Sedation in the Intensive Care Unit: a general overview

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Sedation in the Intensive Care Unit a general
overview

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Current Forces in Critical Care

• Institute of Medicine criteria for quality
• Patient-centered relevant outcomes define right
  care
• Effective the right care
• Safe the right care all the time
• Timely the right care at the right time
• Efficient the right care and only the right
  care
• Equitable the right care for everyone

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Death Caused by Physical Restrains Steven
H.(1992) The Gerontologist
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  (Lusis, 2000)

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  (Gerald,2003)

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Agitation Stress hormone

• Preexisting diseases (pancreatitis)
• Invasive procedures, or trauma.
• Monitoring and therapeutic devices (such as
  catheters, drains, noninvasive ventilating
  devices, endotracheal tubes)
• Routine nursing care (such as airway suctioning
  ,physical therapy, dressing changes, and patient
  mobilization)
• Prolonged immobility

• Inadequate sleep
• Agitation
• Possibly causing exhaustion and disorientation.
• Evokes a stress response characterized by
  tachycardia, increased myocardial oxygen
  consumption, hypercoagulability,
  immunosuppression, and persistent catabolism
• NE ,Epi ,Glucogan ,ADH , Renin, Crotsol,
  Aldosterone, Serotonin, bradykinin, Prostagladin

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Pain assessment

• Visual analogue scale (VAS)
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• Numeric rating scale
• 0-10 ??????(0-10 numeric rating scale) (Geret
  al., 1999 Ger et al., 2004)
• Behavioral-physiological scales
• Family assessment
• Verbal rating scale

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Pain rating scale

• 1. Simple descriptor scale
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• 2. 0-10 numeric rating scale
• 3. Visual analog scale (VAS)
• 4. Faces rating scale

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Behavioral-physiological scale

• Observation of pain-related behaviors
• Movement, facial expression, posturing
• Physiological indicators
• HR, BP, RR

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How to do pain control

• Set the goal and plan of analgesia
• Opioid fentanyl, hydromorphine, morphine
• Scheduled opioid dose/ continuous IV better than
  as needed
• Hemodynamic instability, renal insufficiency
  fentanyl, hydromorphine

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Patient-controlled analgesia vs conventional pain
control
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A response from the past Morphine (and its
side-effects)

• ? Active metabolites accumulation
• ? Constipation
• ? Respiratory depression

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????????????????????
?? ????? ???? ?????? Morphine
2-4 h 30 min 1-4mg
bolus
1-10mg/h infusion Fentanyl
2-5 h 4 min
25-100µg bolus
25-200µg/h
infusion Hydromorphone 2-4 h
20 min 0.2-1mg bolus

0.2-2mg/h infusion Ketamine 2-3 h
30-60 sec 1-2µg/kg/min infusion
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Fentanyl patch

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• 2005/7/15 FDA Issues Public Health Advisory
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• Fentanyl patch???????????????????????????
  Fentanyl patch????????????????????(??????opioids??
  ??)???,????????????????????????

FDA Public Health Advisory 2005/07/15
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Delirium an acutely changing or fluctuating
mental status, inattention, disorganized
thinking, and an altered level of consciousness
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Delirium and Critical IllnessBrain Syndrome

• Rates of delirium in non-critical care setting
  are around 10 to 20
• Rates of delirium in critical care settings are
  around 60 to 80
• Rates of acquired dementia-like critical
  illness brain syndrome following ICU care exceed
  50 With an increasing proportion of inpatient
  critical care beds

1. Inouye et al, NEJM 1999340669-676 2. Ely et
al, JAMA 2004291-1753-1762
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1.Ely, Shintani, Speroff, JAMA 20032892983-91

2.Milbrandt, Crit Care Med 200432955-962
1.delirium was associated with a 3-fold higher
rate of death by 6 months 2. 1.6-fold increase
in ICU costs, and 10-fold higher rate of
cognitive impairment at hospital discharge
(plt0.001)
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Risk Factors, Prevention,and Treatment

