Analgesia, Sedation

and Drug
interactions in ICU

Bad SPA in ICU

--- Stress, Pain and Anxiety ---

Goals of Sedation and Analgesia

Optimize safety for acute care patients and
their caregivers1,2
Relieve pain and anxiety1-3
Attenuate the harmful adrenergic response 1,2
Improve compliance with care1,2
Provide comfort and safety
Facilitate communication with caregivers and
family members1,2
Avoid or reduce delirium1,2,4
Blanchard AR. Postgrad Med. 2002;111:59-74.
Jacobi J, et al. Crit Care Med. 2002;30:119-141.
3
Dasta JF, et al. Pharmacotherapy. 2006;26:798-805.
4
Ely EW, et al. JAMA. 2004;291:1753-1762.
1

SPA for brain CAD

Sedation
Paralysis
Anxiolysis (Analgesia)

Courtesy of M. Ramsay, MD.

Sessler CN, et al. Chest. 2008;133;552-565.

Under
Sedation

Over
Sedation

Targeting Patient Comfort

Oversedation

OnTarget
Sedatio
n

Undersedation

On-target sedation:
Decreases weaning
period1
Is not associated with
muscular atrophy1
Decreases LOS and
cost2
Provides
cardiovascular1 and
intraoperative
hemodynamic stability3
Improves patient
safety1,3
Facilitates neurological
assessment3
1

McGaffigan PA. Crit Care Nursing. 2002;Feb Suppl:29-36.

2
Dasta et al. Pharmacotherapy. 2006;26:798-805.
3
Arbour R. Am J Crit Care Nursing. 2004;13:66-73.

Incidence of Inadequate Sedation

Undersedated1
On-Target1

Oversedated1

Continuous sedation carries the

risks associated with
oversedation and may increase
the duration of mechanical
ventilation (MV)1
MV patients accrue significantly
more cost during their ICU stay
than non-MV patients2
$31,574 versus $12,931,
P<.001
Sedation should be titrated to
achieve a cooperative patient
and daily wake-up, a JCAHO
requirement1,2

8
Kress JP, et al. N Engl J Med.

Example of ICU pain syndromes

Localized Pain

Diffuse Visceral

Neurolgoic

Complex

Surgical Wound

Acute abdomen

Intracranial hemorrhage

Mechaincal Ventilation

Bone Fracture

Myocardial ischemia

Headache-Migraine

Diffuse Joint Painarhralgia

Ulceration

Pneumonia

Elevated ICP

Sickle cell

Pleurodynia

Myocarditis

Compressive neuropathy

Metabolic disorders

Invasive procedure

Pulmonary embolus

SAH

Febrile-Sepsis

Local burn injury

Vascular ischemia

Cranial nerutis

Compartment syndromes

Gastritis

Diabetic neuropathy

Appendicitis

Bowel obstruction

Menigismus

Uretheral Stone

Pancreatitis

Reflex dystrophy

Adapted from Intensive Care Medicine Annual Update 2009

Thunder Project II
Assessign the level of pain and distress
during 6 ICU procedures in 6201 patient
Suctioning, Repositioning
For Adult
Wound CD, repositioning, suctioning,
wound drain removal
For Adolescent
Am J Crit Care 2001;10(4):238-51

Pain and/or Discomfort Should ALWAYS

Be Considered a Cause of ICU Agitation
Mundane/routine aspects of ICU care are the most
troublesome for patients

1990
63% remembered moderate to severe pain
Puntillo. Heart Lung 1990; 19:526
2007
50% remembered unmet analgesic needs
Gelinas. Intensive Crit Care Nurs 2007; 23:298
There has been little progress despite 17 years of focused
attention on pain as an important clinical issue

Footprint of SPA in ICU

70s

90s
Deep Sedation and NMB
use

80s
1974
Rams
y

1981 Lorazepam 1985 Drug

> Diazepam
metabolism
alter by organ
1983 Etomidate function
Mortality
1986
1984 Patient
continuous
Recall
mediazolam
and propofol

1990 NMB
induce
neuromuscular
dysfunction
1995 SCCM
guideline

Literature Citation


,
,

Pain
scale

Sedatio
n scale

Deliriu
m scale

Titrate Taper
Daily wake-up

Fentanyl: 25-100ug, q 5-15

Hydromorphone: 0.25-0.75mg, q
5-15

Morphine: 2-5mg, q 5-15

Acute agitation
Midazolam: 2-5mg, q 5-15
Ongoing sedation
(1)Propofol: 5g/kg/min , q
5
(2)Lorazepam: 1-4mg, q 10-20
(3) 3 Propofol (2)
Haloperidol: 2-10mg, q 20-30

