1. Mike Grounds Professor of Critical Care Medicine St George’s London
Sedation In ICU
Mike Grounds
Professor of Critical Care Medicine
St George’s London

2. “Sedation” from the Latin word “SEDARE” meaning:
to soothe, settle, calm, allay.

3. Sedation
The process of reducing the level of stress and anxiety to produce a calm and mental and physical state.

4. Uses of sedation To improve patient comfort/safety.
To allow compliance with therapy.
As part of a specific therapeutic event.
To reduce the stress response to being in ICU.
To produce amnesia.

5. Indications for Sedation
Mechanical ventilation
Coma
Sleep
Reduction of stress / fear/ anxiety
Intensive care agitation

6. PATIENT Non-pharmacological intervention Anxiety/Fear/Agitation
Psychological
Explanation
Reassurance / encouragement
Physical
Change environment
Touching/massage
Anxiety/Fear/Agitation
Illness/Depression
Environment
ICU Design
Noise
Hard bed
Other patients
Lighting
Insomnia
2 hrs/24 hrs
Fatigue
Disorientation
Pain/Discomfort
Post operative
Insertion of lines
Pharmacological Intervention
Analgesia
Opioids/opiates
“Nitrous oxide”/ketamine
Anaesthetics/hypnotics
Propofol
Ketamine
Dexmedetomidine
“Barbiturates”
“Volatile anaesthetic agents”
“Etomidate”
“Althesin”
Tranqillisers
Benzodiazepines (Midazolam)
Phenothiazines
Butyrophenones
Others
Antidepressants/antipsychotics
PATIENT

7. Anxiety/Fear/Agitation
Illness/Depression
Environment
ICU Design
Noise
Hard bed
Other patients
Lighting
Insomnia
2 hrs/24 hrs
Fatigue
Disorientation
Pain/Discomfort
Post operative
Insertion of lines

8. Illness
Routine/Emergency surgery, Trauma, Internal medicine
Curable / incurable
Anxiety
Anxiety, apprehension, panic
Exhaustion, disorientation, confusion
Elation at being alive
Denial of injury and illness
Anger
Problems with communication
Depression / withdrawal
Psychosis / toxic confusional state
Pain
Mechanoreceptors (fast)
Polymodal nociceptors (slow)

9. Psychological response to Intensive Care treatment
Anxiety. Apprehension. Panic.
Exhaustion. Disorientation. Confusion.
Problems of communication.
Noise.
Sleep deprivation

10. All patients suffer sleep deprivation
Noise
Lighting
24 hour nursing
Bently 1977: BMJ

11. Non-pharmacological intervention
Psychological
Explanation
Reassurance / encouragement
Physical
Change environment
Touching/massage

12. Non Pharmacological Measures to Reduce Stress in the ICU Patient
Reduce anxiety, panic, apprehension
Avoid exhaustion and confusion
Communicate
Design of unit
Real daylight
Windows
Reduce noise
Consider different types of artificial ventilation

13. Factors affecting type and effect of sedation
Critical illness
Age
Impaired elimination or detoxification of drug
Enhanced susceptibility to toxic effects of drugs
Liver enzyme induction
Analgesic requirements
Psychological state

14. PATIENT Non-pharmacological intervention Anxiety/Fear/Agitation
Psychological
Explanation
Reassurance / encouragement
Physical
Change environment
Touching/massage
Anxiety/Fear/Agitation
Illness/Depression
Environment
ICU Design
Noise
Hard bed
Other patients
Lighting
Insomnia
2 hrs/24 hrs
Fatigue
Disorientation
Pain/Discomfort
Post operative
Insertion of lines
Pharmacological Intervention
Analgesia
Opioids/opiates
“Nitrous oxide”/ketamine
Anaesthetics/hypnotics
Propofol
Ketamine
Dexmedetomidine
“Barbiturates”
“Volatile anaesthetic agents”
“Etomidate”
“Althesin”
Tranqillisers
Benzodiazepines (Midazolam)
Phenothiazines
Butyrophenones
Others
Antidepressants/antipsychotics
PATIENT

