
that we chose lead to only 14% of
To accommodate the varying duration
of delirium seen in clinical practice, we
did not require a minimum duration of
study drug treatment, instead allowing
the subject’s intensivist to discontinue
study drug when delirium was thought to
have resolved or the subject was ready to
transfer from the ICU. Given its fluctuating
nature, considering delirium resolved
when first noted to be absent may be
premature, but it is a reasonable and reproducible
event. In addition, study drug
may have been discontinued prematurely
in subjects with hypoactive delirium, although
the optimal way to treat these
patients is not well-defined (3, 50–53).
Whereas the same “as-needed” haloperidol
dosing protocol was used for all study
patients, the average dose of haloperidol
that was administered was lower than the
dose recommended in some guidelines
and may reflect increasing safety concerns
among clinicians regarding the use
of high-dose haloperidol therapy (9, 54).
The greater use of haloperidol in patients
receiving placebo could have diminished
the treatment effect of quetiapine that
was observed.
Devlin JW, et al. Crit Care Med. 2010;38(2):

33. PAD Treatment of Delirium Recommendations
There is no published evidence that treatment with haloperidol reduces the duration of delirium in adult ICU patients (No Evidence).
Atypical antipsychotics may reduce the duration of delirium in adult ICU patients (C).
We do not recommend administering rivastigmine to reduce the duration of delirium in ICU patients (–1B).
Barr J, et al. Crit Care Med 2013; 41:263–306

34. Rivastigmine for Delirium?
FDA approved for dementia of Alzheimer’s or Parkinson’s
Cholinesterase inhibitor
Result
Mortality (vs placebo): 22% vs 8%, P = 0.07
Delirium (vs placebo): 5 vs 3 days, P = 0.06
Conclusion:
Need RCTs for delirium as endpoint
Don’t use rivastigmine for ICU delirium
Survival (%)
Time (days after inclusion)
Lancet Nov 27;376(9755): Epub 2010 Nov 4.
Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial.
van Eijk MM, Roes KC, Honing ML, Kuiper MA, Karakus A, van der Jagt M, Spronk PE, van Gool WA, van der Mast RC, Kesecioglu J, Slooter AJ.
Source
Department of Intensive Care Medicine, University Medical Centre, Utrecht, Netherlands.
Abstract
BACKGROUND:
Delirium is frequently diagnosed in critically ill patients and is associated with adverse outcome. Impaired cholinergic neurotransmission seems to have an important role in the development of delirium. We aimed to establish the effect of the cholinesterase inhibitor rivastigmine on the duration of delirium in critically ill patients.
METHODS:
Patients (aged ≥18 years) who were diagnosed with delirium were enrolled from six intensive care units in the Netherlands, and treated between November, 2008, and January, Patients were randomised (1:1 ratio) to receive an increasing dose of rivastigmine or placebo, starting at 0·75 mL (1·5 mg rivastigmine) twice daily and increasing in increments to 3 mL (6 mg rivastigmine) twice daily from day 10 onwards, as an adjunct to usual care based on haloperidol. The trial pharmacist generated the randomisation sequence by computer, and consecutively numbered bottles of the study drug according to this sequence to conceal allocation. The primary outcome was the duration of delirium during hospital admission. Analysis was by intention to treat. Duration of delirium was censored for patients who died or were discharged from hospital while delirious. Patients, medical staff, and investigators were masked to treatment allocation. Members of the data safety and monitoring board (DSMB) were unmasked and did interim analyses every 3 months. This trial is registered with ClinicalTrials.gov, number NCT
FINDINGS:
Although a sample size of 440 patients was planned, after inclusion of 104 patients with delirium who were eligible for the intention-to-treat analysis (n=54 on rivastigmine, n=50 on placebo), the DSMB recommended that the trial be halted because mortality in the rivastigmine group (n=12, 22%) was higher than in the placebo group (n=4, 8%; p=0·07). Median duration of delirium was longer in the rivastigmine group (5·0 days, IQR 2·7-14·2) than in the placebo group (3·0 days, IQR 1·0-9·3; p=0·06).
INTERPRETATION:
Rivastigmine did not decrease duration of delirium and might have increased mortality so we do not recommend use of rivastigmine to treat delirium in critically ill patients.
Accessed March 2012.
Van Eijk MM, et al. Lancet ;376(9755):

35. Helpful Approach to Delirium Management
Stop
THINK
Lastly Medicate

36. What to THINK if positive for delirium
Toxic Situations
CHF, shock, dehydration
Deliriogenic meds (tight titration)
New organ failure (liver, kidney, etc)
Hypoxemia;
Infection/sepsis (nosocomial), Immobilization
Nonpharmacological interventions
K+ or Electrolyte problems

37. Pain, Agitation, and Delirium Are Interrelated
Barr J, et al. Crit Care Med. 2013;41:

38. PAD Interdisciplinary Team
Integrated Approach to PAD
MD Champion
RN Champion
RT Champion
Pharmacy Champion
Physical Therapy Champion
Hospital Administrators
Family
Patient
Courtesy J Barr, MD

39. Teach your team how to Communicate and Think!

40. If you give a man a fish, he will eat for a day
If you give a man a fish, he will eat for a day. If you teach a man to fish, he will eat for a lifetime. Chinese Proverb

41. Start with the Foundation: Assessment
Pain
CPOT
BPS
Agitation
SAS
RASS
Delirium
CAM-ICU
ICDSC
Barr J, et al. Crit Care Med. 2013;41:

42. Brain Road Map Where is the patient going? (Target Sedation Level)
2. Where is the patient now?
(Current PAD Assessnent)
3. How did they get there?
Drug exposures
© Brian Sloan via Flickr

43. Brain Road Map Script for Rounds
Investigate
(Ask these questions)
Report
(only takes 10 seconds)
Where is the patient going?
Target level of consciousness
(RASS/SAS)
Where is the patient now?
Actual level of consciousness
Delirium assessment
(CAM-ICU/ICDSC)
Pain Assessment Scale
(BPS/CPOT)
How did they get there?
Drug exposures
Without appropriate cognitive status information, management may not match the needs of the patient.

44. Brain Road Map Example Investigate (Ask these questions) Report
(only takes 10 seconds)
Where is the patient going?
Target/Goal is RASS -1/0
Where is the patient now?
Currently:
RASS is -3 (-3 and -4 for past 6 hrs)
CAM-ICU positive
CPOT of 4
How did they get there?
Propofol infusion 40 mcg/kg/min & intermittent fentanyl for pain
Without appropriate cognitive status information, management may not match the needs of the patient.

45. 5 Key Themes 1. Goal = Light sedation 2. Sedative titration method =
Daily Sedative Interruption or
Targeted sedation
3. Avoid/Minimize Benzodiazepines
4. Early Mobility
5. No Med Recommendation for Delirium

47. www.ICUdelirium.org Questions? Brenda.Pun@vanderbilt.edu
The website is a great resource.