1. Sedation and analgesia in ICU
Dr. B. Uma
University College of Medical Sciences & GTB Hospital, Delhi

2. Sedation Sedation comes from the Latin word sedare.
Sedare = to calm or to allay fear
Conscious sedation: A minimally depressed level of consciousness induced by the administration of pharmacologic agents in which a patient retains the ability to independently and continuously maintain an open airway and a regular breathing pattern, and to respond appropriately and rationally to physical stimulation and verbal commands

3. Why is sedation necessary?
To improve patient comfort
Facilitate interventions
To allay fear, anxiety and agitation
Adequate sleep
Avoid pain
Facilitation of mechanical ventilation/airway management/ weaning
Protection against myocardial ischemia
Amnesia during neuromuscular blockade

4. Goals for sedation and analgesia
To minimize physical discomfort or pain during procedures
To minimize psychological disturbance
To maximize the potential for amnesia
To guard patient safety
To control behavior

5. Complications from pain and anxiety
Stimulation of the autonomic nervous system and release of humoral factors → increased heart rate, blood pressure, and myocardial oxygen consumption → myocardial ischemia or infarction
Altered humoral response can lead to hypercoagulability as a result of increased level of factor VIII, fibrinogen, platelet activity, and inhibition of fibrinolysis

6. Complications (contd.)
Stress hormones also produce insulin resistance, increased metabolic rate, and protein catabolism
Immunosuppression with reduction in number and function of lymphocytes and granulocytes
Psychological disturbances - memories of vivid nightmares, hallucinations, and paranoid delusions

7. Assessment of pain and anxiety
Any scoring system should be simple, easily performed, noninvasive, and reproducible. Six levels of sedation are used: 1. Anxious and agitated 2. Cooperative, orientated, and tranquil 3. Responds to verbal commands only 4. Asleep but brisk response to loud auditory stimulus/light glabellar tap 5. Asleep but sluggish response to loud auditory stimulus/light glabellar tap 6. Asleep, no response

8. Commonly used sedation tools
Glasgow coma scale (GCS) – assessment of level of consciousness
6 point Ramsay scale – most commonly used sedation scale
Sedation Agitation Scale (SAS)
Motor Activity Assessment scale (MAAS)
Richmond Agitation–Sedation Scale

9. Glasgow coma scale

10. GCS modified by Cook and Palma

11. Richmond agitation sedation scale
Score
Term
Description +4
Combative
Violent; immediate danger to staff +3
Very agitated
Pulls/ removes tubes, catheters; aggressive +2
Agitated
Frequent non purposeful movement; patient ventilator asynchrony +1
Restless
Anxious or apprehensive
Alert and calm -1
Drowsy
Not fully alert but awakens for >10s, with eye contact, to voice -2
Light sedation
Briefly awakens (<10s), with eye contact, to voice -3
Moderate sedation
Any movement to voice but no eye contact -4
Deep sedation
No response to voice but movement to physical stimulation -5
Unarousable
No response to voice or physical stimulation

12. Ramsay sedation scale
Awake 1 Anxious and/or agitated 2 Cooperative, oriented, and tranquil 3 Responds to commands Asleep 4 Quiescent with brisk response to light glabellar tap or loud auditory stimulus 5 Sluggish response to light glabellar tap or loud auditory stimulus 6 No response

13. Sedation agitation scale
1: Unarousable
2: Very sedated
3: Sedated
4: Calm and cooperative
5: Agitated
6: Very agitated
7: Dangerous agitation

14. Bispectral index
A practical, processed EEG parameter that measures the direct effects of sedatives on the brain
Provides objective information about a patient’s response to sedation
Numerical scale correlates to sedation endpoints
Optimizes sedation assessment and titration

15. BIS monitor
BIS sensor

16. BIS range guidelines

17. Objective sedation assessment
Value of BIS in ICU
Objective sedation assessment
Minimize
consequences
of over- and
under-sedation
Optimize clinical
and economic
outcomes
Improve quality of sedation management

