1. SEDATION AND ANALGESIA IN THE ICU
DR. MUNIRA DILAWER GHEEWALA.

2. Picture depicting Sir Humphrey Davy experimenting Nitrous oxide at the pneumatic institution

3. SOURCES OF PAIN IN THE ICU
Recent Surgery
Pre-existing Disease
Monitoring Devices – ex. Central lines, Pulmonary Artery Catheters.
Endotracheal tubes
Drains , Urinary Catheters.
Nursing Care – Suctioning, Dressing Changes.
Immobilisation

4. CONSEQUENCES OF PAIN Sleep Deprivation Agitation Splinting
Stress Response –
Stimulation of Autonomic Nervous System and release of Humoral factors leads to tachycardia and hypertension and increased myocardial oxygen consumption – myocardial ischemia or Infarction.
Hypercoagulability – altered humoral response leading to increased levels of factor VIII , fibrinogen, platelet activity and inhibition of fibrinolysis.
Immunosuppression – with reduction in number & function of granulocytes & lymphocytes.
Catabolism
Psychological Disturbances – vivid nightmares, hallucinations and paranoid delusions.

5. PAIN ASSESSMENT
Most Reliable and Valid Indicator for Pain assessment is patient’s response and self report.
Therefore patient should be awake if possible.
Intensity –
Verbal Rating Scores – patient self suggests intensity –
no pain/mild/moderate/severe/very severe/worst possible pain.
Visual Analog Scales – depicting on a chart the intensity of pain.
Numeric Rating Scales – scaled from 1-10 depending on the intensity.

6. BEHAVIOURAL PAIN SCALE

7. DELIRIUM AND AGITATION
Fluctuating Mental Status
Disorganized Thinking
Altered level of Consciousness
Inattention
80 % of ICU patients have delirium – may or may not be accompanied by agitation

9. Goal of sedation Daily goal is – AROUSABLE AND COMFORTABLE SEDATION
This approach facilitates reductions in ICU LOS and the Duration of Mechanical Ventilation compared to traditional sedative strategies.
The optimal level of sedation for most patients is – one which offers comfort while allowing interaction with the environment.
Sedation need to be protocolized and titrated to the goal :
Lighten Sedation to appropriate wakefulness daily.
Effect of this strategy on the outcomes :
1-7 day reduction in length of sedation and MV needs
50% reduction in tracheostomies

10. BENEFITS OF ADEQUATE SEDATION AND ANALGESIA
Facilitates Mechanical Ventilation
Creates Anxiolysis, Analgesia, Amnesia
Decreases Oxygen Consumption
Reduces Dyspnea
Prevents Patient self- injury
Induces Sleep
Creates patient unawareness
Improves long term psychiatric outcomes
Permits delivery of efficient care
Reduces Nursing stress while ensuring Nursing safety
Increases family acceptance of ICU care

11. Guidelines - sccm
Depth and Quality of sedation should be routinely assessed in all ICU patients.
RASS and SAS are most valid and reliable scales for assessing quality and depth of sedation in ICU patients.
Use objective measures of brain function to adjunctively monitor sedation in patients receiving neuromuscular blocking agents.
EEG monitoring to be used for Non-Convulsive Seizure activity in ICU patients at risk for seizures, or to titrate electro suppressive medication to achieve burst suppression in ICU patients with elevated intracranial pressures.

12. Target the lightest possible level of sedation and/or use daily sedative interruption.
Use sedation protocols and checklists to facilitate ICU sedation management.
Suggest using Analgesia first – sedation for intubated and mechanically ventilated ICU patients.
Suggest using non-benzodiazepines (either Propofol or Dexmedetomidine) rather than Benzodiazepines (Midazolam or Lorazepam) in mechanically ventilated adult ICU patients.

13. SCORING SYSTEM
Should be simple, easily performed, non invasive and easily reproducible.
Depth and Quality of Sedation should be routinely assessed in all ICU patients.
What is adequate sedation?
RASS : 0-3
RAMSAY : 3
SAS : 3-4

14. RICHMOND AGITATION SEDATION SCALE

15. RAMSAY SEDATION SCALE Awake 1 Anxious and/or agitated
2 Cooperative , oriented and tranquil
3 Responds to commands
Asleep
4 Brisk response to light glabellar tap or loud auditory stimulus
5 Sluggish response to light glabellar tap or loud auditory stimulus
6 No response to light glabellar tap or loud auditory stimulus

16. Sedation AGITATION SCALE
Unarousable
Very sedated
Sedated
Calm and Cooperative
Agitated
Very Agitated
Dangerous Agitation

17. MEASUREMENT OF BRAIN ACTIVITY
Objective measurement of brain function in patients receiving NMBA along with sedation.
Bispectral Index / EEG / Evoked potentials.
BISPECTRAL INDEX
A practical, processed EEG parameter that measures the direct effects of sedatives on the brain
3 components : Patient state Index
Cerebral state Index
Narcotrend Index