15. Sedation in the general ICU Patient types
Medical (e.g. pneumonia, adult respiratory distress syndrome, haematoncology, chronic obstructive pulmonary disease, asthma, cardaiac)
Postsurgical (e.g. abdominal, thoracic, orthopaedic, vascular, cardiac, neurosurgical)
Trauma (multiple, chest, head)
Miscellaneous (cerebrovascular accident, pancreatitis, septic shock, septicaemia, systemic inflammatory response syndrome, delirium tremens, alcohol poisoning, drug overdose) 15

16. Sedation in the general ICU Key issues
Patients who are intubated and mechanically ventilated experience pain, anxiety and other forms of discomfort
Some patients require a light level of sedation
Other patients may need a deep level of sedation
The ability to rapidly change the depth of sedation can be important 16

17. Sedation for less than 24 hours
Short term sedation will depend on local practice
There may be accumulation of sedative drug
Relatively small quantities of drug are used
Low levels of metabolites produced
Virtually any sedative agent can be used

18. Sedation for more than 24 hours
Problematic
Accumulation
Active / toxic metabolites

19. Patient groups with special needs
Head injuries
Cardiac surgery
Asthma stiff lungs/ARDS
Long term ventilation

20. Complications of over sedation
Hypotension
Bradycardia
Coma
Delirium
Failure to cough
Respiratory depression
Immunological depression
Deep vein thrombosis
Renal dysfunction
Ileus
Cost

21. Complications of under-sedation
Pain
Anxiety
Hypertension
Tachycardia
Hypoxia
Hypercarbia
Catheter displacement.

22. Overview Properties of an ideal sedative agent
The key properties of an ideal sedative agent include:
Rapid onset of action
Rapid offset of action
No effects on liver, kidney (inactive metabolites)
Cost-effectiveness
No drug interactions
Wide therapeutic margin 22

23. (Midazolam) Analgesia Opioids/opiates “Nitrous oxide”/ketamine
Anaesthetics/hypnotics Propofol
Ketamine
Dexmedetomidine
“Barbiturates”
“Volatile anaesthetic agents”
“Etomidate”
“Althesin”
Tranquillisers Benzodiazepines
(Midazolam)
Phenothiazines
Butyrophenones
Others Antidepressants/antipsychotics
Haloperidol - Chlorpromazine

24. Routes for administration for sedative and analgesic agents
Oral / nasogastric /gastrostomy
Rectal
Local analgesia
Subcutaneous
Intravenous

25. Intermittent bolus dose
Too much sedation
side effects may outweigh
potential benefits
Effective Range
Patient insufficiently
sedated
Time

26. Blood concentrations of drugs when given as either bolus dose or continuous infusion
Desired concentration of drug in the blood
Time

27. Context-sensitive half=lives of some commonly
used ICU sedative and analgesic agents
200
400
600
800
1000
1200
0.5 2 4 6 8 10
Time (hours)
Context sensitive half time (minutes)
Lorazepam
Midazolam
Propofol
Thiopentone
Alfentanil
Sufentanil
Fentanyl
Remifentanil
Dexmedetomidine
The Context-Sensitive Half-Time describes the time required for the concentration of drug in plasma to decline by 50% after terminating an infusion of a particular duration.
In particular note the context sensitive half times of propofol, alfentanil, and remifentanil

28. Daily Interruption of Sedative Infusions in Critically Ill Patients Undergoing Mechanical Ventilation
John P. Kress, M.D., Anne S. Pohlman, R.N., Michael F. O'Connor, M.D., and Jesse B. Hall, M.D.
Sedation stopped daily until patient awakening.
Sedation not stopped. Results in longer ventilation and longer stay in ICU.
Duration IPPV 7.3 days. ICU stay 9.9 days
Sedation stopped daily to stop accumulation
Results in shorter duration of ventilation
Duration IPPV 4.9 days. ICU stay 6.4 days
Figure 1. Kaplan–Meier Analysis of the Duration of Mechanical Ventilation, According to Study Group.
May 18, N Engl J Med 2000; 342:

29. Pharmacological Intervention Opioids/opiates
Analgesia
Opioids/opiates
Nitrous oxide/ketamine
Anaesthetics/hypnotics
Propofol
Ketamine
Dexmedetomidine
“Barbiturates” “Volatile anaesthetic agents”
“Etomidate” “Althesin”
Tranqillisers
Benzodiazepines (Midazolam)
Phenothiazines. Butyrophenones
Others
Antidepressants/antipsychotics

30. Morphine Alfentanil Remifentanil
Familiar, cheap, mood elevating - Provides safe analgesia for the critically ill
Respiratory depression, cough suppression
Provides safe analgesia for the critically ill
Metabolised in liver to M3 and M6 glucuronide. M6G is very potent analgesic. In liver and renal failure accumulation will occur
Alfentanil
Short acting agent given by continuous infusion - Pure analgesic, little or no sedative effect
Short action terminated by clearance of drug - Eliminated completely by hepatic transformation (P450)
Metabolites are said to be inactive - Short elimination half life
No accumulation with renal failure - Action may be prolonged in liver failure.
Very little cardiovascular depression
Remifentanil
potent ultra short-acting synthetic opioid analgesic
used for sedation - dose range 0.1 (µg/kg)/min to 0.5 (µg/kg)/min
remifentanil rapid hydrolysis by esterases. This means that accumulation does not occur, its context sensitive half life is 4 minutes after a 4 hour infusion.
causes a reduction in sympathetic tone, respiratory depression and analgesia - Dose-dependent decrease in HR and BP and RR.
Muscle rigidity is sometimes noted.

31. Morphine levels in plasma during sedation of critically ill patients12 11 10 9 8 7 6 5 4 3 2 1
Dose
normalized
plasma
conc
Renal failure
No renal failure
days of sedation
Lovstad et al
Clinical Intensive Care 1996

32. Which analgesics are preferable in mechanically ventilated patients?
Morphine good analgesic and mood elevating
metabolites (M6G & M3G) active
slow metabolism in renal failure
Remifentanil good analgesic
very rapid metabolism no accumulation; no active metabolites metabolized by non-specific esterases
The only effective strategy for avoiding overdose is a regular and intermittent trial of dosage reduction or suspension

33. Propofol Widely used in anaesthetics and ICU Short acting
Easy to control
Predictable and reliable
Rapid recovery
Mainly metabolised in liver to inactive products but also metabolised in blood
No active metabolites
Dose dependent decrease in SVR
Does not change cerebral autoregulation
Amnesic (less than midazolam)

34. Target plasma concentration while sedated
Decline of plasma Propofol concentration following ICU infusions of varying durations.
1.1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Plasma Propofol concentration (µg/mL)
Plasma concentration at which patient will wake up
10 day infusion
10 hour infusion
1 hour infusion
Professional Information Brochure FDA USA
Minute after end of infusion

35. Benzodiazepines Long acting Intermediate acting Short acting
Elimination half life greater then 24 hours
Diazepam, nitrazepam
Intermediate acting
Elimination half life 6 to 24 hours
Lorazepam, temazepam
Short acting
Elimination half life less than 6 hours
midazolam

36. Accumulation of Midazolam levels in plasma during sedation of critically ill patients
0.4
0.8
Midazolam
mcg / ml
Hydroxymidazolam
mcg / ml
days
Lovstad RZ et al
Clinical Intensive Care 1996

37. Sedation in the General ICU
Sedation in the General ICU. Propofol vs Midazolam Desired level of sedation
Patient type
Postsurgical,
medical, trauma1
Medical, trauma,
postsurgical,
miscellaneous2
medical, trauma3
Evaluable
patients
(n) 46 42 50 48 53 43
Duration of
infusion
Mean (range) (h) 81 88
(3-24)
(4-47)
Midazolam
Propofol
Desired level of sedation
“Adequate” based on Ramsay 2, 3, 4 or 5
“Effective” after first
hour; rating of synchrony
with ventilator and no
agitated movements
“Adequate” based on Ramsay 2, 3 or 4
(<24 to >500)
Time with adequate sedation(%) 93 82
76.5
66.2 94 73
p<0.01
p<0.05
p<0.01
1. Carrasco G et al
2. Chamorro C et al
3. Aitkenhead C et al

