This document provides an overview and summary of a presentation on assessing pain, sedation, and delirium in intensive care unit patients. It discusses: - The importance of using validated scales like the Richmond Agitation-Sedation Scale (RASS) and Sedation-Agitation Scale (SAS) to accurately assess sedation levels in patients receiving sedatives. - The challenges of assessing delirium given confounding factors like a patient's sedation level, wakefulness, and other psychiatric diagnoses. Scales like the Confusion Assessment Method for the ICU (CAM-ICU) are used but their accuracy depends on a patient's sedation. - How pharmacokinetic factors like drug-

1. ASSESSING PAIN, SEDATION AND DELIRIUM:
PRAGMATICS, PHARMACOKINETICS AND
CONFOUNDERS
November 19 2013
19 november 2013
** All lines are muted upon entry. If you have any questions, please raise
your hand or CHAT to Host **

2. Your Hosts & Presenters
Vos hôtes & et présentateurs
Dr. Denny Laporta, Chair Canadian ICU Collaborative
Président, Collaboration canadienne des soins intensifs
Bruce Harries, Collaborative Director
Directeur de la Collaboration
Dr. Yoanna Skrobik, Intensivist, Hôpital Maisonneuve Rosemont,
Montréal
Paule Bernier, SIA for Quebec Campaign (SHN)
Conseillère en amélioration et sécurité, SSPSM (Québec)
Ardis Eliason, Project Coordinator and Technical Host for today’s session
Coordonatrice de projet et hôte technique
Leanne Couves, Improvement Advisor and Moderator
Conseillère en amélioration et Animateur
11/19/2013
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3. Faculty
Membres de la faculté
Denny Laporta, MC, FRCPC
Claudio Martin, MD, FRCPC
Yoanna Skrobik, MD, FRCPC
Paule Bernier, Dt.P., M.Sc.
John Muscedere, MD, FRCPC
Cathy Mawdsley, RN, M.Sc.
Anne MacLaurin, Project Manager, Canadian
Patient Safety Institute (CPSI) /Coordonatrice de
projets, ICSP
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6. POINTER
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Nurse/
infirmière
Infection
ControlPCI
MD
Educator /Éducateur
Quality Improvement
Professional/Professionnel
en amélioarion de la
qualité
Administrator /Administrateur
Senior Leader
Psychiatry/
psychiatrie
Other/
autre
Pharmacy/
pharmacie
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6

7. Objectives
But de l’appel
 Comprendre quand délirium peut
 Understand when delirium can
et ne peut pas être évalué, et
and cannot be assessed, and how
comment les sédatifs compliquent
sedatives make an accurate
cette évaluation
assessment more complicated
 Comprendre pourquoi la
 Understand why different
génétique, la co-administration de
genetics, administering more than
plusieurs médicaments ou la durée
one drug or duration of sedative
de l'administration des sédatifs
drug administration can change
changent leur effet thérapeutique ;
therapeutic effect and why it
les aspects pertinents aux soins
matters in the critically ill
intensifs sont évalués
11/19/2013
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8. Assessing pain, sedation and delirium:
pragmatics, pharmacokinetics and
confounders
Dr. Yoanna Skrobik

9. Assessing pain, sedation and
delirium: pragmatics,
pharmacokinetics and confounders
Yoanna Skrobik MD FRCP(c)

10. Yoanna Skrobik MD FRCP(c)
And do we really care?

11. Conflicts of interest
 Member, SCCM Pain, Agitation and Delirium
guidelines writing committee
 Investigator initiated research funding, Hospira
 Academic chair, Université de Montréal

12. Academic chair
Astellas
Merck
Pfizer
Baxter
Hospira
Otsuka
Novartis
Lilly

13. assessing pain, sedation and delirium:
pragmatics, pharmacokinetics and confounders







Introduction
Pain scales and their importance
The scales we use for sedation
The scales we use for delirium
Pharmacokinetics and their role in the continuum
The confounders
conclusion

14. assessing pain, sedation and delirium:
pragmatics, pharmacokinetics and
confounders
Introduction: why you should care

15. why we should care (introduction)
• Pain, Sedation and delirium monitoring are mandated
on critical care wards for Canadian hospital accreditation
• Sedatives and opiates are administered to many patients and more medications
are administered in ICU than on most hospital wards
• Excessive sedation is common, and is related to drug kinetics or interaction
• This makes delirium screening challenging