• Aging
• Baseline dementia
• Underlying illness
• Inflammation
• Coagulation
• Metabolic disturbances

• Hypoxemia
• Genetic Predisposition
• Psychoactive Medications
• Sleep Deprivation

Inouye, JAMA 1996275852-57 Dubois, Intens Care
Med 2001271297-1304 Inouye, NEJM
1999340669-676 Jacobi, Crit Care Med
200230119-141 Milbrandt, Crit Care Med.
200533226-9
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1st prevent... 2nd treat ICU delirium

• Treat underlying infection and CHF
• Correct metabolic disturbances and hypoxemia
• Goal-directed delivery of sedation/analgesia
• Frequent reorientation of patient by nurse and
  family
• Stop the ventilator each day to test readiness
  for liberation
• Early mobilization and physical therapy
• Attention to optimizing sleep patterns

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Haloperidol

• Commonly given via intermittent i.v. injection
• The optimal dose and regimen of haloperidol have
  not been well defined.
• Haloperidol has a long half-life (1024 hours)
  and loading regimens are used to achieve a rapid
  response in acutely delirious patients
• IM?IV 2-5 mg loading, M 5 mg /h

• Eric Milbrandt ESICM 17th Annual Congress
  Abstract 251. Presented Oct. 11, 2004
• Haloperidol Improves Survival in Mechanically
  Ventilated, Critically Ill Patients
• Haloperidol has anti-inflammatory effects on
  cytokines by mean dose of 11.5 ( 11.6) mg/day
  for a mean period of 3.5 ( 4.6) days record
  1,095 ICU patients during the past year that were
  mechanically ventilated for a period of longer
  than 48 hours

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Agitation

• Patients factors
• Environmental
• People
• Drugs and devices
• Technology

• ? pain
• anxiety
• VO2 increase
• respiratory drive
• sleep disturbances

Measures process (Ramsay scale) and
communication
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Goals of Analgo-Sedation

• ? Ability to tolerate physical enviroment
• ? Ability to tolerate ICU procedures
• ? Prevention/reduction of stress
• ? Patient safety

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Sedation-agitation scale-I

• 7. Dangerous agitation
• Pulling ET tube, cath, climbing over bed rail,
  striking at staffs, thrashing side to side
• 6. Very agitated
• Not calm, depite frequent verbal reminding of
  limits, requires physical restraints, bites ET
  tube
• 5. Agitated
• Anxious ormildly agitated, attempting to sit up,
  calms down to verbal instructions

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Sedation-agitation scale-II

• 4. Calm and cooperative
• Calm, awakens easily, follows commands
• 3. Sedated
• Difficult to arouse, awakens to verbal stimuli or
  gentle shaking but drifts off again, follows
  simple commands
• 2. Very sedated
• Arouses to physical stimuli but does not
  communicate or follow commands, may move
  spontaneously
• 1. Unarousable
• Minimal or no response to noxious stimuli, does
  not communicate or follow commands

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Ramsay Sedation Scale

• Level of sedation
• 1. Patient is anxious and agitated
• Patient is cooperative, oriented and tranquil
• 3. Patient responds to command only
• 4. Patient exhibits brisk response to light
  glabellar tap or loud auditory stimulus
• 5. Patient exhibits a sluggish response to
  light glabellar tap or loud auditory
  stimulus
• 6. No response to stimuli

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Why should we adopt sedation scoring?
Objective assessment and close, prospective
control of the level of sedation
DeJonghe B et al Using and understanding
sedation scoring systems A systematic review.
Intensive Care Med 2000 26 275285 Brook AD et
al Effect of a nursing-implemented sedation
protocol on the duration of mechanical
ventilation. Crit Care Med 1999 2726092615
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Advantages of Sedation scales
? No risk of over-sedation and under- sedation ?
Optimal end-point for titration of sedation ?
Prospective management of care ? Comparability of
drugs effects
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Over-sedationdrawbacks