,
Benzodiazepin
e opioid

10-25%

Society of Critical Care

Medicine

Recommended Drugs for Use in the

ICU
morphine

Analgesics

fentanyl
hydromorphone
(Dilaudid)
midazolam (Dormicum)

Sedatives

propofol (Recofol)
lorazepam (Ativan)

Anti-delirium

haloperidol (Haldol)

Crit Care Med 2002 Vol 30,

Pain

Anxiety

Analgesia First
Agitation

A1 approach
Delirium

Pain Assessment
Self Rate (awake and responsive)
NRS
VAS

Unable to self rate (sedated, MV pt)

Behavioral Pain Rating Scale (BPRS) 1992
Pain Assessment and Intervention Notation Algorithm
(PAIN) 1997
Behavioral Pain Scale (BPS) 2001
Nonverbal Pain Scale (NVPS) 2003
Critical Care Pain Observational Tool (CPOT) 2006

Visual Analogue Scale (VAS)

The VAS for Pain severity measurement
No Pain

Worst
Possible Pain

The VAS for Treatment Effect

No Pain
Pain
Relief

Complete
Relief

Numeric Rating Scale (NRS)

Behavioral-physiological Scales
Pain-related behaviors (movement, facial
expression, and posturing)
Physiological indicators (Heart rate, blood
pressure, and respiratory rate)
Moderate-to-strong correlation between
behavioral-physiological scale and NRS
(1)

1. Crit Care Med 1997;25:11591166

Behavioral Pain Scale

Crit Care Med 2001;29:22582263

Categories

FLACC Scale
Scoring

Face

No particular expression or
smile

Occasional grimace of frown,

withdrawn, disinterested

Frequent to constant quivering

chin, clenched jaw

Legs

Normal position or relaxed

Uneasy, restless, tense

Arched, rigid or jerking

Activity

Lying quietly, normal

position, moves easily

Squirming, shifting back and

forth, tense

Arched, rigid or jerking

Cry

No cry (awake or asleep)

Moans or whimpers; occasional

complaining

Crying steadily, screams or

sobs, sobs, frequent complaints

Consolability

Content, relaxed

Reassured by occasional touching,

hugging or being talked to ,
detradible

Difficult to console or comfort

Each of the five categories is scored form 0-2, which results in a total score
between zero and ten.

Critical Care Pain

Observational Tool (CPOT)

Gelinas C. Am J Crit Care 2006

Behavioral-physiological scales
Misinterpreted or affected by observer
bias
Underestimation of the degree of pain
experienced by the patient.

Most appropriate assessment Tool

1. Patient involved
2. Ability to communicate
3. Caregivers skill in interpreting pain
behaviors or physiological indicators

Common Analgesic Dosing

Analgesics

Comparative
dose

Intermittent
dose

Infusion dose

Fentanyl

100-200 mcg

0.35-.5 mcg/kg
q0.5-1h

0.7-10mcg/kg/h

Hydromorphone

1.5mg

10-30mcg/kg
q1-2h

7-15mcg/kg/h

Morphine

10mg

0.01-0.15mg/kg
q1-2h

0.070.5mcg/kg/h

Meperidine

75-100mg

Not
Recommend

Not
Recommend

Adapte from John WD Crit Care Clin 2009

Sedation Assessment
Ideal sedation scale should
1.Provide data that are simple to
compute and record
2.Accurately describe the degree of
sedation or agitation within welldefined categories
3.Guide the titration of therapy
4.Have validity and reliability in ICU
patients

Subjective Assessment of Sedation

and Agitation
Golden standard scale has not been
established
Lot of scales are available and validity
and reliability was waited to verify.

Agitation scale use in UVa

A

Severe
Agitated

Continuous/frequent thrashing attempting

to strike staff, pulling ET tube/catheter.

Mild to
Tries to sit up frequently, occasionally
moderately moves extremities, rarely thrashes can
agitated
usually be calmed with verbal reminders

Calm

Not agitated

Depressed

Mentally withdraws from staff not

interested in assisting in their care where
appropriated.

