assessing delirium: pragmatics and confounders

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 **

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

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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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Objectives But de l’appel

Understand when delirium can and cannot be assessed, and how sedatives make an accurate assessment more complicated

Understand why different genetics, administering more than one drug or duration of sedative drug administration can change therapeutic effect and why it matters in the critically ill

Comprendre quand délirium peut et ne peut pas être évalué, et comment les sédatifs compliquent cette évaluation

Comprendre pourquoi la génétique, la co-administration de plusieurs médicaments ou la durée de l'administration des sédatifs changent leur effet thérapeutique ; les aspects pertinents aux soins intensifs sont évalués

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Dr. Yoanna Skrobik

Assessing pain, sedation and delirium: pragmatics, pharmacokinetics and confounders

Assessing pain, sedation and delirium: pragmatics,

pharmacokinetics and confounders

Yoanna Skrobik MD FRCP(c)

Yoanna Skrobik MD FRCP(c)

And do we really care?

Conflicts of interest

Member, SCCM Pain, Agitation and Delirium guidelines writing committee

Investigator initiated research funding, Hospira Academic chair, Université de Montréal

Academic chair

Astellas Merck Pfizer Baxter

Hospira Otsuka Novartis

Lilly

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

assessing pain, sedation and delirium: pragmatics, pharmacokinetics and

confounders

Introduction: why you should care

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

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

ICU PAD Care Bundle

Patient-directed pain control.

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 .

patient evaluation standards

sedation

Monitoring sedation

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

Sedation-Agitation Scale (SAS)

Riker RR, et al. Crit Care Med. 1999;27:1325-1329. Brandl K, et al. Pharmacotherapy. 2001;21:431-436.

Score State Behaviors

7 Dangerous Agitation Pulling at ET tube, climbing over bedrail, striking at staff, thrashing side-to-side

6 Very Agitated Does not calm despite frequent verbal reminding, requires physical restraints

5 Agitated Anxious or mildly agitated, attempting to sit up, calms down to verbal instructions

4 Calm and Cooperative Calm, awakens easily, follows commands

3 Sedated Difficult to arouse, awakens to verbal stimuli or gentle shaking but drifts off

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

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 no eye contact

-4 Deep sedation physical stimulation

-5 Unarousable 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.

Verbal Stimulus

Physical Stimulus

Sedation confounders

And now for a little pharmacology

Cytochrome P450

Some examples

CYP 450 3A4/5: midazolam, fentanyl

CYP 450 2D6:

haloperidol, codeine, oxycodone, and tramadol

CYP 2C19: propofol

Pharmacokinetics, dynamics and genetics

Is it relevant to ICU patients?

Drug-drug interactions

Daniel Ovakim January 19, 2012

The Effect of Critical Illness on the Pharmacokinetics and Dose-Response

Relationship of Midazolam

Results

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)

Patient Characteristics

Results

Midazolam PK

Table 3: Pharmacokinetic Parameters in Study Participants and Healthy Controls

PK Parameter Study Patients Healthy Controls╪

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

Results

Midazolam Clearance

0

200

400

600

800

1000

1200

1400

0 1 2 3 4 5 6 7 8 9

Cle

aran

ce a

t Ste

ady-

Stat

e (C

ss, m

g/m

in)

Patient ID

Clearance at Steady State

Figure 1: Observed intra- and intersubject variability in midazolam clearance at steady-state.

Pharmacodynamic Midazolam characteristics : It’s About Time

• Highly lipid soluble • α-OH midazolam metabolite • CYP3A4 activity decreased in critical illness • Substantial CYP3A4 variability


Carrasco G, et al. Chest. 1993;103:557-564.

0

10

20

30

40

50

60

< 1 1-7 > 7

Extubation Alertness Recovery

Sedation Time (days)

Time to Endpoint (h)


Bauer TM, et al. Lancet. 1995;346:145-147.

Why people develop coma

100 patients

results

coma Occurrence of coma not related to administered

midazolam or fentanyl doses Coma occurrence correlated with the co-

administration of CYP3A4/5 inhibitors (p=0.0046) when adjusted for doses of fentanyl and midazolam

Coma and plasma levels of fentanyl

Coma and plasma levels of midazolam

Coma and the effect of CYP3A4/5 inhibitor co-administration

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’

delirium

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

CAM-ICU (Confusion Assessment Method-ICU)

Delirium scales

ICDSC (Intensive Care Delirium Screening

Checklist)

http://www.icudelirium.co.uk/ www.icudelirium.org

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

ICU Delirium diagnostic challenges

Standardized delirium screening in the ICU setting, and

their inherent methodological flaw Potential confounders

DSM IV criteria

American Psychiatric Association, Diagnostic and Statistical Manual IV, American Psychiatric Press, Inc, Washington, DC, 1994

Confounders:

Other psychiatric diagnoses

Other psychiatric diagnoses

Delirium (10-80%) Depression (35-45%) Post-Traumatic stress disorder (35%)

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!)

wakefulness

DSM IV criteria

American Psychiatric Association, Diagnostic and Statistical Manual IV, American Psychiatric Press, Inc, Washington, DC, 1994

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

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 Posten. AJRCCM 2010:A6701 Ely. JAMA 2001; 286:2703 Gusmao-Flores ICM 2013; epub Haenggi. ICM 2013; epub Patel. AJRCCM 2013; 187:A5237

So what

Delirium is bad for you

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.

Coma is bad for you

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,

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

What now?

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

PATIENT EVALUATION DAY 1 DAY 2 DAY 3 DAY 4 DAY 5 Altered level of consciousness* (A-E) 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)

Intensive Care Delirium Screening Checklist (ICDSC)

Bergeron, N. Dubois M.J. Skrobik, Y. Intensive Care Delirium Checklist : evaluation of a new screening tool. Intensive Care Medicine, 2001

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.

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)

Summary of confounders

Psychiatric diagnoses Sedation level Operationally it boils down to judgement :-)

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

Thank you

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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 87 11/19/2013

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assessing delirium: pragmatics and confounders

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