Pain and Sedation Management for Critically Ill Patients ...file.toraks.org.tr/.../mse2-ppt-pdf/7_joseph_layon.pdf · Pain and Sedation Management for Critically Ill Patients: A Rational

1

Pain and Sedation Management for Critically Ill Patients:

A Rational Approach

AJ Layon, MDAndrea Gabrielli MD, FCCM

Murat Sungur MD

Department of Anesthesiology and Surgery Division of Critical Care Medicine

University of Florida

2

Definitions

SedationThe act of calming, especially by the administration of a sedative drug

HypnosisA state of altered consciousness, artificially induced

Analgesia1

A lessening or absence of the sense of pain without loss of consciousness

Amnesia2

The loss or impairment of memoryStedman’s Medical Dictionary. 1995. 2. Dorland’s Illustrated Medical Dictionary. 28th ed. 1994.

3

DefinitionsAnxiety1

A state of intense apprehension, uncertainty, and fear

Agitation2

A state of anxiety accompanied by motor restlessness1

Delirium1

A temporary state of mental confusion

Psychosis2

A severe mental disorder characterized by loss of contact with reality

Stedman’s Medical Dictionary. 1995. 2. Dorland’s Illustrated Medical Dictionary. 28th ed. 1994.

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Pain !!!

5

Adverse Effects of Pain

Psychological

Respiratory

Cardiovascular

Gastro-intestinal

Neuro-endocrine

Metabolic

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Respiratory ComplicationsPainful surgical incision

Retention of secretion

Atelectasis

Hypoxaemia

HypercarbiaPneumonia

⇓ Diaphragm function

⇓ Pulmonary compliance

Muscle splinting

⇓ Deep coughing

7

Cardiovascular Effects

HemoglobinDiastolic timeEnd-diastolic pressure

Heart RateAfterloadInotropy

Hemoglobin

Diastolic time

End-diastolic pressure

Heart Rate

Afterload

Inotropy

Before…….…..AfterSupply-Demand Balance and Mismatch

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Neuro-endocrine Effects⇑ Sympathetic tone

⇑ Hypothalamic stimulation

ACTH*ADH†

Aldosterone Angiotensin-IICatecholaminesCortisolGlucagon

Growth hormoneIL-1‡

IL-6§

ReninSerotoninTNF||

⇓ Insulin & testosterone

⇑ Na & water retention

⇑ Glucose, free fatty acids and ketone bodies

⇑ O2 consumption

Negative nitrogen balance

9

Assessing Pain

Faces Pain Rating Scale

Visual Analog Scale (VAS)

–No pain worst pain imaginable

Hemodynamics

Pain questionnaire

–Qualitative aspects

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Faces Pain Rating Scale

00 33 44 5511 22

0 1 2 3 4 5 6 7 8 9 10

No pain

Moderate pain

Worst possible pain

Adapted with permission from Chambers, Craig. Pain. 1998;78:29.Sriwatanakul et al. Clin Pharmacol Ther. 1982;32:143-148.

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Assessment of Pain

0

1

2

3

4

5

Pain

inte

nsity

sc

ore

1 2 3 4 5Time

Nurse assessment Patient assessment

Critical Care Medicine 1997;25:1159-1166

12

Behavioral Indicators

0

510

152025

3035

40

Perc

ent

A B C D E F G H I J K LBehavioral Indicators

A: No movement

B: Grimacing

C: Vocalization

D: Restless

E: Hesitant

F: Tense

G: Attention seeking

H: Wrinkled forehead

I: Splinting

J: Drawn around eyes

K: Rigid

L: TearingCritical Care Medicine 1997;25:1159-1166

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Physiological Indicators

0

5

10

15

20

25

30

Perc

ent

A B C D E F G HPhysiological parameter

A: ⇑ Heart rate

B: ⇑ BP

C: ⇑ RR

D: ⇓ BP

E: Perspiration

F: Pallor

G: ⇓ RR

H: ⇓ HRCritical Care Medicine 1997;25:1159-1166

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Assessing Sedation

Ramsay Sedation Scale

Motor Activity Assessment Scale (MAAS)

Observer’s Assessment of

Alertness/Sedation Scale (OAA/SS)

Riker’s Sedation-Agitation Scale (SAS)

Sedation monitors

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Ramsay Sedation Scale

Score Definition

1 Anxious, agitated, or restless

2 Cooperative, oriented, and tranquil

3 Responds to commands

4 Asleep, but with brisk response to light glabellar tap or loud auditory stimuli

5 Asleep, sluggish response to light glabellar tap or loud auditory stimuli

6 Asleep, no response

Adapted from Ramsay et al. BMJ. 1974;2:656-659.

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The Riker Sedation-Agitation ScaleSedation /

Agitation Level Description

1

2

3

4

5

6

7 Dangerous agitation : pulls at ET; tries to remove catheters; limbs over bedrail; strikes staff; thrashes from side to side

Very agitated; does not calm, despite frequent verbal reminding of limits; requires physical constraints; bites ET

Agitated: anxious or mildly agitated; attempts to sit up; calms down to verbal instructions

Calm and cooperative: calms, awakens easily; follows commands

Sedated: 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 notcommunicate or follow commands

Jacobi J et al. Crit Care Med 2002;30:119-41

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Factors Provoking AnxietyPain

Inconsiderate Providers

Alarms

Temperature

Mechanical Devices

Loss of Control

Lights

Nonchanging Environment

Sleep Deprivation

Noises

Memory Loss

Confusion

ICU Psychosis

Fear

Medications

Surgical StressChemical/PhysiologicImbalance

Tesar, Stern. J Intensive Care Med. 1986;1:137-148. Harvey. Am J Crit Care. 1996;5:7-16. Crippen. Crit Care Clin. 1990;6:369-392.

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Anxiety in the ICU

Causes– Pain– Environment– Sleep deprivation– Drug withdrawal

Effects – Agitation delirium psychosis PTSD– CVS

BP; HR – Sleep deprivation

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Sleep Deprivation

Average amount of

sleepin the ICU is 1 hour, 51

minutes per 24 hours

Aurell, Elmqvist. BMJ. 1985;290:1031.