16. Clinical Practice Guidelines for the
Management of Pain, Agitation, and
Delirium in Adult Patients
in the Intensive Care Unit
Authors: Juliana Barr, MD, FCCM; Gilles L. Fraser, PharmD, FCCM; Kathleen Puntillo, RN, DNSc, FAAN; E.
Wesley Ely, MD, MPH, FACP, FCCM; Céline Gélinas, RN, PhD; Joseph F. Dasta, MSc; Judy E. Davidson, DNP, RN;
John W. Devlin, PharmD, FCCM; John P. Kress, MD; Aaron M. Joffe, DO; Douglas B. Coursin, MD; Daniel L. Herr,
MD, MS, FCCM; Avery Tung, MD; Bryce RH Robinson, MD, FACS; Dorrie K. Fontaine, PhD, RN, FAAN; Michael A.
Ramsay, MD; Richard R. Riker, MD, FCCM; Curtis N. Sessler, MD, FCCP, FCCM; Brenda Pun, RN, MSN, ACNP;
Yoanna Skrobik, MD, FRCP; Roman Jaeschke, MD, MSc

17. ICU PAD Care Bundle

18. pain

20. Patient-directed
pain control.

21. pain
 Adult ICU patients, both medical and surgical, routinely
experience pain, both at rest and with routine ICU care .
 Pain in adult cardiac surgery patients, especially women, (i.e.,
incisional pain due to coughing, respiratory care procedures,
and mobilization) remains prevalent and poorly treated .
 Procedural pain is common in adult ICU patients .

22. patient evaluation standards

23. patient evaluation standards

24. patient evaluation standards

25. sedation

26. Monitoring sedation
 The RASS and SAS scales are valid and reliable for
measuring quality and depth of sedation in adult ICU patients .

27. Sedation-Agitation Scale (SAS)
Score
State
Behaviors
7
Dangerous Agitation
6
Very Agitated
5
Agitated
4
Calm and
Cooperative
3
Sedated
2
Very Sedated
Arouses to physical stimuli but does not communicate or
follow commands
1
Unarousable
Minimal or no response to noxious stimuli, does not
communicate or follow commands
Pulling at ET tube, climbing over bedrail, striking at staff,
thrashing side-to-side
Does not calm despite frequent verbal reminding, requires
physical restraints
Anxious or mildly agitated, attempting to sit up, calms down
to verbal instructions
Calm, awakens easily, follows commands
Difficult to arouse, awakens to verbal stimuli or gentle
shaking but drifts off
Riker RR, et al. Crit Care Med. 1999;27:1325-1329.
Brandl K, et al. Pharmacotherapy. 2001;21:431-436.

28. Richmond Agitation
Sedation Scale (RASS)
Score
State
+4
Combative
+3
Very agitated
+2
Agitated
+1
Restless
0
Alert and calm
-1
Drowsy
eye contact > 10 sec
-2
Light sedation
eye contact < 10 sec
-3
Moderate sedation
-4
Deep sedation
-5
Unarousable
Verbal Stimulus
no eye contact
physical stimulation
no response even with physical
Ely EW, et al. JAMA. 2003;289:2983-2991.
Sessler CN, et al. Am J Respir Crit Care Med. 2002;166(10):1338-1344.
Physical Stimulus

29. Sedation confounders

30. And now for a little pharmacology

31. Cytochrome P450

32. Some examples
CYP 450 3A4/5:
midazolam, fentanyl
CYP 450 2D6:
haloperidol, codeine, oxycodone, and
tramadol
CYP 2C19:
propofol

33. Pharmacokinetics, dynamics and
genetics
 Is it relevant to ICU patients?

34. Drug-drug interactions

35. The Effect of Critical Illness on the
Pharmacokinetics and Dose-Response
Relationship of Midazolam
Daniel Ovakim
January 19, 2012

36. Results
Patient
Characteristics
Table 1: Patient Characteristics and Study Details
Variable
Patients enrolled – no.
9
Age – mean +/- SD (range)
56.3 +/- 11 (33-72)
Male sex – no. (%)
7 (78)
Co-morbidities on admission – no.
CHF
1
CKD
1
Hemodialysis
1
Chronic benzodiazepine use
0
Chronic ethanol use
2
Hepatic dysfunction
2
Condition on study enrollment
APACHE II – mean +/- SD (range) 24 +/- 10 (7-43)
Acute kidney injury – no.
4
GCS – mean +/- SD (range)
7 +/- 2 (3-14)
GCS < 8 – no. (%)
6 (67%)
Study details – mean +/- SD (range)
Days in study
8.8 +/- 3.9 (3-14)
Days on MDZ infusion
4.8 +/- 3.1 (1-11)
Days in study off infusion
4.0 +/- 2.9 (0 -10)
Days with GCS < 8
3.8 +/- 4.0 (0-12)
GCS < 8 during study – no. (%)
7/9 (78)

