Remifentanil: Predictable control in the ICU ULT/SLK/06/24993/2 October 2006
Analgesia and sedation in the ICU – the challenges and goals
What are the current challenges with analgesia and sedation in the ICU? Half of patients cannot Over-sedation impedes sleep, 1 with the major efforts to perform daily reason being pain 2 neurological examinations 5 PATIENT INTERACTION PAIN About 60% of patients Over-sedated patients are suffer pain 2 unable to co-operate 6 WEANING AND LENGTH OF STAY Over-sedation delays 41% of ventilation Over-sedation can also weaning and increases time is spent trying prolong duration of mechanical ventilation 5 and associated morbidity 4 to wean a patient 3 ICU and hospital stay 4,5 1. Aurell J et al . BMJ 1985; 290 : 1029 – 32. 4. Ramsay M. Bailliere’s Clinical Anaesthesiology 2000; 14 : 419 – 32. 2. Park G. Minerva Anesthesiol 2002; 68 : 505 – 12. 5. Kress JP et al. NEJM 2000; 342 : 1471 – 7. 3. Esteban A et al. Chest 1994; 106 : 1188 – 93. 6. Park G. Curr Anaesth Crit Care 2002; 13 : 313 – 20.
The balance of over- versus under-sedation Under-sedation Park G. Curr Anaesth Crit Care 2002; 13 : 313 – 20.
The balance of over- versus under-sedation Under-sedation Over-sedation Park G. Curr Anaesth Crit Care 2002; 13 : 313 – 20.
What are the goals of sedation in the ICU? The objective of sedation is to have patients that are optimally sedated, which means that patients are: 1 Calm Co-operative Comfortable Communicative An analgesia-based approach focuses on patient comfort by effectively managing their pain, 2 adding a sedative only when necessary. 3 1. Ramsay M. Bailliere’s Clinical Anaesthesiology 2000; 14 : 419 – 32. 2. Dahaba AA et al . Anesthesiol 2004; 101 : 640 – 6. 3. Muellejans B et al. Crit Care 2004; 8 : R1 – R11.
Possible ICU sedation regimens Preserve vital functions Patient optimally sedated Sedation with hypnotics until Treatment with analgesics the patient is unconscious until patient is comfortable Analgesics (morphine, Further sedation with fentanyl, NSAIDs), if pain hypnotics, if the patient is suspected anxious or agitated Hypnotic-based sedation 21 Analgesia-based sedation Lane M et al . Care Crit Ill 2002; 18 :146 – 7
Hypnotic versus analgesic approach Analgesic approach Hypnotic approach Enables a fast and predictable weaning / Patients are often difficult to wean (accumulation and over-sedation) 1,2 extubation 3 Allows intermittent assessment 3 Patients may be difficult to assess 1 Pain can be an issue 4 Ensures patient is more comfortable 4 Not all analgesics are affected by renal / Renal / hepatic impairment can be an issue 1,5 hepatic impairment 2 Patient can co-operate with nursing staff 2,6 Patients less able to co-operate 2,6 Patient is more aware of surroundings and Patient is asleep and unaware of able to interact with relatives 2 surroundings 2 1. Soltesz S et al . Br J Anaesth 2001; 86 : 763 – 8. 4. Park G. Minerva Anestesiol 2002; 68 : 505 – 12. 2. Park G. Curr Anaesth Crit Care 2002; 13 : 313 – 20. 5. Breen D et al . Crit Care 2004; 8 : R21 – 30. 3. Evans TN et al . Anaesthesia 1997; 52 : 800 – 1. 6. Lane M et al . Care Crit Ill 2002; 18 : 140 – 3.
Remifentanil: A unique opioid for analgesia and sedation in the ICU
Remifentanil – key pharmacokinetic and pharmacodynamic advantages Remifentanil is a unique, short-acting opioid receptor agonist: Rapid onset of effect: t½k e0 = 1.3 minutes 1 Rapid offset of action: context-sensitive half-time of 3.65 minutes, independent of duration of infusion (i.e. ‘context insensitive’) 1,2 Predictable offset with no residual opioid activity 5 – 10 minutes after discontinuation 3 Metabolised by non-specific blood and tissue esterases 1,4 Metabolism results in formation of remifentanil acid, which is 1/4600th as potent as its parent drug 3 1. Egan TD. Clin Pharmacokinet 1995; 29 : 80 – 94. 2. Westmoreland CL et al. Anesthesiology 1993; 79 : 893 – 903. 3. GlaxoSmithKline. Remifentanil HCl (Ultiva) SPC, June 2005. 4. Beers R et al . CNS Drugs 2004; 18:1085-104.
Unique metabolism amongst opioids Rapid offset of Precise titration and rapid action (<10min) 1 recovery 1,4 Rapidly Pharmacokinetics metabolised by Less inter-patient independent of obesity 4 non-specific pharmacokinetic and hepatic or renal variability 4 blood and tissue impairment 5-7 esterases 1, 2 Offset of action No accumulation 1 – 3 independent of duration of infusion 1,2 1. Egan TD. Clin Pharmacokinet 1995; 29 : 80 – 94. 4. Glass PSA. J Clin Anesth 1995; 7: 558 – 63. 2. Beers R, Camporesi E. CNS Drugs 2004; 18 : 085 – 104. 5. Westmoreland CL et al. Anesthesiology 1993; 79 : 893 – 903. 3. Schüttler J et al. Anaesthesia 1997; 52 : 307 – 17. 6. Dershwitz M et al . Anesthesiology 1996; 84: 812 – 20. 7. Dershwitz M et al . J Clin Anesthesia 1996; 8: 88S – 90S.