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Restorative Properties of Sleep

Increased rate of healing –Promotes anabolism

Facilitates growth hormone release

–Counteracts catabolismInhibits cortisol releaseInhibits catecholamine release

Adam, Oswald. BMJ. 1984;289:1400-1401. Adam, Oswald. Clin Sci. 1983;65:561-567.Krachman et al. Chest. 1995;107:1715.

21

Sleep Deprivation:Infection and Immunity

Bacterial translocation from the gut1

Septic burden by pathogenic microorganisms and their toxins in tissues1

Changes in the distribution of peripheral leukocytes2

– Reduction in NK cellsReduction in phytohemagglutinin-induced lymphocyte DNA synthesis3

Decreases the activity of leukocytes and increases interferon levels3,4

1 Everson, Toth. Am J Physiol Regulatory Integrative Comp Physiol. 2000;278:R905-R916. 2 Heiseret al. Eur Arch Psychiatry Clin Neurosci. 2000;250:16. 3 Palmblad et al. Psychosom Med. 1979;41:273. 4. Palmblad et al. Psychosom Res. 1976;20:1998.

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Sleep Deprivation:Cardiorespiratory Function

Human– Volunteers

Increased pressor response to sympathetic stimulation1

Changes in cardiovascular responses to simulated orthostasis2

– PatientsIncreased BP, HR, and urine norepinephrine in hypertensives3

Increased incidence of cardiovascular events3

Rats– Death due to pulmonary edema4

1. Kato et al. Hypertension. 2000:35:1173-1175. 2. Muenter et al. J Appl Physiol. 2000;88:966-972. 3. Lusardi et al. Am J Hypertens. 1999;12:63-68. 4. Rechtschaffen et al. Science. 1982;221:182-184.

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Sleep Deprivation: Cognitive Function

Impaired memory1

Impaired communication skills2

Impaired decision-making3

Confusional state4

– Apathy – Delirium

1. Harrison, Horne. Q J Exp Psychol. 2000;53I:271. 2. Harrison, Horne. Sleep. 1997;20:871-877. 3. Harrison, Horne. Organ Behav Hum Decis Proc. 1999;78:128-145.4. Krachman et al. Chest. 1995;107:1713-1720.

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Causes of Sleep Deprivation in the ICU

Patient-related– Pain1

– Anxiety1

– Underlying illness2

COPDCHF

Medications2

– Morphine– Theophylline

Environment2– Noise– Light

Intensity of nursing care and interventions21. Wood. Intensive Crit Care Nurs. 1993;9:133. 2. Krachman et al. Chest. 1995;107:1713-1720.

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Risks of Undersedation:Agitated Patients

Can injure themselves or others– Self-extubation, decannulation,

wound dehiscence↑ Peripheral oxygen consumption

– Risks of hypoxemia, organ ischemia

↑ Physiologic stress/catecholamine surge

– Changes in immune response, wound healing, coagulation

– Disrupted circadian rhythmsRequire more intensive nursing care

– Restraints– Consequences of excessive

sedationSleep deprivation and posttraumatic stress disorder (PTSD)

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Risks and Consequences of Oversedation

Respiratory depressionHemodynamic instabilityDelayed weaning from ventilatorInability to neurologically access CNS-impaired patients Aspirational pneumoniaIncreased nursing care and costsPressure injuries, venous stasis, muscle atrophy

Shelly MP, Wang DY. Br J Intensive Care. May/June 1992:195-203.

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The Perfect Sedative in the ICU

Provides– Sedation / Anxiolysis– Analgesia– Amnesia

No effect on cardiovascular functionRapid onset and offsetMinimal respiratory depressionNo or inactive metabolites

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The Perfect Sedative in the ICU

No accumulation in renal or hepatic dysfunctionNo interactions with other medicationsNo pain on injectionNo associated tolerance or withdrawalSafe for all ages with no age-related changes in pharmacokineticsCost-effective

Does not exist!

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Difficulties with Choice of Sedatives

Paucity of randomized, controlled studies

Unconvincing results from studies that have been done

Pharmacology changes with duration of infusion– Initial studies on all these medications done with

bolus doses

– Later studies of infusion over time show striking changes in pharmacokinetics

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Can we do it without drugs?..

Back to the basics– Physical contact– Environmental factors– Effective communication– Comfort measures– Reorientation techniques– Uninterrupted sleep periods

Technical interventions– Mechanical interventions (eg, tube patency)– Relaxation techniques (music therapy, therapeutic touch)

Psychosocial– Family visitations and interactions– Spiritual contact

Halloran, Pohlman. Crit Care Nurs. August 1995;(suppl):1-16.

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Pharmacologic Agents Used for Sedation and Analgesia

Analgesics1

– Morphine sulfate– Fentanyl

NSAIDS– Cox2s – Valdecoxib,

ParacoxibBenzodiazepines1

– Lorazepam - Ativan– Midazolam - Versed

Sedative/hypnotics1

– Propofol - DiprovanButyrophenones1

– Haloperidol - Haldolα2 Agonists2

– Dexmedetomidine –Precedex

1. Shapiro et al. Crit Care Med. 1995;23:1596-1600. 2. Bhana et al. Drugs. 2000;59:263-268.

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Opioids

Fentanyl

CH3CH2C-NO

N-CH2CH2

CH2COOH·HO-C – COOH

CH2COOH

C22H28N2O · C6H8O7

Morphine

CH3-N

OH

H O

OH

C17H19NO3

10mg5mg/h$12/d

200ug100ug/h$26/d

33

Opioids: Clinical Effects

Analgesia1

Sedation1

Tolerance1

Respiratory depression1

Withdrawal symptoms1

Hypotension1

Bradycardia2

Constipation1

1. Harvey. Am J Crit Care. 1996;5:11. 2. Wagner, O’Hara. Clin Pharmacokinet. 1997;33:426-453.

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CONTROL30 MINUTESAFTER 15 mgMORPHINE IV

30 MINUTESAFTER 30 mgMORPHINE IV

40 50 60 70

3030

AL

VE

OL

AR

VE

NT

ILA

TIO

N (

/ m

in)

Opioids: Clinical Effects

25

20

15

10

5

ALVEOLAR PCO2 (torr) Miller, 1986

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Opiates: Reversal Agents

Naloxone– Nausea and vomiting– Tachycardia– Hypertension– Pulmonary edema– Cardiac dysrhythmias– Ventricular fibrillation

Naltrexone– Effective orally up to 24 hours

Nalmefene– Longer duration of action than naloxone– Acute pulmonary edema

Stoelting. Pharmacology and Physiology in Anesthetic Practice. 3rd ed. 1999:106-108.

