PACT ModuleSedation

Intensive Care Training ProgramRadboud University Medical Centre Nijmegen

Important concepts

• Prolonged use of sedatives associated with significant side effects - “drug holiday” & sedation scales

• The concept op analgosedation

• Dexmedetomidine and delirium

• Sleep deprivation

The four step model of sedationWhat is the main

problem?

Is sedation the best solution?

How long is sedation necessary?

Give the medication with the ideal profile

Renal failure

• Midazolam ↑↑

• Lorazepam =/↑

• Morphine ↑↑

• Fentanyl =/↑

• Remifentanyl =

• Propofol =/↑

• Dexmedetomidine ↑

Fospropofol

Propylene glycol toxicity

• 19% of patients receiving iv diazepam or lorazepam

• Clinical deterioration, unexplained meta-bolic acidosis with increased anion gap and hyperosmolality, lactic acidosis, hypotension

• Treatment with alcohol infusion combined with hemodialysis or 4-methylpyrazole

Wilson KC. Chest 2005;128:1674-1681

Propofol infusion syndrome

• Bradycardia and cardiac failure

• Metabolic acidosis

• Hyperkalemia

• Rhabdomyolysis

Stop sedatives every day

Medical ICUPregnancy and CPR excluded

Daily stopN = 68

ConservativeN = 60

PropofolN = 31

MidazolamN = 37

Morphine Morphine

PropofolN = 31

MidazolamN = 29

Morphine Morphine

Ramsay 3-4

Length of MV, ICU and HospitalAccumulative dose sedative + complications

Kress JP. NEJM 2000;342:1471-1477

Daily sedative stop

0

5

10

15

20

Duration MV ICU stay Hospital stay

13,0

6,0

4,0

16,0

9,0

7,0

Conservative Daily stop

Day

s

Daily sedative stop

0

5.000

10.000

15.000

20.000

Midazolam Propofol Morphine

Midazolam conservative Midazolam daily stopPropofol conservative Propofol daily stop

Conservative Daily stop

Days awake (%) 9 85.5

CT scan or neurological test

16 6

Auto-extubation 2 4

Tracheostomy 12 16

Complications

Delier and PTSDConservative

(n = 19)Daily stop(n = 13) P-value

Total impact of events score

27.3 ± 19.2 11.2 ± 14.9 0.02

Avoidance subscale score

15.7 ± 10.5 7.8 ± 9.2 0.02

PTSD 6 0 0.06

Recollection of awakening

5 0 0.06

PAIS T score 54.3 46.8 0.08

Awakening and Breathing Controlled trial

• MC (N = 4) RCT comparing daily SAT + SBT versus patient-targeted sedation + SBT

• Adult patients ≥ 18 years old with MV > 12 hours

• Excluded if admitted after CPR, MV > 2 weeks, moribund or profound neurological deficit

• Primary outcome: ventilator-free-days (D28)

Girard TD. Lancet 2008;371:126-134

Girard TD. Lancet 2008;371:126-134

120 minutes

N = 168

N = 167

Awakening and Breathing Controlled trial

• No baseline differences between groups

• SAT/SBT group had 3.1 (0.7 - 5.6) more ventilator-free days compared to control group

• They were discharged 4.3 days earlier from the hospital and had a decreased 1 year mortality rate (44 versus 58%)

Girard TD. Lancet 2008;371:126-134

Awakening and Breathing Controlled trial

• Similar duration of delirium but 1 day less coma in SAT/SBT group

• Increased incidence of self-extubation (10 versus 4%) but similar rate for requiring reintubation

• Tendency to decreased tracheostomy (13 versus 20%, p = 0.06)

Girard TD. Lancet 2008;371:126-134

Girard TD. Lancet 2008;371:126-134

Daily interruption versus no sedation• Expected duration of MV > 24 hrs

• No sedation (N=70) vs propofol/midazolam with daily interruption (N=70)

• Both groups bolus doses of morphine

• Primary outcome: ventilator free days at D 28

StrØm T. Lancet 2010;375:475-480

Daily interruption versus no sedation

0

7,5

15,0

22,5

30,0

No sedation Daily interruption

9,6

13,9

Vent

ilato

r fre

e da

ys a

t D 2

8Difference 4.2 days (95% CI 0.3 - 8.1, p = 0.02)

Shorter LOS ICU and Hospital but higher incidence agitated delirium (20 vs 7%)StrØm T. Lancet 2010;375:475-480