Ramsay Sedation Scale

Score

Definition

Patient is anxious, agitated or restless

Patient is cooperative, oriented, and tranquil

Patient responds to commands only

Patient is asleep, but exhibits brisk response to

light glabellar tap or lound auditory stimuli

Patient is asleep, but exhibits a sluggish

response to light glabellar tap or loud auditory
stimuli

Patient is asleep and exhibits no response

Ramsay MA et al. Controlled sedation with alphaxalone-alphadolone.Br Med J, 1974:2:656-

Dr Ramsay

RASS: Richmond Sedation-Agitation

Scale
Score

Term

Description

+4

Combative

Overtly combative or violent; immediate danger to staff

+3

Very agitated

Pulls on or removes tube(s) or catheter (s) or has aggressive

behavior toward staff

+2

Agitated

Frequent nonpurposeful movement or patient-ventilator

dyssynchrony

+1

Restless

Anxious or apprehensive, but movements not aggressive or vigorous

Alert and calm

-1

Drowsy

Not fully alert, but has sustained (more than 10 seconds) awakening,
with eye contact, to voice

-2

Light sedation

Briefly (less than 10 seconds) awakens, with eye contact, to voice

-3

Moderate
sedation

Any movement (but no eye contact) to voice

-4

Deep Sedation

No response to voice, but any movement to physical stimulation

-5

Unarousable

No response to voice or physical stimulation

Sessler CN et al, The Richmond Agitation-Sedation Scale: validity and reliability in adult
intensive care unit patients. Am J Respir Cri Care Med. 2002:166:1338-1344

SAS: Riker Sedation-Agitation Scale

Score

Definition

Description

Dangerously
agitated

Pulls at endotracheal tube (ET), tries to remove catheters, climbs

over bedrail, strikes staff, thrashes from side to side

Very
agitated

Dose not calm despite frequent verbal reminding of limits,

requires physical constraints, bites ET tube

Agitated

Anxious or mildly agitated, attempts to sit up, calms down to

verbal instructions

Calm and
cooperative

Calms, awakens easily, follows commands

Sedative

Difficult to arouse, awakens to verbal stimuli or gentle shaking

but drifts off again, follows simple commands

Very sedated

Arouses to physical stimuli but does not communicate or follow

commands, may move spontaneously

Unarousable

Minimal or no response to noxious stimuli, does not

communicate or follow commands

Riker RR et al. Prospective evaluation of the Sedation-Agitation Scale for adult

critically ill patients. Cri Care Med. 1999:27:1325-1329

Objective Assessment of Sedation

Heart rate variability

Lower-esophageal contractility
EEG
BIS

Patient-specific Sedation Goals

Monitoring Strategies
BIS Monitoring

Bedside outcome measures

Pulse oximetry
Respiratory rate
ICP
Wake-up assessment score

BIS Monitoring

BIS Range Guidelines

BIS

Hypnotic State

100

Awake
Light to Moderate Sedation

70

Light Hypnotic State

Low Probability of Explicit Recall<70

60

Moderate Hyponotic State

Low Probability of Consiousness <60

40

Deep Hypnotic State

EEG Supression

BIS= Bispectral Index

Common Sedatives Dosing

Comparative
dose

Intermittent
dosage

0.03-0.1mg/kg
qo.5-6h

0.035mg/kg/hr

0.020.06mg/kg q26h

0.010.1mg/kg/hr

Midazolam

0.106mg/kg/hr

0.020.08mg/kg
q0.5-2h

0.040..2mg/kg/hr

Propofol

1.66mg/kg.hr

580mcg/kg/min

Diazepam
Lorazepam

Infusion
dosage

Adapte from John WD Crit Care Clin 2009

June 25: At about 1:30 a.m., Murray again tried to get Jackson to sleep without propofol
and gives the singer a 10-milligram tablet of Valium, but Jackson is unable to sleep.
Around 2 a.m.: Murray injects Jackson with two milligrams of lorazepam, pushed slowly
into the singers IV. But again, Jackson cant sleep.
Around 3 a.m.: Murray then gives two milligrams of midazolam to Jackson, also pushed
slowly into the IV. Jackson remains awake.
Around 5 a.m.: Murray gives the singer another two milligrams of lorazepam but
Jackson still cant sleep.
Around 7:30 a.m.: Murray administers another two milligrams of midazolam. Murray
claims he is continuously at Jacksons bedside, monitoring the singer with a pulse
oximeter [connected to Jackson's finger] and measuring his pulse and oxygen
statistics. But Jackson remains awake.
Around 10:40 a.m.: Murray gives Jackson 25 milligrams of propofol diluted with
lidocaine to keep Jackson sedated after repeated demands for the drug by the singer.
Jackson finally falls asleep, and Murray continues to monitor him.
After 10 minutes: Murray states he left Jacksons bedside to use the restroom and is
gone for no more than two minutes. Upon his return, Murray finds Jackson not
breathing. Murray begins CPR, and gives Jackson 0.2 milligrams of flumazenil, an
antidote for certain overdoses.