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OpioidsOpioids

Local anesthetics

NSAIDs

Ana

lges

ic e

ffic

acy

Time after surgeryTheoretical time course of analgesic efficacy of opioid analgesics, local anesthetic, and nonsteroidal anti-inflammatory drugs (NSAIDs) when used as part of a “balanced” analgesic approach to minimizing postoperatie discomfort.

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Analgesics – Fentanyl vs Morphine

No comparative studies are availableFentanyl would seem to be the better of the two– No histamine release – more hemodynamically

stable– Slightly shorter onset– Much shorter half-life

30–60 min vs 2–9 hr

– No active metabolites

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On further examination…– Fentanyl has a much larger volume of distribution than

morphine – its half-life prolongs from 30–60 min to 9–16 hr with prolonged infusion

– Fentanyl exhibits striking tachyphylaxis – dosing requirements increase dramatically with prolonged infusion

Shafer A, White PF, Schuttler J, Rosenthal MH. Use of a fentanyl infusion in the intensive care unit: tolerance to its anesthetic effects? Anesthesiology. 1983;59:245-248.

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Analgesics – Fentanyl vs MorphineRecovery

Period (mins)100

FentanylSufentanil

Alfentanil

Remifentanil

80

60

40

20

0 120 240 360 480 600

Infusion Duration (mins)

Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics, and rational opioid selection. Anesthesiology. 1991;74:53-63.

40


On further examination…– Fentanyl’s hemodynamic stability is due

to its lack of histamine release, negative inotropy or vasodilatation

– Fentanyl is, however, a powerful inhibitor of endogenous catecholamines; this causes severe hypotension in patients whose blood pressure is dependent on endogenous catecholamines

41

Types of Opioid Utilized

24

1.7

33

33

MorphineFentanylSufentaOther

Eur J Clin Pharmacol (2002)58: 73-77

42

Opioids: Route of Administration

0102030405060708090

100

%

IV IM Epidural Other

FentanylMorphineDemerol


43

Dosing Schedule

Dasta et al -prospective observational study*

Information on prescribing and administering of opioid, benzodiazepine and muscle relaxants

N=221

90% of drug prescribed on PRN basis

% Total Dose

Administered dose*Crit Care Med 1994; 22:974-980

30%

44

Patient Controlled Analgesia

Useful in non-critically ill patients

Stable drug concentration

Increased patient autonomy

Better pain control in post-CABG patients†

†Crit Care Med 1999; 27:2218-2223 †J

Cardiothorac Vasc Anesth 1998; 12:654-658

0

500

1000

1500

2000

2500

Piri

tram

id(m

g)

Day

1

Day

2

Day

3

Tot

al

StandardPCA

** *

*

*p < 0.05

45

Patient Controlled Analgesia

0

1

2

3

4

5

6

STD-Satisfaction PCA-SatisfactionPCA-Pain STD-Pain

Improved pain satisfaction

Decreased pain scoring

Improved SpO2

Improved FEV1

Improved VC

*J Cardiothorac Vasc Anesth 1998; 12:654-658

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Epidural Use in the ICU

Limited clinical data availableLow et al conducted postal survey*Assess the utilization of epidural catheters under various clinical scenariosNo standard plan of careNo algorithm for patient variables related to epidural.

*Acta Anaesthesiol Scand 2002; 46: 799-805

47

Benefits of Epidural in the ICU

Pain controlEarly mobilizationDecreased incidence of deep venous thrombosisImproved pulmonary mechanicsIncreased splanchnic blood flowDecreases duration of post-operative ileus

48

Chest Wall Trauma

Chest wall trauma -8% of all trauma admissions

Marker of severity of injury

Rib fractures found in 10% of patients after trauma

Associated with significant morbidity and prolonged ICU stay*

Chest Surg Clin N Am 1997; 7:239-261

49

Multiple Rib Fractures

Endothoracic Fascia

Subserous Fascia

Pleura

Intercostal nerve

INTERPLEURAL BLOCK

INTERCOSTAL NERVE BLOCKTHORACIC

PARA-VERTEBRAL

BLOCK

INTRATHECAL (lumbar)

EPIDURAL (thoracic &

lumbar)

Systemic Opioids

Intercostal nerve block

Inter-pleural analgesia

Epidural analgesia

Thoracic paraverterbral block

50

Contra-indication to Regional But…

Multiple other injuries

Haemodynamic instability

Associated spinal injury

Mask intra-abdominal injury

Associated Horner Syndrome makes neuro assessment difficult

0

1

2

3

4

5

6

7

8

Day 1 Day 2 Day 3

Epidural-VASIV PCA-VASEpidural-MIFIV PCA-MIF

*

*

Ann Surg 1999; 229: 684-691

51

Respiratory ComplicationsPainful surgical incision/ fracture

Regional⇓ Diaphragm function

⇓ Pulmonary compliance

Muscle splinting

⇓ Deep coughing

Retention of secretion

Atelectasis

Hypoxaemia

HypercarbiaPneumonia

52

Epidural and Splanchnic Circulation

Ai et al performed randomized controlled study in rabbits*

Saline & lidocaine epidural group

pHi and endotoxin measured

Improvement in pHi in local epidural group

7

7.05

7.1

7.15

7.2

7.25

7.3

7.35

pHi

Baseline1 Baseline2 Hypoxia1 Hypoxia2

Saline epidural Local epidural

†

†

† p< 0.01

*Anesthesiology 2001;94: 263-9

53

Epidural and Splanchnic Circulation

GI system fertile source for inflammatory mediatorsSplanchnic mal-perfusion increases mediator releaseSpackman et al conducted a double blinded randomized controlled study*Randomized to morphine and epiduralEpidural shown to improve splanchnic perfusion Widened indication profile