Quick response to changes in infusion rate Remifentanil and alfentanil have a similar time to peak effect in healthy volunteers After a 2 hour infusion Remifentanil has a more rapid offset of effect than alfentanil Alfentanil Remifentanil effect site concentration (%) effect site concentration (%) Proportion of the maximal Proportion of the maximal 100 100 Rapid onset Rapid offset 75 75 50 50 25 25 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 0 60 120 180 240 300 Time (min) Time (min) Egan T et al. Anesthesiology 1996; 84 : 821 – 33.
Lack of accumulation after use Remifentanil’s short context -sensitive half-time results in an offset of action independent of the duration of infusion (context insensitive) Time to 50% drop in concentration 100 Fentanyl at effect site (minutes) 75 Alfentanil 50 Sufentanil 25 Remifentanil 0 0 100 200 300 400 500 600 Duration of infusion (minutes) Simulation from a study in healthy volunteers (n=10) showing time necessary to achieve a 50% decrease in drug concentration in the blood (or plasma) after variable-length intravenous infusions Sufentanil is not licensed in the UK Egan TD et al. Anesthesiology 1993; 79 : 881 – 92.
Remifentanil in organ-impaired patients There is no significant difference in Remifentanil clearance between healthy control subjects and patients with kidney failure 1 or liver disease 2 Kidney failure 1 Liver disease 2 2.0 2.0 Remifentanil (ng/ml) Remifentanil (ng/ml) 1.5 1.5 1.0 1.0 0.5 0.5 Remifentanil 0.05 μg/kg/min Remifentanil 0.05 μg/kg/min 0.0 0.0 0 60 120 180 240 300 0 50 100 150 200 250 300 Time (min) Time (min) Renal failure (CrCl 9ml/min, n=15) Hepatic impairment (n=5) Control subjects (CrCl 88ml/min, n=8) Healthy subjects (n=5) Patients with severe hepatic impairment should be closely monitored and the dose of Remifentanil titrated to individual need, 3 as these patients may be more sensitive to the respiratory depressant effects of Remifentanil. 2 1. Hoke JF et al. Anesthesiol 1997; 87 : 533 – 41. 2. Dershwitz M et al. Anesthesiology 1996; 84 : 812 – 20. 3. GlaxoSmithKline. Remifentanil HCL (Ultiva) SPC. June 2005.
Why should Remifentanil be used in the ICU?
Remifentanil: why should it be used in the ICU? Remifentanil can be precisely titrated, facilitating patient interaction and assessment 1 – 3 Remifentanil enables a shorter weaning time and a reduction in the time spent on mechanical ventilation compared with traditional opioid analgesics 3 – 5 4. Dahaba AA et al . Anesthesiol 2004; 101 : 640 – 6. 1. Soltesz S et al . Br J Anaesth 2001; 86 : 763 – 8. 2. Muellejans B et al. Crit Care 2004; 8 : R1 – R11. 5. Muellejans B et al . Crit Care 2006; 10 : R91. 3. Wilhelm W et al. Eur J Anaesth 2004; 21 (Suppl): A-705
Precise down-titration facilitating interaction and assessment Remifentanil facilitates rapid emergence from analgesia and sedation allowing patient interaction within 10 minutes (n=10) 1 Faster recovery from analgesia and sedation with Remifentanil/propofol compared with fentanyl/midazolam facilitates neurological examination and potentially reduces the need for diagnostic investigations such as CT scans 2 1. Soltesz S et al . Br J Anaesth 2001; 86 : 763 – 8. 2. Wilhelm W et al. Eur J Anaesth 2004; 21 (Suppl): A-705. 3. Glass PSA. J Clin Anesth 1995; 7 : 558 – 63.
Precise up-titration facilitating interaction and assessment Remifentanil can be easily titrated: allowing painful, stimulating procedures to be performed 1 – 3 allowing painful procedures to be carried out in patients with head trauma without compromising haemodynamic stability 3 and can be administered at higher doses without concerns about accumulation 4 4. Soltesz S et al . Br J Anaesth 2001; 86 : 763 – 8. 1. Muellejans B et al. Crit Care 2004; 8 : R1 – R11. 2. Dahaba A et al. Anesthesiology 2004; 101 : 640 – 6. 3. Engelhard K et al. Acta Anaesthesiol Scand 2004; 48 : 396 – 9.
Remifentanil improves patient comfort Effective analgesia reduces pain and resulting anxiety, Ensures patient is Allows for better decreasing the need for pain-free, rather interaction with hypnotic agents 19,21,22 family and carers 21 than over- sedated 19,21,22 1. Lane M et al. Care Crit Ill 2002; 18 : 140 – 3. 2. Park G . Curr Anaesth Crit Care 2002; 13 : 313 – -20. 3. Lane M et al. Care Crit Ill 2002; 18 : 146 – 7.
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