18. Recommendation for Assessment of Sedation
The use of a validated sedation assessment scale (SAS, MAAS, or Vancouver Interaction and Calmness Scale [VICS]) is recommended. (Grade of recommendation = B)
The SCCM guidelines state: Objective measures of sedation, such as Bispectral Index, have not been completely evaluated and are not yet proven useful in the ICU. (Grade of recommendation = C)

19. Sedation therapy NON PHARMACOLOGICAL THERAPY:
Good communication with regular reassurance from nursing staff
Environmental control such as humidity, lighting, temperature, and noise
Explanation prior to procedures
Management of thirst, hunger, constipation, and full bladder
Variety for the patient e.g. radio

20. Pharmacologic therapy
The sedative agent should possess the following qualities:
Both sedative and analgesic properties
Minimal cardiovascular side effects
Controllable respiratory side effects
Rapid onset/offset of action
No accumulation in renal/hepatic dysfunction
Inactive metabolites
Inexpensive
No interactions with other ICU drugs

21. Pharmacologic therapy
Benzodiazepines
Propofol
Etomidate
Ketamine
Barbiturate
Short acting opioids
Alpha 2 agonists
Inhalational agents

22. Benzodiazepines
Anxiolytic, anticonvulsant, amnesic, hypnotic and provide some muscle relaxation
Effects are mediated by depressing the excitability of the limbic system via reversible binding at GABA-benzodiazepine receptor complex
Minimal cardiorespiratory depressant effect
The common drugs in this class are diazepam, midazolam, and lorazepam

23. Benzodiazepines: Midazolam
Water-soluble
Short elimination half life (1-4 hrs)
No long acting metabolites
In ICU patients, midazolam's elimination half-life may be greatly prolonged and clinically important accumulation may occur
Minimal dose: 1 to 2 mg bolus
0.5 to 10 mg/hr

24. Benzodiazepines: Diazepam
Elimination half-life of 21 to 37 hours
Major active metabolite, desmethyldiazepam, has a half-life of 48 to 96 hours
In terms of cost, diazepam has a clear advantage, being one-tenth the price of midazolam.
Minimal dose: 5 to 10mg bolus
Infusions not recommended

25. Benzodiazepines : Lorazepam
Lower lipid-solubility than midazolam
Less hypotesnion
Metabolised by liver to inactive metabolites
Lower cost
Loading dose: mg/kg
Infusion dose: mg/kg/hr

26. MIDAZOLM
LORAZEPAM
DIAZEPAM
LOADING DOSE
mg/kg
mg/kg
mg/kg
MAINTANENCE DOSE
mg/kg/hr
mg/kg/hr
Rarely used
ONSET
1-5 min
5-20 min
2-5 min
DURATION
1-2 hrs
2-6 hrs
2-4 hrs
CARDIAC EFFECTS
Minimal
Present
RESPIRATORY EFFECTS
Important depressant effect
ANALGESIA
None
AMNESIA
Potent
ACTIVE METABOLITES
Yes No
COST/24HRS
4 mg/hr: $37
2 mg/hr: $52
8 mg q 4h: $24

27. Flumazenil Benzodiazepine antagonist
Given in incremental doses of 0.2 to 0.5 mg upto 3 mg
Onset – 2 min
Duration- 30 to 60 min

28. Propofol The mode of action of propofol is via the GABA receptor
Rapid onset of action; metabolized rapidly hepatically and extrahepatically
Recovery within 10 minutes of discontinuation, can accumulate with prolonged use
Ideally infused via a large or central vein
Prolonged infusions –increase triglyceride and cholesterol levels
A theoretical maximum recommended dose is 4 mg/kg/hour.