7.06

7.08

7.1

7.12

7.14

7.16

7.18

7.2

7.22

7.24

0 6 24Epidural Morphine

p =0.062

*Intensive Care Med 2000; 26:1638-1645

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Cardiovascular Effects

⇓ Hemoglobin

⇓ Diastolic time

⇑ End-diastolic pressure

⇑ Heart Rate

⇑ Afterload

⇑ Inotropy

Epidural ⇑ Pain control

Hemoglobin

Diastolic time

End-diastolic pressure

Heart Rate

Afterload

Inotropy

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Not All Good News…...

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Does Epidural Change Post-Operative Cardiac Outcome?

NO YESPeyton et al.Anesth & Analg 2003;96:548-54

Baron et al.Anesthesiolgy 1991; 75: 611-618

Christopherson et al.Anesthesiology 1993;79: 422-434

Hjortso et al.Acta Anaesthesiol Scand 1985; 29:705-716

Tuman et al.Anesth & Analg 1991; 73:696-704

Yeager et al. Anesthesiology 1987; 66(6): 729-736

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Does Epidural Change Post-Operative Cardiac Outcome?

Controversial

Improves outcome in high risk patients

No difference seen in lower risk population

Insufficient numbers in study

Highest risk at 72-96 hours post surgery

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No Matter What Opioid You Are Using…

Re-evaluate the need for analgesia before discharge to a regular ward

80% of in-hospital Cardiac Arrest are Hypoxic

59

NSAIDS

Prostaglandin synthesis interference

Actions: anti-inflammation, antipyresis, analgesia

Acetaminophen for antipyresis

Side effects: gastropathy, nephrotoxicity, coagulopathy

ASA hypersensitivity

60

NSAIDS

Cell membrane phospholipidsCell membrane phospholipids

PhospholipasePhospholipase

CyclooxygenaseCyclooxygenase

NSAIDsArachidonic acidArachidonic acidArachidonic acidArachidonic acid NSAIDs

EndoperoxidesEndoperoxides

ThromboxaneThromboxaneProstaglandinsProstaglandins ProstacyclinProstacyclin

Oxygen freeOxygen freeradicalsradicals

The proposed mechanism of action of the nonsteroidal anti-inflammatory drugs (NSAIDs)

61

NSAIDS in the ICU

Analgesic benefits not studied in ICU patients

Increased risk of bleeding

Increased risk of renal dysfunction

Increased incidence of peptic ulcer disease

Increased risk of broncho-spasm in patients with aspirin allergy

62

NSAIDS in the ICU…

63

Acetaminophen in Cardiac Surgery100

90

1 2 3Time (days)

80

Oxy

codo

ne(m

g)

70Relatively safe

No platelet dysfunction

Minimal renal dysfunction

Maximum daily dose <4g

Relative contra-indication in hepatic dysfunction

60

5040

3020

100

PropacetamolPlacebo

10

9876543210

0 6 12 18 24 30 36 42 48 54 60 66Time (h)

VA

S (d

urin

g de

ep b

reat

h)

Anesth Analg 2002;95: 813-819

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Classes of NSAIDS

Propionic – ibuprofen, naproxen

Acetic – indomethicin, tolmetin

Salicytic – ASA, diflunisal

Anthranilic – phenylbutazone

Pyrrolopyroles – ketorolac

COX-2 inhibitors – celecoxib, rofecoxib, valdecoxib

65

COX-2 Inhibitors

Cyclooxygenase – 1: responsible for cellular functions (“housekeeping” enzyme for platelets, kidneys, and stomach)

Cyclooygenase – 2: responsible for inflammatory response and mitogen activity– Polyposis prophylaxis

– Lack of platelet aggregation inhibition

66

Valdecoxib

Mechanism of action: NSAID with typical anti-inflammatory, analgesic, antipyretic

Pharmokinetics– Maximal plasma concentrations in 3 hours

– Bioavailability 83% after po administration

– No age or gender differences were seen in pharmacokinetics that require dosage adjustment

67

COX-2 InhibitorsSelective COX-2 inhibition

Less GI, renal and platelet dysfunction

Opiate sparing

Oral and IV formulation available

Tang et al compared placebo vs. IV parecoxib†

Decreased PCA opioid requirement

No change in pain management or opioid side effect 0

10

20

30

40

50

60

Mor

phin

e(m

g)

Control Parecoxib20mg

Parecoxib40mg

* *

†Anesthesiology 2002;96:1305-1309

68

Valdecoxib vs Opoids After Hip Arthroplasty…

Multicenter, double blind, multidose study

Placebo, 20mg, 40 mg b.i.d valdecoxib given pre- and post-operatively

IV-PCA MSO4

40% less morphine in treatment groups

VAS-pain Patient Satisfaction improved in valdecoxib groups

69

Sedative-Hypnotics

Available Agents

– Propofol

– Midazolam

– Lorazepam

70

Propofol

Advantages• Sedation1

• Hypnosis1

• Anxiolysis1

• Muscle relaxation1

• ICP1

• Cerebral metabolic rate1

• Relief of bronchospasm1

Limitations• Respiratory depression (enhanced

by opioids)1

• Hypotension1

• Decreased contractility2

• Lack of analgesia3

• Hypertriglyceridemia1

• Preservative issues4

• Potential for infection necessitates need for regular changing of lines5

1. Harvey. Am J Crit Care.1996;5:7-16. 2. Lerch, Park. Br Med Bull. 1999;55:90. 3. Wagner, O’Hara. Clin Pharmacokinet. 1997;33:435. 4. Propofol [package insert]. 5. Prielipp et al. Crit Care Clin. 1995;11:986.