Using his cell phone, Murray calls Jacksons personal assistant, Michael
Amir Williams, and asks him to send security upstairs for an
emergency.Murray continues CPR and before security arrives he leaves
Jackson and runs to the hallway and downstairs to the kitchen, where he
asks the chef to send up Jacksons 12-year-old son, Prince Michael I. Murray
continues CPR. The boy arrives upstairs and summons security.
At 12:21 p.m.: Jackson staff member Alberto Alvarez dials 911, and the Los
Angeles Fire Department responds on the scene shortly thereafter. Murray
waits for the ambulance while conducting CPR, and later accompanies
Jackson to the hospital.

Complications of ICU
Sedation
Prolonged ICU stay
Prolonged mechanical
ventilation/increased VAP risk
Increase in CNS evaluation/testing
Physiologic dependence (withdrawal
reactions)
Respiratory depression

Avoid Oversedation impact outcome

Fraser and Riker. CCM 2007; 35:635

Analgesics
Fentanyl

Hydromorphone

Morphine

CCr 10-30
ml/min

CCr < 10
ml/min

+++

End Stage liver

Dz

+++

+++

+++

Obesity
Continuous IV
infusion
Genetic factors

Sedatives
Propofol

Lorazepam

Midazolam

Dexmedetomid
ine

CCr 10-30
ml/min

+++

CCr < 10
ml/min

End Stage
liver Dz

Obesity

Continuous
IV infusion

Genetic
factors

+++
+
+++
+

+++
+++
+++
+++
+++

N
+
N
N
N

Terminology
ICU Psychosis
Acute Confusional State
Acute Brain Failure
ICU syndrome
Postoperative Cognitive disorder (POCD)
Septic encephalopathy
Encephalopathy

Semin Respir Crit Care Med 2001; 22:115

126
Intensive Crit Care Nurse 1996; 12:173
182

What is delirium ?
A disturbance of consciousness
with inattention, accompanied by a
change in cognition or perceptual
disturbance, that develops over a
short period of time (hours to days)
and fluctuates over time
(DSM IV 2000 )

Incidence

16-83%

11%
16 %

Aldemir M 2001
Bergeron 2001
Kishi Y 1995

SICU DSM III

Mixed ICDSC
ER

19 %
22 %
32 %
48 %
70 %
71.8 %
81.3 %
81.7 %
83.3 %

Dubois MJ 2001
Lin SM 2004
Ouimet S 2007
Thomson JW 2005
McNicoll L 2003
Peterson JF 2006
Ely Ew 2001
Ely Ew 2004
Ely EW 2001

Mixed ICDSC
MICU CAM ICU
Mixed ICDSC
MICU CAM ICU
MICU CAM ICU
MICU CAM ICU
MICU CAM ICU
MICU CCU CAM ICU
MICU CCU CAM ICU

Psychomotor Variants of
Delirium :
Hyperactive ("wild man!")
Hypoactive ("out of it!, pleasantly
confused)
Mixed delirium (features of both),
with reversal of normal day-night
cycle (sundowning)
JAMA 1987; 258: 1789-92

1.6% hyperactive, 43.5% hypoactive,

54.1% mixed

J Am Geriatr Soc 2006; 54:479484

So What?
Why is Delirium Important?
3 criteria:

Common, Morbidity & Costly!

on admit? 15-20%
in hospital? 7-31%
Ortho? 25-65%
ICU: 90%!

Death 6 times by
6 months
Cognitive drop 10
times at discharge

LOS doubles
Ventilation
time double
++ hospital $

Premature
institutionalization

Ely. ICM2001; 27, 1892-1900 Ely, JAMA 2004; 291: 1753-1762

Lin, SM CCM 2004; 32: 2254-2259 Milbrandt E.,CCM 2004; 32:955-962.
Jackson. Neuropsychology Review 2004; 14: 87-98.

