critically ill patients differs from other patients because of their altered Pk/Pd, hence sedation must be titrated to desired response

1. Dr. Surendra
FNB-CCM
RTIICS KOLKATA

2. Hypnosis
± Muscle
Relaxation
Analgesia
•Latin word sedare = to calm or to allay fear = sedation

3. Conscioussedation
• A minimally depressed level of consciousness
induced by theadministration of
pharmacologic agentsin which apatient
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

4. THE PATIENT IS HERE!

5. Chest 2008;133;552-565

6. Complications from pain and
anxiety
Stimulation of theautonomic nervoussystem and
releaseof humoral factors→ increased HR, BP, and
myocardial oxygen consumption → myocardial
ischemiaor infarction
Altered humoral responsecan lead to
hypercoagulability asaresult of increased level of
factor VIII, fibrinogen, platelet activity, and inhibition
of fibrinolysis

7. Cont……..
Stresshormonesalso produceinsulin resistance,
increased metabolic rate, and protein catabolism
Immunosuppression with reduction in number and
function of lymphocytesand granulocytes
Psychological disturbances- memoriesof vivid
nightmares, hallucinations, and paranoid delusions

8. DeliriumDelirium
80% of ICU patients have delirium
*may or may not be accompanied by agitation

9. Indications and Goals
Facilitate mechanical ventilation
Create anxiolysis, analgesia, amnesia
Decrease oxygen consumption
Reduce dyspnea
Prevent patient self-injury
“Rest” patient for weaning trials
Induce sleep

10. Cont……
Create patient unawareness
Improve long-term psychiatric
outcomes (?)
Permit delivery of efficient care
Reduce nursing stress
Ensure nursing safety
Increase family acceptance of ICU
care
Weinert, et al. AJCC. 2001; 10:156

11. Sedation EvaluationSedation Evaluation
Should be integral component of treatment
algorithms
precise dosing
reduced sedative and analgesic drug use
shorter duration of MV
reduced need for vasopressor therapy
reduced incidence of over sedation

12. Guidelines---SCCM-2013

13. scoring system
should besimple, easily
performed, noninvasive, and
reproducible.

14. Richmond Agitation-Sedation Scale (RASS)
Sedation Agitation Scale [SAS]
Motor Activity Assessment Scale
Ramsay Sedation Scale
Adaptation to the Intensive Care Environment
(ATICE) instrument
Minnesota Sedation Assessment Tool (MSAT).
Glasgow comascale(GCS) – assessment of level of
consciousness

16. 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
0 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

17. Ramsay sedation scale
Awake
1 Anxiousand/or agitated
2 Cooperative, oriented, and tranquil
3 Respondsto commands
Asleep
4 brisk responseto light glabellar tap
or loud auditory stimulus
5 Sluggish responseto light glabellar
tap or loud auditory stimulus
6 No response

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

19. What is “adequate sedation”?
RAAS -0-3
SAS – 3-4
RAMSAY- 3

20. Measurement of Brain ActivityMeasurement of Brain Activity
Bispectral index (BIS)
Patient state index
Cerebral state index
Narcotrend index
•Objective physiologicObjective physiologic
parametersparameters
•Numerical displayNumerical display
•Near-continuous measurementNear-continuous measurement

21. Bispectral index
A practical, processed EEG parameter that
measuresthedirect effects of sedativeson the
brain
.

22. BIS range guidelines

23. Value of BIS in ICU
Minimize
consequences
of over- and
under-sedation
Improve quality
of sedation
management
Objectivesedation assessment
about apatient’sresponseto sedation
Optimizeclinical
and economic
outcomes
Numerical scale correlates to
sedation endpoints

24. BIS
Prone to artifacts
‘Electromyography‘ activity interferes with BIS
measures of sedation
Confounding factors that may influence BIS
scores
Hypoglycemia / Sleep / temperature / Age
Drugs
aminophylline, epinephrine, and ketamine.
Increase variability of BIS in the critically ill pts
Cannot be relied upon in circulatory arrest or

25. Daily interruption of sedation &
analgesia [1B]
Allows better assessment of a patient’s sedative needs
Reduces drug bioaccumulation
Reduced incidence of posttraumatic stress disorder
Reduced complications of critical illness
More ventilator-free days and earlier ICU and
hospital discharge, at the expense of a higher
incidence of self-extubation