71

Sedative-HypnoticsAvailable Agents

Propofol– Ultra short-acting after bolus dose and short-

term infusion

– Short duration of action useful especially for short-term sedation of:

intubated patients after surgical procedures

the patient with changing neurologic status requiring frequent neurological evaluation

the elderly —continued

72


Propofol– Duration of action prolonged after infusion of

longer than 72 hr (Albanese J, Martin C, Lacarelle B, Saux P, Durand A, Gouin F. Pharmacokinetics of long-term propofol infusion used for sedation in ICU patients. Anesthesiology 1990;73:214-7)

– Negative inotrope, vasodilator – can cause hypotension

– Infection risk

– Hyperlipidemia

73

Propofol Syndrome

Increased mortality initially evident in pediatric population

Led to “moratorium” on the use of propofol for pediatric patients by the manufacturer

Later seen in adult patients

74

Propofol Syndrome

Characterized by:– Metabolic Acidosis

Sometimes with a high anion gap.Sometimes with a lactic acidosis.Many times with an uncharacterized metabolic acidosis.

– Rhabdomyolysis– Myocardial Dysfunction– Death

75

Propofol Syndrome

Characteristics in head injury patients– Noted 5 fatal cardiac arrests after high dose Propofol

infusion– Reviewed data from 1996-9

Of 67 patients – 7 had deaths that seemed consistent with Propofol syndromeFound that patients with doses of Propofol higher than 5 mg/kg/hr had a much higher mortality than if dose was lower

Lancet 2001; 13:357:117-18.

76

Propofol Syndrome

Possible Etiologies– Decreased transmembrane electrical potential and

alteration of electron transport across inner mitochondrial membrane

Marik, PE. Curr Pharm Des 2004; 10: 3639-49.

– Alteration in microcirculatory blood flow measured via invivo microvideoscopy of the sublingual microcirculatory network.

Koch, M. Crit Care Med 2004; 32(12 suppl): A41

77

Benzodiazepines: Pharmacodynamics

Amnesia

Sedation/anxiolysis

Anticonvulsant

Relief of muscle spasm

Lerch, Park. Br Med Bull. 1999;55:89.

78

Midazolam: Clinical Effects

Sedation, anxiolysis, and amnesia1

Rapid onset of action intravenously1

Possible accumulation in liver failure2

Anterograde amnesia3

Prolonged recovery after long-term use4

Combination with opioids increases hypotensive effects5

Half Life 2.5 Hours1. Wagner, O’Hara. Clin Pharmacokinet. 1997;33:430, 434. 2. Lerch, Park. Br Med Bull. 1999;55:89, 90. 3. Harvey. Am J Crit Care. 1996;5:11. 4. Shafer. Crit Care Med. 1998;26:949, 953. 5. Heikkilä et al. Acta Anaesthesiol Scand. 1984;28:689.

79


Midazolam– Rapid onset of action (usually 2–5 min) – Short duration of action after bolus dose

(~15 min) due to redistribution– Longer-acting after short-term infusion

(~1–2 hr)– Long half-life after long-term (72 hr) infusion

with large inter-patient variability (3–15 hr)

Swart EL, van Schijndel RJ, van Loenen AC, Thijs LG. Continuous infusion of lorazepam versus midazolam in patients in the intensive care unit: sedation with lorazepam is easier to manage and is more cost-effective. Crit Care Med. 1999;27:1461-1465.

80

Lorazepam: Clinical Effects

Sedation, anxiolysis, and amnesia1

Preferred for prolonged sedation2

Slower onset of action than midazolam2,3

Half Life 8-20 Hours

Less hypotension than with midazolam2

Retrograde and anterograde amnesia

1. Lerch, Park. Br Med Bull. 1999;55, 90. 2. Shafer. Crit Care Med. 1998;26:952-953. 3. Wagner, O’Hara. Clin Pharmacokinet. 1997;33:430, 434. 4. Harvey. Am J Crit Care. 1996

81


Lorazepam– Slow onset of action (10–20 min) – Intermediate half-life (6 hr) after bolus dose due

to metabolism– Longer acting after 72-hr infusion

(12–32 hr)– Prolongation of effect and decreased drug

requirements in the elderly

82

Sedative-Hypnotics

Lorazepam

Midazolam

Propofol

0 60 120 180 240 300 360 420 480Infusion Duration (min)

0120

240

360

480

600

720

840

960C

onte

xt S

ensi

tive

Hal

f-T

ime

(min

)

Greenblatt DJ, et al. J Pharm Sci 1982;71:248-252;Persson P, et al. Br J Anaesth 1987;59:548-556;Klotz U, et al. Eur J Clin Pharmacol 1984;26:223-226.

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Benzodiazepines:Reversal Agents

Flumazenil– Transiently antagonizes the benzodiazepine

component of ventilatory depression and sedation during use with opioids

– Reverses CNS and circulatory side effects of benzodiazepines within 2 minutes

– Useful for diagnostic evaluation

Stoelting. Pharmacology and Physiology in Anesthetic Practice. 3rd ed. 1999:138.

84

Sedative-Hypnotics

One study comparing propofol (P) vs midazolam (M) and lorazepam (L) for ICU Trauma patients– Randomized, open label — 2 – 4 days

– Over sedation occurred most often with L

– Under sedation occurred most often with P

– Fewest titrations required with M

– Cost P > M > L

McCollam JS, O'Neil MG, Norcross ED, Byrne TK, Reeves ST. Continuous infusions of lorazepam, midazolam, and propofol for sedation of the critically ill surgery trauma patient: a prospective, randomized comparison. Crit Care Med 1999;27:2454-2458.