• ? Respiratory depression
• ? Hypotension
• ? Bradycardia
• ? Venous stasis
• ? Increased lenght of ventilation
• ? Increased ICU lenght of stay
• ? Increased costs
• ? Failure to evaluate CNS alterations

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Society of Critical Care Medicine
morphine Analgesics fentanyl hydro
morphone midazolam Sedatives propofol
lorazepam Anti-delirium haloperidol
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benzodiazepine
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lorazepam

• 2 mg bolus iv
• 2mg /h for 7 days
• Residual lorazepam effect gt 3 days after
  discontinuation of the infusion
• Lorazepam solvent polyethtlene glycol (PEG),
  propylene glycol (PG)
• Lactic acidosis
• Acute tubular necrosis

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Midazolam

• Anterograde amnesia??????????,????????????????,?
  ???
• ??(Metabolism)
• Midazolam????????????????????-hydroxy-midazol
  am???40-50??????????
• ??(Elimination)
• ????????????1.5-2.5??,??????300-400??/????????
  midazolam,???????bolus??????????????-hydroxy-midaz
  olam??????????????????glucuronic
  acid??(???)????????
• 60??????????????????,?????????midazolam???????ICU?
  ?,????????????????????,????????????????
• ????????????(reduced hepatic function)????????????
  ???

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Midazolam

• Midazolam?????????(???cytochrome P450
  IIIA)????????????????????????midazolam??????,?????
  ??????????,????????? titeate ???
• ???? ????
• ketoconazole (Olkkola et al., 1994)
• fluronazole (Ahonen et al., 1999)
• itraconazole (Olkkola et
  al., 1993)
• erythromycin (Olkkola et al., 1994)
• diltiazem (Backman et al., 1994)
• verapamil (Backman et al., 1994)
• cimetidine (Sanders et al., 1993 Kanto
  et al., 1983),

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benzodiazepine (Pharmacology)

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• Anxiolytic effect Conflict
  test Valium Dormicum 1 1
• Sedative effect Conflict test Valium Dormicum
  1 2
• Irritation threshold Anger reaction Valium
  Dormicum 1 2
• Muscle relaxant Pole-climbing test
  Valium Dormicum 1 1
• Anticonvulsant Standard test Valium Dormicum
  1 1
• Data from F. Hoffmann La Roche Ltd., Basel,
  Switzerland

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Anexate(Flumazenil)

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• Benzodiazepin????????????????
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Midazolam-Induced Sedation for Upper
Gastrointestinal Endoscopy Assessment of
Endoscopist and Patient Satisfaction Anterograde
amnesia

• 352 patients upper gastrointestinal endoscopy
  were sedated with midazolam given
• Ages of the patients ranged between 16 and 79
  years (average 41.6 12.7 years).
• Anterograde memory was found in 310 (88.0)
• 342 patients (98.0) cooperated well
• Side effects were rarely seen (3.6), and
  included nausea, vertigo, and vomiting
• Acceptability of further endoscopy in 338
  (96.0)
• No significant cardiopulmonary problems
• Gastroenterology Nursing Volume 26(4)
  July/August 2003 pp 164-167