26. Sedation therapy
NON PHARMACOLOGICAL THERAPY:
Good communicationwith regular reassurancefrom
nursing staff
Environmental control such ashumidity, lighting,
temperature, and noise
Explanationprior to procedures
Management of thirst, hunger, constipation, and full
bladder

27. Critically ill patients are
different
Pharmacokinetics of various drugs are altered
including - drug bioavailability, volume of
distribution, and clearance.
Hepatic dysfunction
Decreased hepatic blood flow
Renal dysfunction
Alteration in volume status
Plasma protein binding

28. Pharmacologic therapy
Thesedativeagent should possessthefollowing
qualities:
Both sedativeand analgesic properties
Minimal cardiovascular sideeffects
Controllablerespiratory sideeffects
Rapid onset/offset of action
No accumulation in renal/hepatic dysfunction
Inactivemetabolites
Inexpensive
No interactionswith other ICU drugs

29. Pharmacologic
therapy
Benzodiazepines
Propofol
Etomidate
Ketamine
Barbiturate
Short acting opioids
Alpha2 agonists
Inhalational agents

30. Benzodiazepines
Anxiolytic, anticonvulsant, amnesic, hypnotic and
providesomemusclerelaxation
Effectsaremediated by depressing theexcitability of
thelimbic system viareversiblebinding at GABA-
benzodiazepinereceptor complex
Minimal cardiorespiratory depressant effect
Thecommon drugsin thisclassarediazepam,
midazolam, and lorazepam

31. Pharmacodynamic response
Patient-related factors can affect the BZD
response
age
concurrent pathology
prior alcohol use
concurrent therapy with other sedative drugs
Higher volume of distribution and slower clearance in
elderly.

32. MIDAZOLM LORAZEPAM DIAZEPAM
LOADING DOSE 0.01-0.05 mg/kg 0.02-0.04 mg/kg 0.05-0.2 mg/kg
MAINTANENCE
DOSE
0.02-0.1 mg/kg/hr 0.01-0.1 mg/kg/hr Rarely used
ONSET 1-5 min 5-20 min 2-5 min
DURATION 3-11 hrs 2-6 hrs 2-4 hrs
CARDIAC
EFFECTS
Minimal Minimal Present
RESPIRATORY
EFFECTS
Important
depressant effect
Important
depressant effect
Important
depressant effect
ANALGESIA None None None
AMNESIA Potent None None
ACTIVE
METABOLITES
Yes No Yes
S/E Low BP Low BP, glycol/
nephrtoxicity
Low BP, pleibitis

33. Propofol
Themodeof action of propofol isviatheGABA
receptor
Rapid onset of action 1-2 min;
metabolized rapidly hepatically and extrahepatically
Recovery within 10 minutesof discontinuation, can
accumulatewith prolonged use
Ideally infused viaalargeor central vein
Prolonged infusions–increasetriglycerideand
cholesterol levels
A theoretical maximum recommended doseis4
mg/kg/hour.

34. Propofol (contd.)Bolusdose– not recommended
Infusions@25 to 100μg/kg/hr
Theoretical maximum dose- 4mg/kg/hr
Cautiousabout propofol infusion syndrome

35. Propofol: adverse effects
Hypotension
 Reliable, dose-related
 Decreased SVR and contractility (CO)
Respiratory depression
 Apneawith bolusdosing
Synergistic CV and respiratory depression with
opioids
Vehicle(soybean emulsion):
 Hypertriglyceridemia
 Venoirritation
 Infection

36. Propofol infusion syndrome
Propofol infusion syndromeisan adversedrug event
associated with high doses(>4 mg/kg per hour or >67
µg/kg per minute) and long-term (>48 hours) useof
propofol.
Clinical features:
- Cardiomyopathy with acutecardiac failure.
- Myopathy.
- Metabolic acidosis, K+
- Hepatomegaly.
Inhibition of FFA entry into mitochondria failureof
itsmetabolism.