29. Propofol (contd.) Bolus dose – not recommended
to 100μg/kg/hr
Theoretical maximum dose- 4mg/kg/hr
Cautious about propofol infusion syndrome

30. Propofol: adverse effects
Hypotension
Reliable, dose-related
Decreased SVR and contractility (CO)
Respiratory depression
Apnea with bolus dosing
Synergistic CV and respiratory depression with opioids
Vehicle (soybean emulsion):
Hypertriglyceridemia
Venoirritation
Infection

31. Propofol infusion syndrome
Propofol infusion syndrome is an adverse drug event associated with high doses (>4 mg/kg per hour or >67 µg/kg per minute) and long-term (>48 hours) use of propofol.
Clinical features:
- Cardiomyopathy with acute cardiac failure.
- Myopathy.
- Metabolic acidosis, K+
- Hepatomegaly.
Inhibition of FFA entry into mitochondria  failure of its metabolism.

32. Management
Supportive treatments addressing the clinical manifestations
The propofol infusion should be discontinued immediately
Alternative sedative should be started
Intravenous crystalloid and colloid replacement and vasopressor and/or inotropic support
Cardiac pacing may be used for symptomatic bradycardia
Hemodialysis or continuous renal replacement therapy to treat the acute renal failure

33. Ketamine Ketamine acts at the N-methyl-D-aspartate (NMDA) receptor
In subanesthetic doses, sedative and analgesic
Generally not used because of the increase in blood pressure, intracranial pressure (ICP), and pulse rate
Bronchodilatory properties, sometimes has a role in severe asthma
In the ICU conjunction with a narcotic
Dose : 5 to 30 μg/kg/min

34. Others
ETOMIDATE :For maintenance of hypnosis, target concentration of 300 to 500 ng/mL may be achieved by administration of a two- or three-stage infusion
BARBITURATES: Barbiturates such as Pentothal have been used in the ICU, especially in the management of patients with head injuries and seizure disorders. They cause significant cardiovascular depression and accumulate during infusions, leading to prolonged recovery times.

35. Others (contd.) BUTYROPHENONES AND PHENOTHIAZINES
An aggressive dosing regimen of haloperidol may be useful in a patient with delirium to promote calm, 2 to 10 mg IV every 10 to 15 minutes until the desired response is achieved
VOLATILE AGENTS
Isoflurane has been used in concentrations of up to 0.6% for longterm sedation, with minimal cardiorespiratory side effects and rapid awakening.
Desflurane has been shown to be effective in sedation, with rapid offset of effects.

36. Others (contd.) Shorter acting opioids
Fentanyl, alfentanyl, remifentanyl
Muscle relaxants
α2 agonists
Clonidine
dexmedetomidine

37. Alpha-2 Agonists N H Cl
Clonidine
CH3 N H
Dexmedetomidine

38. 2 Agonists Dexmedetomidine Clonidine Selectivity: 2:1 1620:1
Imidazole derivate 31:1
t1/2  2 hrs
94% protein bound
Eliminated by liver/kidney
Sedative
Only available in IV form
Clonidine
Selectivity: 2:1 250:1
Imidazole derivate 16:1
t1/2  10 hrs
Antihypertensive

39. Dexmedetomidine Pharmacology of dexmedetomidine alpha 2 agonist
Molecular targets + neural substrates
locus ceruleus
natural sleep pathways
Clinical paradigms for use of dextomed in anesthesia
sedation + analgesia w/o respiratory depression
attenuation of tachycardia
smooth emergence + weaning from mechanical ventilation

40. Pharmacokinetics Rapid redistribution: 6 min
Elimination half-life: 2 h
Vd steady state: 118 L
Clearance: 39 L/h
Protein binding: 94%
Metabolism: biotransformation in liver to inactive metabolites + excreted in urine
No accumulation after infusions h
Pharmacokinetics similar in young adults + elderly

41. Sedation Typical doses (target plasma levels 0.3-1.2 ng/ml):
0.5 ug/kg load, 0.5 ug/kg/hr infusion
1.0 ug/kg load, 0.7 ug/kg/hr infusion
Increase dose by bolus/infusion
Load only - short procedures
Patients with high sympathetic activity may need very high doses