18. BIS RANGE GUIDELINES

19. ADVANTAGES OF BIS DISADVANTAGES OF BIS
Objective sedation assessment to patient’s response
Optimizes clinical and economic outcomes
Minimizes consequences of over and under sedation
Improves quality of sedation management
Numerical scale correlates to sedation endpoint.
Prone to artefacts
Electromyography activity interferes with BIS measures of sedation
Confounding factors influencing BIS scores
Hypoglycaemia , Sleep , Temperature , Age, Drugs (Aminophylline, Epinephrine, Ketamine)
Increase variability of BIS in critically ill patients
Cannot be relied upon in circulatory arrest or hypothermia.

20. EEG MONITORING
EEG monitoring to be used for Non-Convulsive Seizure activity in ICU patients at risk for seizures, or to titrate electro suppressive medication to achieve burst suppression in ICU patients with elevated intracranial pressures.

21. Target the lightest possible level of sedation and/or use daily sedative interruption.
Daily interruption of sedation and analgesia :
Allow better assessment of patient’s sedative needs
Reduces drug bioaccumulation
Reduces incidence of post-traumatic stress disorder
Reduces complications of critical illness
More ventilator free days and earlier ICU and hospital discharge…but at the expense of a higher incidence of self- extubation.

22. SEDATION THERAPY
Use sedation protocols and checklists to facilitate ICU sedation management.
Suggest using Analgesia first – sedation for intubated and mechanically ventilated ICU patients.
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

23. Sedation and analgesia – pharmacologic therapy
The pharmacologic agent should possess the following qualities:
Both Sedative and Analgesic properties
Anxiolytic , Amnestic and Anticonvulsant properties
No prolonged effects on memory
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
No long term psychological effects

24. SEDATION / ANALGESIA OPTIONS
Rule out reversible causes of discomfort and anxiety – Hypoxemia, Hypercarbia, toxic/drug side effects.
Assess comorbidities of the patient.
Keep in mind the potential side effects of the drug chosen.
Target irreversible aetiologies of Pain and Agitation.

25. PHARMACOKINETIC CONSIDERATIONS
Patient’s Fluid Volume Status
Capillary Leak (Changing volume of distribution)
Serum Protein Levels
Renal and Hepatic Function
Hepatic Blood Flow
Competition of combinations of drugs for carrier molecules, metabolic and excretory pathways.

26. Choice of analgesia OPIOID ANALGESIA
Natural chemical derivative of opium
Act on opioid receptors (mu, kappa and sigma receptors) present in the central nervous system and other body systems
Effects – Analgesia, Sedation, Euphoria, Pupillary constriction, Respiratory depression, Bradycardia, Nausea, Vomiting, Constipation, Urinary retention, Pruritis & Physical Dependence
Most commonly used drugs for pain relief in the ICU
Given as intravenous bolus doses or infusions
No amnestic effects like Benzodiazepines

27. CLASSIFICATION OF OPIOIDS
Semisynthetic & synthetic agents
Phenylpiperidine derivatives – pethidine, fentanyl
Methadone Derivatives – Methadone, Dextropropoxyphene
Benzomorphan derivatives – Pentazocine
Thebaine Derivatives- Buprenorphine
Morphine & its analogues
Morphine
Diamorphine
Codeine (Hydrocodone)

28. Commonly used iv opioids
FEATURES
MORPHINE
FENTANYL
HYDROCODONE
Onset of action
5-10 mins
1-2 mins
5-15 mins
Bolus Dosing
2-4 mg every 1-2 hrs
mcg/kg every hr
mg every 1-2 hrs
Infusion Rate
2-30 mg/hr
mcg/kg/hr
0.5-3 mg /hr
Lipid Solubility x
600x
0.2x
Active Metabolites
Yes No
Histamine Release
Dose Adjustment for Renal Failure
Decrease by 50%
None

29. Some other opioids REMIFENTANYL
Ultra short acting opioid given by continuous iv infusion
1.5mcg/kg loading dose f/b continuous infusion at mcg/kg/hr
Analgesic effects are lost within 10 mins of stopping the infusion
Drug Metabolism is by non-specific esterases in the plasma – no dose adjustment in hepatic or renal failure
Most advantageous in Traumatic Head Injury patients where frequent assessment of cerebral function is required
Abrupt cessation can cause withdrawal – beneficial if combined with a longer acting opioid

31. pentazocine An Agonist on K –receptors
a weak antagonist at mu and delta receptors
Used to relieve moderate pain
analgesia by activating receptors in the spinal cord
Less euphoria compared to morphine
Can be administered orally or parenterally
Adverse Reactions –
Dysphoria – higher doses can cause Hallucinations , Nightmares, Tachycardia , Hypotension and Dizziness
Tolerance and dependence on repeated use
Combined with Phenergan to avoid side effects like nausea and vomiting and give a mild sedative effect
Oral tablets have Naloxone combination to prevent crushing and iv abuse