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Lorazepam vs Midazolam Infusion data
Prospective randomized trial
Lorazepam (n10) Midazolam (n10) p-value
Time to achieve adequate initial sedation (min) 124 ? 168 105 ? 101 NS
Infusion rate at point of initial sedation (mg/kg/hr) 0.06 ? 0.05 0.15 ? 0.15 NS
Maximum infusion rate (mg/kg/hr) 0.1 ? 0.06 0.29 ? 0.20 0.006
Mean infusion rate (mg/kg/hr) 0.06 ? 0.04 0.24 ? 0.16 0.004
Total time of infusion (hr) 77 ? 66 108 ? 60 NS
Total drug administered (mg/kg) 5.4 ? 7.0 23.3 ? 19.0 0.01
Pohlman A.S., et al. Crit Care Med 1994 22
1241-1247
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Lorazepam vs Midazolam
Time to achieve adequate sedation
Time of neurologic recovery
p NS
p NS
4000
300
250
3000
200
2000
Time (mins)
150
100
1000
50
0
0
Midazolam
Lorazepam
Midazolam
Lorazepam
Pohlman A.S., et al. Crit Care Med 1994 22
1241-1247
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Propofol vs Midazolam Effectiveness of sedation
n97
First hour of treatment
After first hour of treatment

p NS
plt 0.01
80
70
70
60
60
50
50
40
Assessments
40

30
30
20
20
10
10
0
0
Effective
Acceptable
Ineffective
Effective
Acceptable
Ineffective
Chamorro C., et al. Crit Care Med 1996 24
932-939
midazolam
propofol
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Propofol vs Midazolam Monitoring the patient
state of sedation
Prospective randomized multicenter trial
n97
80
plt 0.05
70
60
50
Assessments
40
30
20
10
0
Very easy
Easy
Moderate
Difficult
Chamorro C., et al. Crit Care Med 1996 24
932-939
propofol
midazolam
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Sedation in the general ICUSpeed of recovery
after sedation
1. Chamorro C et al. 1996. 2. Aitkenhead C et al.
1989. 3. Wolfs C et al. 1991.
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Hemodynamic Effects of Midazolam and Propofol

• Parameter Midazolam Propofol Comment Ref
• BP, 1st hr incr 21 decr 17 1
• SBP decr 12 decr 24 p lt 0.01 2
• MAP NC decr 17 3
• MAP NC decr 33 4
• Decr SBP 31 pts 68 pts decr gt 20 5
• Propofol (1-2.5 mg/kg bolus, then 3 mg/kg/h)
  decreased MAP by 43, CI by 23, SVRI by 30
  6
• 1.. Boeke et al. J Drug Dev 1989 2. Geller et
  al. Anesthesiology 1991
• 3. Kox et al. Br J Anaesth 1990 4. Pappagallo et
  al. Minerva Anest 1992
• 5. Weinbroum et al. ICM 1997
  6. Martin et al. Acta Anaesth Scand ?4

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Sedation of the ICU patients during mechanical
ventilation propofol or midazolam?

• ? Propofol and midazolam achieved optimal
  sedation when administered by specified dosing
  protocol
• ? Propofol had a faster awakening time
• ? Time to sedation was not significantly
  different
• VO2 decreased similarly in both groups

Propofol is the preferred sedative when rapid
awakening (e.g., for neurologic assessment or
extubation) is important. (Grade of
recommendation B)
Kress J., et al. AJRCCM 1996 153 1012-1018
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• propofol did not produce amnesia as often as
  midazolam . Like the benzodiazepines, propofol
  has no analgesic properties.
• Provides 1.1 kcal/mL from fat and should be
  counted as a caloric source. Long-term or
  high-dose infusions may result in
  hypertriglyceridemia
• Pancreatitis has been reported following
  anesthesia
• Prolonged use (48 hours) of high doses of
  propofol (66 g/kg/min infusion) has been
  associated with lactic acidosis, bradycardia, and
  lipidemia in pediatric patients -FDA against
  the use for the prolonged sedation
• incidence of infectious complications---no more
  than 12 hours

Clinical practice guidelines for the sustained
use of sedatives and analgesics in the critically
ill adult Crit Care Med 2002 Vol. 30, No. 1
66
Continuous IV Sedation and Duration of Mechanical
Ventilation

• Patients receiving continuous IV sedation
• younger
• lower PaO2/FIO2
• more ARDS
• more chemical paralysis
• CIVS had longer LOSs after adjustment for age,
  SOI, mort, MV indication, paralysis, trach, OSF

p lt 0.001, p 0.007
Kollef MH, et al. Chest 1998114541
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Complications of Sedative Medications