37. Results
Midazolam PK
Table 3: Pharmacokinetic Parameters in Study Participants and Healthy
Controls
Study Patients
Healthy Controls╪
PK Parameter
Mean +/- SD
Range
Mean +/- SD
Range
CLss (mL/min) 418 +/- 324 31-1157
376
267-485
T½ (h) 16.0 +/- 9.6
2.3-34.9
3.2
1.0-4.0

38. Results
Clearance at Steady-State (Css, mg/min)
Midazolam Clearance
1400
1200
Clearance at Steady State
1000
800
600
400
200
0
0
1
2
3
4
5
6
7
8
9
Patient ID
Figure 1: Observed intra- and intersubject variability in midazolam
clearance at steady-state.

39. Pharmacodynamic Midazolam characteristics :
It’s About Time
• Highly lipid soluble
• α-OH midazolam metabolite
• CYP3A4 activity decreased in critical illness
• Substantial CYP3A4 variability

40. Pharmacodynamic Midazolam characteristics :
It’s About Time
Carrasco G, et al. Chest. 1993;103:557-564.
60
40
Extubation
Alertness Recovery
30
20
10
0
<1
1-7
>7
Sedation Time (days)
Time to Endpoint (h)
50

41. Pharmacodynamic Midazolam characteristics :
It’s About Time
Bauer TM, et al. Lancet. 1995;346:145-147.

43. Why people develop coma

44.  100 patients

46. results

47. coma
 Occurrence of coma not related to administered
midazolam or fentanyl doses
 Coma occurrence correlated with the coadministration of CYP3A4/5 inhibitors (p=0.0046)
when adjusted for doses of fentanyl and
midazolam

48. Coma and plasma levels of fentanyl

49. Coma and plasma levels of fentanyl

50. Coma and plasma levels of midazolam

51. Coma and the effect of CYP3A4/5 inhibitor coadministration

52. Bottom line
• Validated scales include SAS, RASS and probably MASS
• Ramsay and Glasgow not valid
• These scales should drive lowering sedation over time or
discontinuing it for longer periods
• The longer you are on sedatives and the more combined
drugs you receive the more likely you are to be ‘deep’

53. delirium
Van der Mast. PhD Thesis, Delirium After Cardiac Surgery, Erasmus University, Rotterdam,
1994

54. Delirium scales
ICDSC
(Intensive Care Delirium Screening
Checklist)
http://www.icudelirium.co.uk/
CAM-ICU
(Confusion Assessment Method-ICU)
www.icudelirium.org

55. Delirium diagnosis in the ICU: how hard
can it be?

56. ICU Delirium diagnostic challenges
 Standardized delirium screening in the ICU setting, and
their inherent methodological flaw
 Potential confounders

57. DSM IV criteria
American Psychiatric Association,
Diagnostic and Statistical Manual IV, American
Psychiatric Press, Inc, Washington, DC, 1994

58. Confounders:
 Other psychiatric diagnoses

59. Other psychiatric diagnoses
 Delirium
(10-80%)
 Depression (35-45%)
 Post-Traumatic stress disorder (35%)

60. Delirium incidence
From 10% to > 85%

Intensive Care Med 27:1892-1900

JAMA 286:2703-2710

Crit Care Med 29:1370-1379

JAMA 291:1753-1762

Crit Care 5:265-270

Gen Hosp Psychiatry 17:371-379

Crit Care Med 32:2254-2259

J Am Geriatr Soc 51:591-598

Lancet 2010 Nov 27;376(9755):1829-37
…………..(10% of 6572 patients screened!)

61. wakefulness

62. DSM IV criteria
American Psychiatric Association,
Diagnostic and Statistical Manual IV, American
Psychiatric Press, Inc, Washington, DC, 1994

66. The data when delirium is considered
in the light of sedation level
 CAM-ICU and RASS comparison: 69% of CAM-ICU positive
assessments occurred in patients with a RASS ≤ 0
 Over half of the patients with a RASS of -2 and 25% of those
with a RASS -1 were considered not assessable
 Among patients whose RASS scored changed more than two
levels from the previous day, delirium with the CAM-ICU was
five times more likely …..
 Numerous studies support the sedation level-positive delirium
screening relationship

67. Prevalence of delirium is a
function of wakefulness
Prevalence
CAM-ICU
positive (%)
Sedated
Wakeful
Absolute
Difference
Riker
45-75
12
30
Ely
83
40
43
Haenggi
53
31
22
Poston
73
49
24
Gusmao-Flores
89
32
57
Patel
?
?
30
IF this is related to sedation, patients should transition from CAM positive to
CAM negative when sedation is lightened
Riker. CCM 2012; 40:1092
Haenggi. ICM 2013; epub
Posten. AJRCCM 2010:A6701
Ely. JAMA 2001; 286:2703 Gusmao-Flores ICM 2013; epub
Patel. AJRCCM 2013; 187:A5237

68. So what

69. Delirium is bad for you

70. Delirium and outcomes
 Delirium is strongly associated with increased mortality and
LOS in adult ICU patients.
 Delirium is moderately associated with the development of
post-ICU cognitive impairment in adult ICU patients.