37. Management
Supportivetreatmentsaddressing theclinical
manifestations
 Thepropofol infusion should bediscontinued
immediately
 Alternativesedativeshould bestarted
 Intravenouscrystalloid and colloid replacement and
vasopressor and/or inotropic support
 Cardiac pacing may beused for symptomatic
bradycardia
 Hemodialysisor continuousrenal replacement
therapy to treat theacuterenal failure

38. Ketamine
Ketamineactsat theN-methyl-D-aspartate(NMDA)
receptor
In subanesthetic doses, sedativeand analgesic
Generally not used becauseof theincreasein blood
pressure, intracranial pressure(ICP), and pulserate
Bronchodilatory properties, sometimeshasarolein
severeasthma
In theICU conjunction with anarcotic
Dose: 5 to 30 μg/kg/min

39. Others
ETOMIDATE :For maintenanceof hypnosis, target
concentration of 300 to 500 ng/mL may beachieved
by administration of atwo- or three-stageinfusion
BARBITURATES: Barbituratessuch asPentothal
havebeen used in theICU, especially in the
management of patientswith head injuriesand seizure
disorders. They causesignificant cardiovascular
depression and accumulateduring infusions, leading
to prolonged recovery times.

40. Others (contd.)
BUTYROPHENONESAND PHENOTHIAZINES
An aggressivedosing regimen of haloperidol may be
useful in apatient with delirium to promotecalm, 2 to
10 mg IV every 10 to 15 minutesuntil thedesired
responseisachieved
VOLATILE AGENTS
Isofluranehasbeen used in concentrationsof up to
0.6% for longterm sedation, with minimal
cardiorespiratory sideeffectsand rapid awakening.
Desfluranehasbeen shown to beeffectivein
sedation, with rapid offset of effects.

41. Others (contd.)
Shorter acting opioids
Fentanyl, alfentanyl, remifentanyl
α2 agonists
Clonidine
dexmedetomidine
Musclerelaxants
Fentanyl
50-100μg
1-2 min
30-60 min
50-350μg/hr
No
No
Loading dose
Onset
Duration
Infusion rate
Active metabolites
Histamine release

42. α2 Agonists
Clonidine
Selectivity: α2:α1 250:1
Imidazolederivate16:1
t1/2 β 10 hrs
Antihypertensive
Dexmedetomidine
Selectivity: α2:α1 1620:1
Imidazolederivate31:1
t1/2 β 2 hrs
94% protein bound
Eliminated by liver/kidney
Sedative
Only availablein IV form

43. Dexmed.Dexmed. Clinical paradigms
Sedation
without
respiratory
deppressio
n
Sympat
holytic smooth emergence+
weaning from mechanical
ventilation
Molecular targets+ neural
substrates
1.locusceruleus
2.natural sleep pathways

44. Pharmacokinetics
Rapid redistribution: 6 min
No accumulation after infusions12-24 h
Typical doses(target plasmalevels0.3-1.2 ng/ml):
Onset 5-10 min
Et1/2 1.8-3.1 hr
1 ug/kg loading doseover 10 min f/b 0.2-0.7
ug/kg/hr infusion
Load only - short procedures
Patientswith high sympathetic activity may need
very high doses

45. Clonidine
Clonidine issynergistic with opioidsand actsat the
spinal cord to inhibit nociceptiveinputs, thus
imparting analgesia
It iscontraindicated in hypovolemiaand can cause
hypotension, bradycardia, and dry mouth

46. The Art of Sedation
Under sedation:
Fighting theventilator.
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.

47. Titration of Sedative
Medications
Large variation in dose requirements
Altered PK/PD in critically ill
Acute and chronic tolerance
Differences in severity of symptom or behavior
Most drugs are titrated to effect
Similar to hypertensive medications

48. How to titrate sedative
medications
Identify the target symptom or behavior
“Measure” the intensity or severity
Agree on the appropriate symptom level for that
patient at that time
Realize that changes will occur

49. Propofol
Hypertriglyceridemia
CVSdepression
Hypotension
α2-agonists
Hypotension
Bradycardia
Benzodiazepines
Hypotension
Respiratory depression
Agitation/Confusion
Ketamine
Hypertension
Secretions
Dysphoria
General
Over sedation
Delayed awakening/extubation

50. Respiratory
depression
ConfusionVasodilation
Gut motility
depression
Opioids

51. WEANING FROM SEDATION

52. Hooper. Critical Care Clinics - 25 (July 2009)
Before Assesing daily
awakening exclude
Raised ICT
NMB
Very high PEEPn FiO2
CABG- immediate postop

53. Results: ABC Trial
SAT + SBT = more Ventilator-free days
15 v 12 (p =0.02)
Less days in ICU: 9 v 13
Less coma but more self-extubations
Decreased risk of dying up to 1 yr
Girard Lancet 371:126 2008