Assessment Tools
Requires Patient Participation
Congnitive test for Delirium 1996
Abbreviated Cognitive Test for Delirium 1997
CAM-ICU 2001
NEECHAM 1999
Delirium Detecting Scale 2005

No Patient Participation Requires

ICU Delirium Screening Checklist 2001

CTD

Hart 1996

Sen:100%
Spe:95%

Abbreviated CTD Hart 1997

Sen:94.7 %
Spe:98.8 %

CAM ICU

Ely EW 2001
Ely EW 2004
Lin SM 2004
McNicoll 2005
Pun BT 2005

Sen:73 %
Spe:100 %

NEECHAM

Csokasy 1999
Immers 2005

Sen:97.2 %
Spe:82.8 %

DDS

Otter 2005

Sen:69 %
Spe:75 %

ICDSC

Bergeron 2001

Sen:99 %
Spe:64 %

Delirium
1. Acute onset of mental status changes or a fluctuating
course

&
2. Inattention

&
3. Disorganized
Thinking

or

4. Altered level of
consciousness

Courtesy of W Ely, MD JAMA 2001; 286:27032710

1. Sensitivity
and
specificity
are both
>90%
2. inter-rater
reliability
(k 0.96)

Antipsychotics
Atypical

Haloperidol

CCr 10-30
ml/min

CCr < 10
ml/min

End Stage liver

Dz

Obesity
Continuous IV
infusion
Genetic factors

Train-of-Four (TOF)

Four twitches every 0.5 second

1 twitch --- 90-95 % receptor occupied
2 twitch --- 80-90 % receptor occupied
3 twitch --- 70-80 % receptor occupied
4 twitch --- < 50 % receptor occupied
Optimal relaxation: 1-2 twitches
Preserve one twitch at least

 : NMBA
ICU ?
; Grade E
: ( ) ( )
ICU pancuronium NMBA
Grade C; Grade E

 Randomized, controlled studies:

No clear benefit for newer agent
instead of pnacuronium

No evidence to suggest:
The risk of prolonged paralysis are
increased with the use of one particular
NMBA

Need for NMBAs ?

Mechacnical
ventilation
Tetanus
ICP
Yes
Is the patient
adequately sedated ?
No

Yes
Yes

Still need for

NMBAs?

Optimize
sedatives and
analgesics

Yes
Contraindicatio
n to vagolytic
drug?
No
Hepatic or
renal
dysfunction ?
No
Pancuronium
bolus/infusio
n?

No

Continue
sedatives and
analgesics

Yes

Yes

Avoid pancuronium if
hepatic or renal dysfuntion,
use atracrium or
cisatracrium
atracrium or
cisatracrium
bolus/infusion

Clinical practice guidelines for sustained neuromuscular blockade in the critically ill adult
patient. Crit Care Med 2002; 30:142-156

Common NMB Dosing

NMB

Intermitte
nt dose
and
duration

Infusion
dose

Note

Atracrium

0.5mg/kg
Less than 1
hr

0.5mg/kg/h

Hoffman
elimination

Cisatraciu
m

0.10.2mg/kg

0.18mg/kg/
h

Pancuroniu
m

0.1mg/kg
For almost
1 hr

4-10mg/h

Rocuronium

Hoffman
elimination

Tachycardia

35mg
60Rapid
For abount
100mg/hr
Onset
45 mins
Adapte from IMPACT Sedation and analgesia
skills and technique Update July 2010

Nov. 5th. 2010

64

Materials and Methods

Patient Population:
March 2006~ March 2008, 20 ICUs in France

Inclusion criteria

ETT for acute hypoxemic respiratory failure

PaO2: FiO2< 150 with PEEP> 5 cm H2O(>48 hrs)
Tidal volume 6~ 8 ml/kg of predicted BW(>48 hrs)
Bil. pulmonary infiltrates consistent with
edema(>48 hrs)
Absence of clinical evidence of Lt atrial HTN
PCWP< 18 mm Hg
Echocardiography
Crackle in auscultation
Nov. 5th. 2010

65

Results

Nov. 5th. 2010

66

Materials and Methods

Study Treatment
Cisatracurium besylate Vs. placebo
A 3-ml rapid IV infusion of 15 mg of
cisatracurium besylate or placebo
Continuous infusion of 37.5 mg/ hr for
48 hrs

Sedation, monitor with RASS

Nov. 5th. 2010

67

Results

Nov. 5th. 2010

68

Result
Primary
Outcome
Hazard ratio for
death at 90
days: 0.68
(95% CI: 0.48
to 0.98; P =
0.04), after
baseline
adjustment
The crude 90day mortality:
31.6% vs.
40.7% (P =
0.08).
Nov. 5th. 2010

69

Result

Nov. 5th. 2010

70

Sedation is for the patients,

not for the staff.
Analgesia is humans right
in the ICU.

Muscle relaxation is the last

choice in the critically ill.

 Choose Medication according to

patients premorbidity and current
condition
Sedation use is fatal without proper
knowledge.
Dont overlook Delirium.

Time for Dinner

Bon Appetit