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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.
4
Pain !!!
5
Adverse Effects of Pain
Psychological
Respiratory
Cardiovascular
Gastro-intestinal
Neuro-endocrine
Metabolic
6
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
8
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
10
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.
11
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
13
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
14
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
15
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.
16
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
17
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.
18
Anxiety in the ICU
Causes– Pain– Environment– Sleep deprivation– Drug withdrawal
Effects – Agitation delirium psychosis PTSD– CVS
BP; HR – Sleep deprivation
19
Sleep Deprivation
Average amount of
sleepin the ICU is 1 hour, 51
minutes per 24 hours
Aurell, Elmqvist. BMJ. 1985;290:1031.
20
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.
22
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.
23
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.
24
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.
25
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)
26
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.
27
The Perfect Sedative in the ICU
Provides– Sedation / Anxiolysis– Analgesia– Amnesia
No effect on cardiovascular functionRapid onset and offsetMinimal respiratory depressionNo or inactive metabolites
28
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!
29
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
30
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.
31
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.
32
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.
34
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
35
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.
36
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.
37
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
38
Analgesics – Fentanyl vs Morphine
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.
39
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
Analgesics – Fentanyl vs Morphine
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
Eur J Clin Pharmacol (2002)58: 73-77
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
46
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
54
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
55
Not All Good News…...
56
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
57
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
58
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
64
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
Sedative-HypnoticsAvailable Agents
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
Sedative-HypnoticsAvailable Agents
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
Sedative-HypnoticsAvailable Agents
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.
83
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
Eur J Clin Pharmacol (2002)58: 73-77
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
The Fine Balance in Patient Comfort
AnxietyAgitation
HypertensionTachycardiaArrhythmias
Myocardial ischemiaWound disruption
Patient injury
104
The Fine Balance in Patient Comfort
DepersonalizationDelayed emergenceDelayed weaning
Pressure injuryVenous stasisMuscle atrophyIncreased cost
105
Choosing the Right DrugCombination
106
SedationSedationSedation
HypnosisHypnosis AnxiolysisAnxiolysisAmnesiaAmnesia
AnalgesiaAnalgesiaAnalgesia
R Sladen, ASA 2001
107
SedationSedationSedation
HypnosisHypnosis AnxiolysisAnxiolysisAmnesiaAmnesia
Patient ComfortPatient ComfortPatient Comfort
AnalgesiaAnalgesiaAnalgesia
R Sladen, ASA 2001
108
SedationSedationSedation
HypnosisHypnosis AnxiolysisAnxiolysisAmnesiaAmnesia
AnalgesiaAnalgesiaAnalgesia
OpioidsOpioids
R Sladen, ASA 2001
109
SedationSedationSedation
HypnosisHypnosis AnxiolysisAnxiolysisAmnesiaAmnesia
AnalgesiaAnalgesiaAnalgesia
BenzodiazepinesBenzodiazepines
R Sladen, ASA 2001
110
SedationSedationSedation
HypnosisHypnosis AnxiolysisAnxiolysisAmnesiaAmnesia
PropofolPropofol
AnalgesiaAnalgesiaAnalgesia
R Sladen, ASA 2001
111
HypnosisHypnosis AnxiolysisAnxiolysisAmnesiaAmnesia
α2 Agonistsα2 Agonists
SedationSedationSedation AnalgesiaAnalgesiaAnalgesia
R Sladen, ASA 2001
112
AnalgesiaAnalgesiaAnalgesiaSedationSedationSedation
DexmedetomidineDexmedetomidine Primary
AdjunctSedation
Midazolam
R Sladen, ASA 2001
113
SedationSedationSedation AnalgesiaAnalgesiaAnalgesia
DexmedetomidineDexmedetomidine Primary
Propofol AdjunctSedation
R Sladen, ASA 2001
114
SedationSedationSedation AnalgesiaAnalgesiaAnalgesia
FentanylFentanyl AdjunctAnalgesia
DexmedetomidineDexmedetomidine Primary
R Sladen, ASA 2001
115
SedationSedationSedation AnalgesiaAnalgesiaAnalgesia
MorphineMorphine AdjunctAnalgesia
DexmedetomidineDexmedetomidine Primary
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
Goals of Sedation in the ICU
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
Goals of Sedation in the ICU
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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