• Cardiovascular alterations
• Respiratory depression, apnea
• Prolonged sedation
• The titration of the sedative dose to a defined
  endpoint is recommended with
• systematic tapering of the dose or daily
  interruption with retitration to
• minimize prolonged sedative effects. (Grade of
  recommendation A)
• Tolerance and tachyphylaxis
• Withdrawal Sx
• Drug-specific
• Propofol Increased triglycerides
• Lorazepam precipitation

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Short-term sedation (24-48 H)

• Status asthmaticus
• COPD with acute exacerbation, but without sepsis
• Agitation due to mechanical ventilation without
  major sepsis
• Delirium in ICU
• Severe CAP, acute respiratory failure, unable to
  tolerate ET tube

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What drugs for short-term sedation

• Midazolam 2-5mg iv until acute exacerbation event
  controlled
• Check the indication of sedation on 2nd and 3rd
  day
• Stop
• Tappering
• Switch to long-term sedation

Midazolam is recommended for shortterm use
(Grade of recommendation A)
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Long-term sedation (gt 72 H)

• Severe sepsis and septic shock
• ARDS with refractory hypoxemia
• Prone position

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What drugs for long-term sedation (1)

• Midazolam 2-5mg iv q515 min until acute event
  controlled
• Start continuous midazolam, titrated to the level
  of sedation
• Check the sedation level everyday
• Check the indication on 3rd and 4th day
• Stop or tappering
• Add lorazepam 1-2 amps q2-6 hours, tappering
  midazolam to the defined level of sedaiton

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What drugs for long-term sedation (2)

• On 6-10th days
• Tapering the lorazepam, depending on the
  indication of sedation
• Restarting the midazolam or propofol to replace
  the role of lorazepam
• Preparing the patient wake-up and weaning

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Summary
? Individualized approach to sedation ? Propofol
is useful for deeper level of sedation and more
rapid awakening ? Benzodiazepines should be used
to provide rapid amnesia (midazolam) or long-term
sedation (lorazepam) ? Randomized studies needed
to investigate safety profile/cost-efficiency of
new generation-opioids, that present promising
aspects
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Dexmedetomidine Underused for Anesthesia,
Sedation

• The alpha-2 agonist is a sedative with analgesic
  and anxiolytic properties. It was granted FDA
  approval
• SCCM 35th Critical Care Congress Situational
  Sedation and Analgesia, presented January 9,
  2006 abstract
• Approximately 70 of the audience indicated that
  they never used the agent
• used in combination with propofol, opioids, and
  anxiolytic agents

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Dexmedetomidine

• respiratory stability and easy routine stability
• slow the heart rate, the hemodynamic response is
  predictable
• "there is no need to discontinue the drug prior
  to extubation."
• No loading dose is required with the drug
• High dosage cause significant bradycardia and
  hypotension
• need to use caution when administering it to
  patients with hypovolemia or heart block
• very expensive
• more pain and discomfort and poorer sleep quality
  than other sedatives, such as propofol

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• dexmedetomidine in 39 children admitted to the
  pediatric intensive care unit (PICU) after heart
  surgery between October 2004 and June 2005
• ranged in age from 3 months to 18 years

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• 92 of the patients needed no supplemental
  medication with fentanyl, midazolam, or other
  sedative agents while receiving dexmedetomidine,
• 79 received minimal or no supplemental analgesia
• Reduction in systolic blood pressure was less
  than 8 and heart rate reduction was less than
  12 in the first 4 hours
• no appreciable hemodynamic changes
• no evidence of respiratory depression
• no cases of rebound or withdrawal after either
  weaning or abrupt discontinuation of the drug
• Survival was 100.

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• ???????????????????????,??diazepam,???????????????
  ,???????????dexmedetomidine

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