32. TRAMADOL Acts via the mu receptor
Also Inhibits uptake of Serotonin and Noradrenaline with presynaptic stimulation of serotonin release
Used for moderate to severe pain in the post-operative patient
Dose – mg (i.v. , oral or i.m.) hourly up to a maximum of 600 mg/day

33. Side effects of opioids
Vasodilatation and Hypotension
Respiratory Depression
Depression of Gut Motility
Confusion

34. THE ABSTINENCE SYNDROME
Withdrawal Symptoms that occur on sudden cessation/reduction of opioid medication.
Irritability
Tremors
Aggression
Fever
Diaphoresis
Piloerection
Pupillary Dilatation
Diarrhoea
Insomnia
Treatment – Reinstitution of and then slow withdrawal of opioid or introduction of opioid in combination with a BZD

35. NON OPIOID ANALGESIA – NSAIDS and others
KETOROLAC
IBUPROFEN
ACETAMINOPHEN
Dosing
30 mg i.v. or i.m. every 6 hrs for up to 5 days
mg i.v. every 6 hrs
1 gram i.v. every 6 hrs
Reduce dosing by 50 % for age>65yrs or body weight <50kg.
Daily dose should not exceed 4 grams.
Comment
NSAID
Has anti-inflammatory and antipyretic effects.
Actions are similar to ketorolac.
No anti-inflammatory effects which is a major disadvantage n critically ill patients..
Serious complications are uncommon when treatment is limited to less than 5 days.
Serious complications are uncommon when used for short term pain relief.
Since it is not a NSAID , the side effect profile for this group is safe except for hepatotoxicity in high doses.
Side effects of NSAIDS – Renal Dysfunction, GI Bleeding, Increased bleeding tendency due to platelet inhibition.

36. Neuropathic pain
Pain attributed to Diabetic Neuropathy and other Chronic illnesses causing nerve root pain
Recommended Drugs : Gabapentin – 600 mg every 8 hrs
( MOA: acts on postsynaptic voltage gated calcium channels – inhibition of calcium influx & decrease in presynaptic excitatory neurotransmitter release)
Carbamazepine – 100 mg every 6 hrs
Pregabalin – same mechanism of action as gabapentin but higher efficacy and faster onset of action.

37. Choice of sedatives BENZODIAZEPINES
Anxiolytic, Anticonvulsant, Amnesic, Hypnotic and provides some muscle relaxation.
Effects are mediated by depressing the excitability of the limbic system via reversible binding at GABA receptor complex
Minimal Cardiorespiratory depressant effect
Common Drugs in this class are Diazepam, Midazolam and Lorazepam
Patient related factors that affect BZD response – Age, Concurrent pathology, Prior alcohol use, Concurrent therapy with other sedative use
Higher Volume of Distribution and slower clearance in the elderly

38. MIDAZOLAM LORAZEPAM DIAZEPAM
LOADING DOSE
mg/kg
mg /kg
mg/kg
MAINTENANCE DOSE
mg/kg/hr
mg/kg/hr
Rarely used
ONSET
1-5 mins
5-20 mins
2-5 mins
DURATION
2-4 hrs
2-6 hrs
3-11 hrs
CARDIAC EFFECTS
Minimal
Present
RESPIRATORY EFFECTS
Important Depressant Effect
ANALGESIA
None
AMNESIA
Potent
ACTIVE METABOLITES
Yes No
SIDE EFFECTS
Low BP
Low BP/ Propylene glycol toxicity & nephrotoxicity
Low BP, Phlebitis

39. propofol The mode of action of Propofol is via the GABA receptor
Rapid onset of action – 1-2 mins
Metabolised rapidly hepatically and extrahepatically
Recovery is within 10 mins of discontinuation, can accumulate with prolonged use
Ideally to be infused via a large or a central vein
Prolonged infusions – increase Triglyceride and Cholesterol levels
Theoretical maximum dose is 4 mg/kg/hr
Bolus Dose – not recommended
Infusions at 25 to 100 mcg/kg/hr
Caution : PRIS – Propofol Related Infusion Syndrome

40. Propofol – adverse effects
Hypotension
Dose related
Decreased SVR and Contractility (Cardiac output)
Respiratory Depression
Apnea can occur with Bolus Dosing
Synergistic Cardiovascular and Respiratory Depression with Opioids
Vehicle (Soybean Emulsion)
Hypertriglyceridemia
Phlebitis
Infection

41. Propofol related infusion syndrome
Adverse drug event associated with high doses(>4 mg/kg/hr or >67mcg/kg/min) and long term use for >48 hrs
Clinical Features
Cardiomyopathy with acute cardiac failure
Bradycardia
Myopathy with or without Rhabdomyolysis
Severe Metabolic Acidosis
Hyperkalemia
Renal Failure
Hepatic Dysfunction
Inhibition of Free Fatty Acid entry into the mitochondria due to mitochondrial respiratory chain inhibition by propool results in failure of fat metabolism.