42. Clonidine
Clonidine is synergistic with opioids and acts at the spinal cord to inhibit nociceptive inputs, thus imparting analgesia
It is contraindicated in hypovolemia and can cause hypotension, bradycardia, and dry mouth

43. The Art of Sedation Under sedation: Fighting the ventilator.
V/Q mismatch.
Accidental extubation.
Catheter displacement.
CV stress  ischemia.
Anxiety, awareness.
Post-traumatic stress disorder.
Over sedation:
Tolerance, tachyphylaxis.
Withdrawal syndrome.
Delirium.
Prolonged ventilation.
CV depression.
 neuro testing.
Sleep disturbance.

44. Unwanted side-effects
General
Over sedation
Delayed awakening/extubation
Benzodiazepines
Hypotension
Respiratory depression
Agitation/Confusion
2-agonists
Hypotension
Bradycardia
Propofol
Hypertriglyceridemia
CVS depression
Hypotension
Ketamine
Hypertension
Secretions
Dysphoria

45. Analgesia in ICU
Pain is ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’. Thus, perception of sensory events is a requirement, but actual tissue damage is not. Although a majority of ICU patients receive parenteral analgesics routinely , 50% of patients discharged from the ICU remember pain as their worst experience while in the ICU. This emphasizes the need for effective pain control in the ICU.

46. Indices of pain severity applicable in the critically ill
Subjective
Visual analogue scale
Numeric rating scale
Verbal descriptor scale
Objective
Vital signs measurements
Behavioural responses

47. І─────────────────І Verbal rating scale None mild moderate severe
Visual analog scale
І─────────────────І
No pain
Worst pain

48. Recommendation for assessment of pain
Use of the numeric rating scale(NRS) is recommended to assess pain. (Grade of recommendation = B)
Patients who cannot communicate should be assessed through subjective observation of pain and physiological indicators and the change in these parameters following analgesic therapy. (Grade of recommendation =B)

49. Analgesics used in ICU
Pain in the critically ill is best treated with a pure opioid agonist
In a recent clinical guideline, the recommended choices have been narrowed to morphine, fentanyl, and hydromorphone.
Other drugs with analgesic properties and variable use in critically ill patients are :
meperidine (pethidine)
tramadol
nonsteroidal anti-inflammatory drugs (NSAIDs)
mixed opioid agonist-antagonist agents
ketamine, a sedative drug with analgesic qualities
α2 agonists.

50. Opioids :Morphine Plasma levels do not correlate with clinical effect.
Low lipid solubility causes slow equilibration across BBB.
Metabolized in the liver by conjugation. Morphine-6-glucuronide active metabolite with sedative action.
The analgesic dose is highly variable, and may be delivered as an intermittent boluses or as a continuous infusion.
Minimal cardiovascular side effects
Relatively contraindicated in asthma and renal failure

51. Morphine CNS effects mediated via μ1 and μ2 receptors
Analgesia: pain components
Affective- greater effect
Sensory
Euphoria
Sedation
Mood change
Mental cloudiness

52. Fentanyl
Fentanyl : synthetic opioid derived from meperidine (pethidine)
Short-acting opioid with rapid onset
After prolonged infusion the duration of action approaches that of morphine
Does not accumulate in renal failure
It does not cause histamine release and is suitable for analgesia in the hemodynamically unstable patient

53. Alfentanyl Alfentanil is a synthetic opioid
Onset of action about five times faster than fentanyl, due to the small volume of distribution
Less lipid soluble
The duration of action is about one-third that of fentanyl
Alfentanil has minimal cardiovascular effects

54. Remifentanil
Remifentanil, an ultra-short-acting opioid metabolized by nonspecific tissue esterases
Rapid onset of action
Does not accumulate after infusions even in organ dysfunction.
Selective mu-receptor agonist.
Potency similar to fentanyl.
Terminal half-life < 10 min.
Rapid blood-brain equilibrium.
Can cause significant bradycardia