85

Sedative-Hypnotics

Many studies comparing propofol (P) with midazolam (M) for sedation after CABG– P extubated sooner after d/c than M– Decreased morphine requirements after P– Lower PaCO2 after extubation in P– Generally similar quality of sedation– Propofol patients more hypotensive but no difference

in cardiac endpoints– Earlier extubation not followed by earlier ICU

discharge

86

Sedative-Hypnotics

Review article looking at 49 randomized controlled trials (Ostermann ME, Keenan SP, Seiferling RA, Sibbald WJ. Sedation in the intensive care unit: a systematic review. JAMA. 2000; 283:1451-1459)

– The main conclusion — more studies needed

– Propofol is at least as effective as midazolam – Propofol exhibits a faster time to extubation than

midazolam

87

Sedative-Hypnotics

Other Conclusions– It is NOT clear that this results in a decrease in

total time of ventilation or in a shorter ICU time– Use of propofol results in more problems with

hypotension than midazolam– No difference was found in comparing

midazolam with lorazepam.

—continued

88

Sedative-Hypnotics

Other Conclusions, cont’d.

– Other studies since then have had differing results:Lorazepam is a useful alternative to midazolam, with easier management of sedation level, no difference to awakening, and significant cost savings

Swart EL, van Schijndel RJ, van Loenen AC, Thijs LG. Continuous infusion of lorazepam versus midazolam in patients in the intensive care unit: sedation with lorazepam is easier to manage and is more

cost-effective. Crit Care Med. 1999;27:1461-1465.—continued

89

Sedative-Hypnotics

Other Conclusions, cont’d.

– Other studies since then have had differing results:Significantly delayed emergence from sedation with lorazepam compared with midazolam (15 hr to 31 hr)

Barr J, Zomorodi K, Bertaccini EJ, Shafer SL, Geller E. A double-blind, randomized comparison of i.v. lorazepam versus midazolam for sedation of ICU patients via a pharmacologic model.

Anesthesiology. 2001;95:286-298.

90

Haloperidol: Clinical Effects

For treatment of delirium in critically ill adults1

Does not cause respiratory depression1

Metabolism altered by drug-drug interactions2

Altered sensory perception (rambling, incoherent speech, disorientation)2

Adverse effects include QT interval prolongation, extrapyramidal symptoms, neuroleptic malignant syndrome (rare)1

1. Harvey. Am J Crit Care. 1996;5:11. 1998:10, 11. 2. Crippen. Crit Care Clin. 1990;6:369-392.

91

Neuroleptics

Haloperidol– “Stuns”, does not sedate– Indicated for delirium, not sedation– No respiratory depression or significant

hemodynamic side effects– Can cause extrapyramidal symptoms and QT

prolongation– Can have a prolonged effect when used for a

prolonged period of time

92

α2 Agonists

ClonidineSelectivity: α2:α1 200:11

t1/2 β 10 hrs1

PO, patch, epidural2

Antihypertensive1

Analgesic adjunct1

IV formulation not available in US

DexmedetomidineSelectivity: α2:α1 1620:13

t1/2 β 2 hrs3

Intravenous3

Sedative-analgesic3

Primary sedativeOnly IV α2 available in the US

1. Maze. White paper; 2000. 2. Khan et al. Anaesthesia. 1999;54:150. 3. Kamibayashi, Maze. Anesthesiology. 2000;93:1345-1349.

93

α2 Agonists:Pharmacodynamics

Sedation/hypnosis1

Anxiolysis1

Analgesia1

Sympatholysis (BP/HR, NE)1

Reduces shivering2

Neuroprotective effects3

No effect on ICP3

No respiratory depression1

1. Aantaa et al. Drugs of the Future. 1993;18:49-56. 2. Kamibayashi, Maze. Anesthesiology.

94

αα22--Receptor SubtypesReceptor Subtypes

α2A

?

?

α2A

α2C

α2A

α2AAnxiolysis

α2B

α2B

XX

α2B

X

Physiology of Physiology of αα2 2 AdrenoceptorsAdrenoceptors

Reprinted with permission from Kamibayashi, Maze. Anesthesiology. 2000;93:1346.

95

Alpha-2 agonist

Dexmedetomidine– Sedation and analgesia– No (minimal) respiratory depression– Causes unique type of sedation that allows for easy arousal

with preserved respiratory drive, with quick return to sedated state, without changing infusion rate

– Has ceiling on dosePackage insert dose range 0.2–0.7 µg/kg/hr for 24 hoursDoses over 0.7 µg/kg/hr and for longer periods of time now starting to be studied.Causes hypotension, especially with volume depletion and loading dose.

96

Dexmedetomidine:Prescribing Information

Indications– Sedation of initially intubated and MV patients during treatment in

OR, Angiography, ICU– Sedation and management of agitated patients in ED?– Successful weaning of ventilated patients– Management of alcohol withdrawal patients

Contraindication– Caution in patients with advanced heart block

Drug interactions– Vagal effects can be counteracted by IV administration of

anticholinergic agents

Disease effecting clearance– Clearance is lower in patients with hepatic impairment

97

Dexmedetomidine

Advantages• Has sedative, analgesic,

and anxiolytic effects1

• Respiratory stability2

• Predictable hemodynamic response1

• Arousable and oriented patient3

• No need to discontinue before extubation4

• Antishivering5

Limitations• May reduce HR and BP (caution in

hypovolemia, shock, and heart block)4

• Potentiates effects of opioids, sedatives and anesthetics4

• Dry mouth4

• Vasoconstriction at high dose4

1. Aantaa et al. Drugs of the Future. 1993;18:49-56. 2. Frangoulidou et al. In: Sedation.1998:40-50. 3. Mantz, Singer. In: Redefining Sedation. 1998:23-29. 4. Precedex™ [packageinsert]. 5. Kamibayashi, Maze. Anesthesiology. 2000;93:1345-1349.

98

Clinical Strategies for Patient Comfort and Safety in the ICU

What are the goals of sedation and analgesia?

