Sedation and analgesia in ICU

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

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. 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 • Infusions@ 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: 0.02-0.06 mg/kg • Infusion dose: 0.01-0.1 mg/kg/hr

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 • Infusions @25 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 discontinuedimmediately • 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. H Cl N N Clonidine N Cl H CH3 Dexmedetomidine N CH3 N CH3 Alpha-2 Agonists

38. Clonidine Selectivity: 2:1 250:1 Imidazole derivate 16:1 t1/2  10 hrs Antihypertensive Dexmedetomidine 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 2 Agonists

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 12-24 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 • 2-agonists • Hypotension • Bradycardia Benzodiazepines Hypotension Respiratory depression Agitation/Confusion 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. Verbal rating scale Visual analog scale 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