38. Sedation in the General ICU. Propofol vs Midazolam
Speed of recovery after sedation
Patient type
Medical, trauma,
postsurgical,
miscellaneous
Postsurgical,
medical, trauma
Postsurgical
(abdominal)
Evaluable
patients
(n) 32 18 21 17
Duration of
infusion
Mean (range) (h) 81 88 20
approx. 6h
Recovery time
Mean (min)
Midazolam
Propofol
Recovery
endpoint
Maximum level of consciousness
Weaning from ventilator
Spontaneous ventilation 23
137
p<0.05 5
148
p<0.001
16.4
85.2
p<0.01
(3-24) (4-47)
1. Chamorro C et al
2. Aitkenhead C et al
3. Wolfs C et al

39. Alpha 2 Adrenoreceptor Agonists (clonidine / dexmedetomidine)
CNS
Sedation / hypnosis / anaesthesia
Anxiolysis
Analgesia
CVS
Attenuates hypertension / tachycardia
Vasoconstricts at high doses
Other
Renal – diuresis / natriuresis
GI - decreases secretions

40. Dexmedetomidine vs Midazolam or Propofol for sedation during prolonged mechanical ventilation. Jakob, Ruokeonen, Grounds, Saraphoia, Pocock, Bratty, Takala. JAMA :
Lacks overt respiratory depressant effects
Can wean the patient from ventilator without completely stopping sedation. May be a bridge to extubation in difficult to wean patients
Possibly deceases the opioid requirements
May be useful in patients with drug dependency such as alcohol or opioid dependency
Metabolised in liver so beware in patients with liver disease
Care must be taken in patients with preexisting cardiac conduction defects, bradycardia, or hypovolemia.
May be a choice in patients who develop delirium
Prodex Study
Dexmedetomidine is no better and no worse than midazolam or propofol.
Dex had a shorter duration of ventilation when compared to midazolam but not when compared with Propofol
Patients were better able to communicate about their pain than propofol or midazolam
Greater number of adverse events were seen in Dex patients
Dexmedetomidine is safe and may be an alternative non-benzodiazepine agent to maintain LIGHT to MODERATE sedation

41. (possibly some analgesia)
SEDATION
ANALGESIA
Anxiolysis
Amnesia
Hypnosis
Ketamine
Propofol
Propofol
Midazolam. Lorazepam. Diazepam
Morphine
Morphine. Remifentanil
(possibly some analgesia)
Dexmedetomidine
Dexmedetomidine

42. Sedation Guidelines NO Reassess at least hourly YES Pain Sedation
Grounds 2018
Sedation Guidelines
Is the Patient Comfortable
Reassess at least hourly NO
YES
Non pharmacological intervention
Pain
Morphine Remifentanil
Sedation
Propofol midazolam dexmedetomidine
Delirium
Haloperidol/chlorpromazine
Stop all sedation and analgesia at least once a day restart when patient “wakes”

43. Thank You
For Listening.

44. On Behalf of the Sedation Committee of the Intensive Care Society,
Intensive Care Society Review of Best Practice for Analgesia and Sedation in the Critical Care
EDITORS: Tony Whitehouse, Catherine Snelson, Mike Grounds
CONTRIBUTING AUTHORS: Mike Grounds, Catherine Snelson, Tony Whitehouse, Jeremy Willson, Laura Tulloch, Lucie Linhartova, Anwar Shah, Richard Pierson, Kaye England
65 page carefully researched guidelines with 249 references
Published June 2014
On Behalf of the Sedation Committee of the Intensive Care Society,
United Kingdom