Can existing drugs achieve these goals:– Alone or in combination?– By bolus or infusion?

Is there an unmet need?– Can dexmedetomidine fill it?

Clinical challenges:– What are they and how can we meet them?

99

Achieving Optimal PatientComfort in the ICU

AnalgesiaAnalgesia

AnxiolysisAnxiolysisSedation

Sedation

HypnosisHypnosis

Amnesia

100

Often a Neglected Problem

05

10152025303540

%

Opioids NSAIDS A+ B No therapy

Drug therapy within 48 hours in ICU


101

Treatment AlgorithmIs patient comfortable

and at goal?

Reassess goal daily

Titrate and taper therapy

Consider daily wake-up

Taper if > 1wk high dose therapy

H-D unstable

Fentanyl, Hydromorphone

H-D stable

Morphine

Repeat until controlled,scheduled and PRN dose

IVP doses > 2 hrs?

Consider continuos infusion of opioid

Set analgesia goal

No Yes

Rule out & correct reversible causes

Use non-pharmacological treatment and optimize environment

Use pain scale to assess pain

Crit Care Med 2002; 30:119-141

102

The Fine Balance in Patient Comfort

103


AnxietyAgitation

HypertensionTachycardiaArrhythmias

Myocardial ischemiaWound disruption

Patient injury

104


DepersonalizationDelayed emergenceDelayed weaning

Pressure injuryVenous stasisMuscle atrophyIncreased cost

105

Choosing the Right DrugCombination

106

SedationSedationSedation

HypnosisHypnosis AnxiolysisAnxiolysisAmnesiaAmnesia

AnalgesiaAnalgesiaAnalgesia

R Sladen, ASA 2001

107



Patient ComfortPatient ComfortPatient Comfort


R Sladen, ASA 2001

108




OpioidsOpioids

R Sladen, ASA 2001

109




BenzodiazepinesBenzodiazepines

R Sladen, ASA 2001

110



PropofolPropofol


R Sladen, ASA 2001

111


α2 Agonistsα2 Agonists

SedationSedationSedation AnalgesiaAnalgesiaAnalgesia

R Sladen, ASA 2001

112

AnalgesiaAnalgesiaAnalgesiaSedationSedationSedation

DexmedetomidineDexmedetomidine Primary

AdjunctSedation

Midazolam

R Sladen, ASA 2001

113



Propofol AdjunctSedation

R Sladen, ASA 2001

114


FentanylFentanyl AdjunctAnalgesia


R Sladen, ASA 2001

115


MorphineMorphine AdjunctAnalgesia


R Sladen, ASA 2001

116

Rationale for Economic Evaluations

Safety and efficacy are no longer sufficient– Optimal use of limited resources needs to

be justified– Third-party payers and others demand

evidence of cost-effective data for new drugs

– What is the added value of the increased costs?

Chalfin. Semin Respir Crit Care Med. 1999;20:263-270.

117

Costs of Analgesic / Sedative Agents in the ICU

191.5212.7715.001.000.53Haloperidol

336.34109.820.050.02286.00Dexmedetomidine

307.3687.82350.00100.000.04Propofol

171.005.7015.000.500.48Lorazepam

243.6013.9235.002.000.29Midazolam

65.763.292.000.101.37Fentanyl

18.481.2315.001.000.05Morphine

– $ per Day –– mg/hr –

High Cost

Low Cost

High Dose

Low DoseCost

per mg

118

Rationale for Economic Evaluations

Safety and efficacy are no longer sufficient– Optimal use of limited resources needs to be

justified– Third-party payers and others demand

evidence of cost-effective data for new drugs– What is the added value of the increased

costs?

Chalfin. Semin Respir Crit Care Med. 1999;20:263-270.

119

Cost of Undersedation

Patient discomfort and dissatisfactionLong-term psychological effectsIncreased use of paralytic drugsIncreased metabolic demandsAssociated cardiovascular consequences

120

Cost of Oversedation

Unable to adequately examine the patientExpensive diagnostic imaging and other testsPossible late diagnosis of treatable problemsProlonged mechanical ventilation timeProlonged stay in the ICU

121

Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.

Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM, Crippen DW, Fuchs BD,

Kelleher RM, Marik PE, Nasraway SA Jr, Murray MJ, Peruzzi WT, Lumb PD; Task Force of the American College of Critical Care Medicine (ACCM)

of the Society of Critical Care Medicine (SCCM), American Society of Health-System Pharmacists (ASHP),

American College of Chest Physicians.

Volume 30, No. 1 2002

28 Recommendations

122

Goals of Sedation in the ICU

ACCM Guidelines – 2002– 28 total recommendations– Analgesia should be provided with IV doses of common opiates

(fentanyl, morphine, hydromorphone).– Fentanyl is preferred for a rapid onset of analgesia in

acutely distressed patients.– Morphine or hydromorphone are preferred for intermittent therapy

over fentanyl because of their longer duration of effect.

– Midazolam or diazepam should be used for the rapid sedation of the acutely agitated patient.

– Fentanyl or hydromorphone are preferred for patients with hemodynamic instability or renal insufficiency. —continued

123


ACCM Guidelines – 2002, cont’d.

– Propofol is the preferred sedative when rapid awakening is important (eg, for neurosurgical assessment or extubation).

– Midazolam is recommended for short-term use only, as it produces unpredictable awakening and time to extubation when infusions continue for more than 48–72 hours.

– Lorazepam is recommended for the sedation of most patients via intermittent IV administration or continuous infusion.

– Triglyceride concentrations should be monitored after 2 days of propofol infusion, and total lipid intake should be included in the nutrition support prescription.

—continued

124


ACCM Guidelines – 2002, cont’d.– The potential for opiate, benzodiazepine or propofol withdrawal

should be considered after high doses or more than approximately7 days of therapy. The dose should be tapered systematically toprevent withdrawal symptoms.

– Haloperidol is the preferred agent for the treatment of delirium in the critically ill patient.