42. MANAGEMENT
Supportive treatments addressing the clinical manifestations
The propofol infusion should be discontinued immediately
Alternative Sedative agent should be started
Intravenous Crystalloid and colloid replacement and vasopressor or inotropic support
Cardiac pacing for symptomatic bradycardia
Hemodialysis or continuous renal replacement therapy to treat acute renal failure

43. KETAMINE Acts at the N-Methyl-D-Aspartate (NMDA) receptor
Prevents Nitric Oxide Synthase release
In sub anaesthetic doses it acts as a sedative and analgesic
Increases Blood pressure, Intracranial pressure and Heart rate
Bronchodilator properties, sometimes used in severe asthma
In the ICU used in conjunction with a narcotic (opioid or BZD)
Dose : 5-30 mcg/kg/min

44. others
ETOMIDATE
Can produce hypnosis with concentrations of ng/ml
BARBITURATES
Pentothal and Thiopentone have been used in the ICU in management of patients with head injuries and raised intracranial pressures & in treatment of refractory status epilepticus.
They cause severe cardiovascular depression and accumulate during infusions leading to prolonged recovery times
VOLATILE AGENTS
Isoflurane used in concentrations of up to 0.6% for long term sedation with minimal cardiorespiratory side effects and rapid awakening
Desflurane is an effective sedative with rapid onset of effects

45. BUTYROPHENONES AND PHENOTHIAZINES
HALOPERIDOL –
Useful in patients with delirium to calm them
Dopamine receptor antagonist
Can be given oral, intramuscular and intravenous
Intravenous route is the most preferable – improved absorption, no pain during injection, less patient anxiety and less EPS
Bolus dosing – 0.5 mg in elderly to maximum of 10 mg in severe agitation
30 min interval between the doses to gauge effect of previous dose
Combination with BZD can be used for rapid sedation – lowers total dose and hence less S/E (like EPS)
Side Effects – EPS, Seizures, Neuroleptic Malignant Seizures, Tardive Dyskinesia, Hypotension, QT prolongation (main S/E)
QUETIAPINE - treatment of delirium in patients of Parkinson’s Disease and Lewy Body Dementia

46. AlPHA 2 AGONISTS CLONIDINE
Synergistic with opioids and acts the spinal cord to inhibit nociceptive inputs, thus imparts analgesia
Contraindicated in hypovolemia and causes hypotension, bradycardia and dry mouth
Selectivity : alpha 2 : alpha 1 – 250:1
T ½ is 10 hrs
Is sometimes used as an antihypertensive

47. DEXMEDETOMIDINE Causes Anxiolysis, Amnesia, Analgesia
Sedation occurs without respiratory depression
Is also a sympatholytic
Molecular targets & Neural substrates : Locus ceruleus and natural sleep pathways
Smooth emergence & weaning from mechanical ventilation
Selectivity : alpha 2 : alpha 1 – 1620:1
94% protein bound
Eliminated by liver and kidney
Onset is 5-10 mins , Rapid Redistribution is 6 min & T ½ is 2 hrs
Only available in iv form
Dosing – 1 mcg/kg loading dose over 10 mins f/b mcg/kg/hr infusion
Even after hrs of infusion no risk of accumulation

48. Regional analgesia techniques
Nerve blocks for Thoracic and Abdominal wall – Intercostal Nerve Block , Paravertebral Block , Interpleural Analgesia and Transversus Abdominis Plexus Block
Peripheral Nerve blocks for upper and lower extremities
Epidural analgesia – Long acting drugs – Ropivicaine and Bupivicaine
Better side effect profile with excellent patient tolerance but minimally used in ICU
Most useful in chronic pain syndromes – prevention and treatment.

49. THE ART OF SEDATION Under Sedation Fighting the ventilator
V/Q mismatch
Accidental Extubation
Catheter Displacement
Cardiovascular stress & Ischemia
Anxiety , Awareness about procedures
Post – traumatic stress disorder

50. Over Sedation
Tolerance, tachyphylaxis
Withdrawal Syndrome
Delirium
Prolonged Ventilation
Cardiovascular Depression
Sleep Disturbance
Inability to test neurological function

51. Titration of sedative medications
Identify the target symptom or behaviour
Assess the severity
Agree on the appropriate symptom level for that patient at that time
Realize that changes will occur
Titrate the drug level to the achieve desired effect

53. THANK
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