Frontal EMG monitoring

• BIS and EntropyTM confounded by frontal EMG activity

• Development of Responsiveness Index (RI 0 = completely unresponsive, 100 = fully responsive) based on frontal EMG responsiveness

• Development set (N = 30) - Test set in cardiac surgery patients (N = 15)

Walsh TS. BJA 2011;107:710-718

Development

Test

Walsh TS. BJA 2011;107:710-718

SE - state entropyRE - response entropy

Walsh TS. BJA 2011;107:710-718

Dexmedetomidineα2 adrenoreceptor agonist

• Sedation and anxiolysis via receptors within locus ceruleus

• Analgesia via receptors in the spinal cord

• Attenuation of the stress response without significant respiratory depression

N = 106

Sedation up to 5 days

Pandharipande PP. JAMA 2007;298:2644-2653

% patients within 1 point target RAAS score

N = 106

Pandharipande PP. JAMA 2007;298:2644-2653

Dexmedetomidine and delirium prevalence

Riker RR. JAMA 2009;301:489-499

Dexmedetomidine and ICU length of stay

0

2

4

6

8

Time to extubation ICU length of stay

7,6

5,6 5,9

3,7Day

s

Dexmedetomidine Midazolam

Riker RR. JAMA 2009;301:489-499

Bradycardia most notable adverse effect

Antipsychotics for ICU delirium

Girard TD. Crit Care Med 2010;38:428-437

Antipsychotics for ICU delirium

Devlin JW. Crit Care Med 2010;38:419-427

N = 36

Remifentanyl

• Selective μ-opioid receptor agonist

• Rapid onset of action (1 minute)

• Metabolised by non-specific plasma esterases

• Context-sensitive half-time of 2-3 minutes independent of duration of infusion

Analgesic-based sedation in the ICU

Breen D. Crit Care 2005;9:R200-R210

Time to extubation

Tan JA. Anaesthesia 2009;64:1342-1352

Length of ICU stay

Tan JA. Anaesthesia 2009;64:1342-1352

Remifentanyl vs fentanyl during MV

N = 60Prospective Randomized Double Blind study

0

25

50

75

100

VAS ≤ 3 or BPS ≤ 6 Maintenace 90% of time Maintenance 80% of time

(%)

Remifentanil FentanylP = 0.44 P > 0.99 P = 0.09

Spies C. Intensive Care Med 2011;37:469-476

Primaryoutcome

No differences in duration MV, complications and LOSBehavioural Pain Scale

Sleep disturbances in the ICU

• Prolonged sleep latencies

• Sleep fragmentation and frequent arousals

• Decreased sleep efficiency

• Predominance of stage 1 & 2 NREM sleep

• Decreased or absent stage 3 & 4 NREM and REM sleep

Consequences

• Impaired immune function and host defense

• Protein catabolism with negative nitrogen balance

• Increased psychological disturbances and decrease in quality of life measures

Impaired immune function

• Infection results in increase in amplitude or intensity of slow-wave NREM sleep

• Sleep deprivation results in decreased PMN and lymphocyte counts, dysfunctional NK cells and PMN’s and impaired antigen speci- fic defenses

Sleep deprivation in ICU

Sleep deprivation

Patient careactivities

Lightning practicesDiagnostic procedures

Noise Sedatives & analgesics

Stress Psychosis

Organ dysfunction PainInflammatory

response

Pathophysiological factors

Environmental factors

Ventilator mode and sleep

Cabello B. Crit Care Med 2008;36:1749-1755

Effect of sedatives

• Benzodiazepines and propofol increase total sleep time by prolonging stage 2 sleep but they decrease SWS and REM sleep

• Zolpidem and zopiclone (γ-aminobutyric acid type A receptor agonists do not suppress SWS and have a less negative effect on REM sleep

• Dexmedetomidine enhances SWS

Sleep promotion in the ICU (1)

• Noise reduction‣ Individual patient rooms, ear plugs, monitor alarm settings, conversation

• Diurnal lightning practices‣ Reduce lightning during the night and use blindfolds

• Sleep promoting agents‣ zolpidem, zopiclone or gaboxadol (increases SWS), dexmedetomidine or

melatonin

Sleep promotion in the ICU (2)

• Avoid sleep reducing agents

• Benzodiazepines, opioids, inotropic agents, lipid soluble β-blockers, H2-receptor blockers, proton pump inhibitors, high-dose corticosteroids, β-lactam antibiotics, quinolones

• Adequate uninterrupted time for sleep

• Reduce nighttime assessment and monitor alarms