– Patients should be monitored for ECG changes (QT prolongation and arrhythmias) when receiving haloperidol.

Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002; 30:119-141.

125

Effect of Rational Use Guidelines

Implementation ofGuideline Policy

Before After(Days) (Days)

Hospital LOS 34.3 23.3

ICU LOS 19.1 9.9

Duration ofmechanical ventilation 13.0 7.0

LOS = length of stay.Adapted from Mascia et al. Crit Care Med. 2000;28:2304.

126

Assessing the Degree of Sedation: The Riker Sedation-Agitation ScaleSedation /

Agitation Level DescriptionDescription

1

2

3

4

5

6

7 Dangerous agitation : pulls at ET; tries to remove catheters; limbs over bedrail; strikes staff; thrashes from side to side

Very agitated; does not calm, despite frequent verbal reminding of limits; requires physical constraints; bites ET

Agitated: anxious or mildly agitated; attempts to sit up; calms down to verbal instructions

Calm and cooperative: calms, awakens easily; follows commands

Sedated: 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 notcommunicate or follow commands

Jacobi J et al. Crit Care Med 2002;30:119-41

127

Continuous vs Intermittent Sedation in the Patient with Severe Sepsis

Continuous sedation (without active titration or tapering)

–May prolong mechanical ventilation with:

Increased ICU stayIncreased risk of nosocomial pneumonia

Intermittent sedation– Daily interruption to

wakefulness– Reduces duration of

mechanical ventilation– Decreases ICU stay– Facilitates examination– Reduces diagnostic studies

Kollef MH, et al. Chest 1998;114:541-8.Kress JP, et al. N Engl J Med 2000;342:1471-7.

128

Prompt Extubation: Reduced Cost and Length of Stay

Example: CABG (n=100)

Study arms:

– Early extubation (1 to 6 hr)

– Late extubation (12 to 22 hr)

Results:

– ↓ total costs by 25%

– ↓ ICU costs by 53%

– ↓ hospital and ICU lengths of stay

– Shifts high ICU costs to lower ward costs

– Improves resource utilization; increases throughput

Cheng DCH et al. Anesthesiology. 1996;85:1300-1310.

129

In Conclusion…

NonpharmacologicTreatment

NonpharmacologicTreatment

Sleep Promotion

Sleep Promotion

CombinationTherapy

CombinationTherapy

EnvironmentalControl

EnvironmentalControl

NursingCare

NursingCare

AnalgesiaAnalgesia

PhysicianManagementPhysicianManagement

SedationSedation DeliriumControl

DeliriumControl

130

Future Directions

Expanded role for dexmedetomidine?As medications come off patent:– Role for sufentanil in ICU?

Ethuin et al, Intensive Care Med. 2003 Nov

– Role for remifentanil in ICU?Muellejans et al, Crit Care. 2004 Feb

Constantly changing landscape — some generics get more expensive as time goes on.Increased titration of sedatives

131

Add- on Slides

132

Dexmedetomidine May Facilitate Early Extubation

No respiratory depressionPatient is arousableAblation of neurohormonal stressSynergy with anesthetics and analgesics– Lower doses of anesthetics and analgesics

Pain control without the sedating effects of opioidsLess use of diureticsFacilitates daily wake-up for longer term intubated patientsHerr. 2003; in press.

133

Failure to Wean From the Ventilator:Advantages of Dexmedetomidine

Transitioning from propofol to dexmedetomidine

Does not cause respiratory depressionActivates natural sleep pathways; patient is easily arousedMay facilitate weaning patients off the ventilatorMaintains adequate sedation and calmness after extubationFacilitates assessment of patient comfort and pain levels

134

Head Injury: Issues

Difficulty achieving awakening state– Increased hippocampal blood flow– Release of catecholamines– Decreased GABA activity; increased neuronal activity

The “hyperadrenergic syndrome”– Tachycardia– Hypertension– Hyperventilation– Sweating– Muscle rigidity– Elevated ICP

135

Head Injury: Sedation

Issues with head injury patientsFrequently agitated or combative

– Must be sedatedPeriodic neurologic assessments needed

– Patient must be cooperative

Use of dexmedetomidineCan be used as primary agentProvides cooperative sedationTitrate to effectBlunt hyperadrenergic response

136

Use of Dexmedetomidine in the Burn Unit

Alpha-2 agonist effect greatly assists in the management of burn patients; includes blunting of catecholamine surgeUse in intubated and nonintubated burn patientsAdminister as a standard load once patient is euvolemic(range: 0.4 to 0.7 mcg/kg)Lower dose (range) for less severe burns and nonintubatedpatients

– 0.2 to 0.4 mcg/kg for routine burn care– 0.6 mcg/kg for delicate patients

137

Dexmedetomidine Protocol for Trauma

Initiation of dexmedetomidine– Loading dose: none– Gradual step-up in dose based on heart rate– Titrate to sedation scale

Lower doses (<0.7 mcg/kg/hr)– Adequate for non-CNS injury

Higher doses (<2.0 mcg/kg/hr)– Agitation associated with CNS injury – Withdrawal from alcohol or other drugs

138

Alcohol Withdrawal and Trauma

Spinal cord injury occurs mostly in males who are intoxicatedExperience agitation; at risk for exacerbating underlying injuryBenzodiazepines are typically used

– Intubation and ventilation are often requiredDexmedetomidine is an alternative

– Spontaneous breathing– Hemodynamic stability– Adequate sedation– Prevention of autonomic effects of withdrawal– Pain control

139

Summary

Overall goals of sedation are to increase patient safety and comfort and facilitate managementBoth undersedation and oversedation are associated with deleterious consequencesDexmedetomidine can help optimize sedation and patient care via:

– Unique mechanism of action on natural sleep pathway that permitspatients to be well rested yet easily aroused

– Synergism with other agents, resulting in significant dose reductions– Pain control and no respiratory effects

Keys to success include appropriate patient selection and properadjustment of protocols

140

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