55. Morphine
Hydromorphone
Fentanyl
Loading dose
5-10 mg
1-1.5 mg
50-100μg
Onset
10-20 min
5-15 min
1-2 min
Duration
2-3.5 hrs
2-3 hrs
30-60 min
Infusion rate
1-5 mg/hr
mg/hr
50-350μg/hr
Active metabolites
Yes No
Histamine release
Cost / 24hrs
5mg/hr: $ 16
0.75 mg/hr: $ 10
100μg/hr: $ 5.50

56. Epidural analgesia
Opioids
Concentration
Morphine
μg/ml
Fentanyl
2- 5 μg/ml
Adverse effects of epidural analgesia are more common with morphine than fentanyl. Epidural morphine can produce respiratory depression, and the onset can be delayed up to 12 hours . The incidence of respiratory depression is equivalent with epidural and intravenous morphine. More frequent side effects of epidural analgesia include pruritis, nausea, and urinary retention.

57. Unwanted side-effects of opioids
Vasodilation
Confusion
Respiratory depression
Gut motility depression

58. Other opioid agonists Tramadol
Synthetic 4-phenyl-piperidine analog of codeine
Stimulates the µ-receptor
1/5th to 1/10th as potent as morphine
Analgesic doses of tramadol may produce less respiratory depression and have minimal effects on gastrointestinal motor function

59. Naloxone Opioid antagonist
Used to restore spontaneous ventilation in patients who breathe inadequately after opioid overdose
Onset of action is 1 -2 min
Duration of effect is min
Dosage – 0.4 to 0.8mg
Side effects: tachycardia, hypertension, pulmonary edema

60. Non steroidal anti inflammatory drugs
There is only one NSAID approved for use in the United States: ketorolac.
Nonspecific inhibitor of cyclooxygenase with strong analgesic activity and moderate anti inflammatory activity
Metabolized in the liver and excreted by the kidneys
Dose: 30 mg IV or 60 mg IM, f/b 30 mg IM or IV every 6 hours (maximum of 120 mg/day) for up to 5 days

61. iv paracetamol
The time course of action is quick with iv paracetamol as it reaches peak concentration as soon as infusion is complete (about 15 minutes).
According to the product information, the analgesic effect starts within 5 minutes, peaks at 1 hour and lasts 4 to 6 hours.

62. Clinical practice guidelines for sedation and analgesia from the Society of Critical Care Medicine and American College of Critical Care Medicine Pain

63. Pain
An assessment of pain and the response to therapy should be regularly assessed using an appropriate pain scale.
Therapeutic plans and goals should be developed for all patients.
Recommended intravenous opioids are fentanyl for acute distress, fentanyl or hydromorphone for patients with hemodynamic instability or renal insufficiency, and morphine and hydromorphone for longer-term therapy.
Scheduled doses or continuous infusions are preferred over intermittent boluses.
Nonsteroidal anti-inflammatory drugs and acetaminophen can be useful adjuncts, but beware of renal insufficiency or gastrointestinal bleeding.

64. Sedation
Treatment of pain and other reversible causes should be conducted before sedating an agitated patient.
A treatment plan/goal should be established for each patient; therapy should be assessed with a sedation scale.
Midazolam or diazepam is useful for the acutely agitated patient.
Propofol is preferred when rapid awakening is crucial; triglyceride levels should be monitored for >2 d of continuous infusions.
Lorazepam is recommended for longer infusions.
Doses should be tapered daily to assess underlying mental status, and sedation protocols can be helpful and beneficial.

65. Guidelines for sedation and analgesia in ICU

67. References
Gabrielli A, Layon A, Joseph, et al. Anesthesia in the ICU. Civetta, Taylor, & Kirby's: Critical Care, 4th Edition; Lippincott Williams & Wilkins:2009
Marino, PL. Analgesia and Sedation. ICU Book, 3rd Edition; Lippincott Williams & Wilkins:2007
Miller RD. Critical care protocols. Miller’s Anaesthesia. 7th edition:2010

68. Thank you