72. Coma is bad for you

74. Probably not six of one…
 of 102 ICU patients, coma or a positive CAM-ICU result were 10
times more likely to occur prior to sedation interruption .
 Patients with “delirium” that cleared as sedation was lightened
(termed “drug-related delirium”) had outcomes virtually identical
and better than patients who never had delirium
 This dramatic difference was consistent for ventilator-, ICU-, and
hospital-free days and for one year mortality,

75. Sedation-related delirium and time on the ventilator,
in the ICU and in the hospital

76. What now?

77. icdsc

78. 重症监护谵妄筛查表（第一版）
武汉市同济医院
 4/8 or more corresponds to a delirium diagnosis

79. Intensive Care Delirium Screening
Checklist (ICDSC)
PATIENT EVALUATION
Altered level of consciousness* (A-E)
DAY 1
DAY 2
DAY 3
DAY 4
DAY 5
If A or B do not complete patient evaluation for the period
Inattention
Disorientation
Hallucination - delusion – psychosis
Psychomotor agitation or retardation
Inappropriate speech or mood
Sleep/wake cycle disturbance
Symptom fluctuation
TOTAL SCORE (0-8)
Bergeron, N. Dubois M.J. Skrobik, Y.
Intensive Care Delirium Checklist : evaluation of a new screening tool.
Intensive Care Medicine, 2001

80. icdsc
 Of ICDSC’s 8 features “psychomotor slowing” should not be
considered if this slowing is attributable to sedative
administration
 consciousness is recognized to be the least valid ICDSC
component, particularly when the ICDSC is performed by
nurses.

81. CAM ICU
 The validity of the level of consciousness component has not
been tested with the CAM-ICU to date.
 Should probably stratify positive score by RASS (-1,0 or 1 vs. -2
or less)

82. Summary of confounders
 Psychiatric diagnoses
 Sedation level
 Operationally it boils down to judgement :-)

83. In conclusion
 Pain assessment is the first priority
 Sedation should be validated with a reproducible scale
 Deep sedation is a lot more likely the longer you have been on
sedatives and the more simultaneously metabolized drugs you
are on (especially if doses, even prn, are not titrated down)
 Delirium assessment should be documented with simultaneous
sedation score levels to ensure the data analysis can account
for the sedation confounders subsequently
 Other psychiatric diagnoses and their role remain unexplored

84. Thank you

85. QUESTIONS?
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86. “Taking the Pulse” Poll
Sondage « prendre le pouls »
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87. Canadian ICU Collaborative
Faculty
Paule Bernier, P.Dt., Msc, Sir MB David Jewish General Hospital (McGill University), Montreal
Paul Boiteau MD, Department Head, Critical Care Medicine, Alberta Health Services; Professor of Medicine, University of
Calgary
Leanne Couves, Improvement Advisor, Improvement Associates Ltd.
Bruce Harries, Collaborative Director, Improvement Associates Ltd.
Denny Laporta MD, Intensivist, Department of Adult Critical Care, Jewish General Hospital; Faculty of Medicine, McGill
University
Anne MacLaurin, Project Manager, Canadian Patient Safety Institute (CPSI) /Coordonatrice de projets, ICSP
Claudio Martin MD, Intensivist, London Health Sciences Centre, Critical Care Trauma Centre; Professor of Medicine and
Physiology, University of Western Ontario; Chair/Chief of Critical Care Western
Cathy Mawdsley, RN, MScN, CNCC; Clinical Nurse Specialist – Critical Care, London Health Sciences Centre;
John Muscedere MD, Assistant Professor of Medicine, Queens University; Intensivist, Kingston General Hospital
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88. Reminders
Rappels
 Call is recorded
 Slides and links to
recordings will be
available on Safer
Healthcare Now!
Communities of Practice
 Additional resources are
available on the SHN
Website and
Communities of Practice
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seront disponibles sur Des
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sécuritaires maintenant!
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 Des ressources
supplémentaires sont
disponibles sur le site Web
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de Pratique

89. THANK YOU
MERCI

90. This National Call is hosted by:
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