daniel.conway@cmmc.nhs.uk

Remifentanil in ICU @ Manchester Royal Infirmary

Daniel Conway

Consultant in Critical Care

Manchester Royal Infirmary

Sedation & Analgesia on ICU – an uncomfortable paradigm

Traditional analgesics will accumulate over time + metabolites

Painful procedures, general discomfort should be treated

Excess sedation extends length of stay and may worsen PTSD symptoms

Inadequate sedation or analgesia may worsen PTSD symptoms

Moving Away from Sedation

• Early detection of neurological problems– Stroke / bleeds / hypoxia– Delirium

• Early extubation before tracheostomy• ‘Fast track’ major surgery with regional

analgesia• Withdrawal and weaning• Reduced ICU length of stay

Shorter Acting Agents

• Propofol Carsson, Kress Crit Care Med 2006

– Rapid offset due to redistribution– Hypotension & ? acidosis

• Alfentanil– Minimal metabolites– Less accumulation than morphine & fentanyl

• Remifentanil– Esterase metabolism– Rapid offset

Remifentanil Pharmacokinetics

• Rapid offset 6-8 minutes

• Independent of Renal / Hepatic Function

• Independent of BMI

• Titratable– Analgesia– Respiratory depression

Stable context sensitive t1/2

Egan Anaesthesiology 1993;79: 881-92

Hypnotic or Narcotic ????

Hypnotic or Narcotic ????

BDZ & Propofol• GABA agonist• Anxiolytic / amnesic• Prolong Ventilation• Cause delirium• Contribute to long

term cognitive dysfunction

Opioids & α2 agonists

• Hypotensive• Analgesic• Withdrawal phenomena• Less delirium ?• Long term cognition?

Remifentanil on ICU?

• Neurological examination

• Analgesia for procedures

• Patients with hepatic and renal impairment

• Fast track extubations– Surgical– Short stay medical eg overdose

• All Patients who require analgesia ????

Remifentanil on general ICU Breen D, Karabinis A et al Crit Care 2005

• Open Label RCT remi v midaz/ morph fent

• 105 patients in 15 ICU’s

• Exclusions: NMBA, surgery, epidural, sensit

• Remi dose 0.2 mcg/kg/min

• Time to extubation, LOS on ICU

• SAS, Pain Index, mAP, 6 day follow up

Remifentanil on ICU Breen D, Karabinis A et al Crit Care 2005

• ↓ Midaz dose

• Similar Sedation & Pain scores

• ↑ Vomiting with remi

• Non-sig ↓ in ICU LOS with remi

Remifentanil on ICU Breen D, Karabinis A et al Crit Care 2005

• Re-intubations 7/25 remi v 2/12 hypnotic

Head Injury

Remifentanil With Head Injury Karabinis A et al Crit Care (2004)

• Analgesia based v hypnotic regime – Remifentanil v Fentanyl v Morphine– Midazolam or propofol also used

Remifentanil 15mcg/kg/hr (0.25mcg/kg/min)

• 161 patients in 17 hospitals open label RCT

• LOS, SAS, mAP, HR, ICP and CPP

• Time to extubation

Remifentanil With Head Injury

Karabinis A et al Crit Care 2004

• Similar mAP HR• No difference in ICP or

CPP• ↓ Propofol requirement• Optimal sedation

– 95% of time – remi– 99% of time -

fentanyl

Improved time to neurological assessment with remi

Karabinis A et al Crit Care 2004

Hypnotic v Analgesic sedationPark, Lane B J Anaes 2007

• 12 wk hypnotic based drugs

• 12 wk analgesics (predominantly remi)

• All ventilated patients

• Excluded if NMBA

• Looked at Mortality / LOS / dreams memory

• Looked at drug use

Hypnotic v Analgesic sedationPark, Lane B J Anaes 2007

• 111 Hyp and 96 Ana patients

• Age 58 v 56

• APACHE II 16.5 v 18.1

• ICU Mortality 23% v 26%

• Hosp Mortality 31% v 35%

• Time on Vent 37h v 71h n/s

• LoS ICU 67 v 118

Hypnosis v AnalgesiaPark, Lane BJA 2007

• 37% of patients could be managed with remifentanil alone

• 40-50% experienced dreams or hallucinations which most found unpleasant

• 5 accidental extubations in analgesic (3 on remi) vs 2 in hypnotic

• Remi reduced propofol requirements

Remifentanil on ICU: Tolerance, Side Effects and Withdrawal

It’s an opioid !• Tolerance with prolonged infusion Vinik An Anal 98

• Side Effects– Bradycardia and Hypotension– Nausea/Vomiting/Ileus– Respiratory Depression

• Withdrawal phenomena Apitzsch Anaesthetist 99

Remifentanil and GlycineBonnet MP, Benhamou D et al Int Care Med 07

• Glycine: inhibitory neurotransmitter

• Remi powder has 3mg glycine for each mg remi

• 72 hour infusion, toxic levels NOT reached

• Correlation between remi rate and glycine levels

• Glycine accumulation with ↓ Creat CL

Remifentanil in Manchester

Implementing Remifentanil @ MRI

• Consultants Agree Patient Group

• Pharmacist produces guidelines

• Nurse Education Practitioner

• Regular Meetings

• Audit use month on month

• Guidelines modified

Remifentanil on ICU @ MRI

• Indication– Analgesia and sedation– Head injury / early extubation– Hepatic and Renal Impairment

• Contra-indications– Spont Vent or NIV or paralysed– Opioid intolerance– Bolus administration

Remifentanil Guideline MRI

• Duration 3 Days max

• Constitution– 100μg/ml in 50 ml N/Sal or 5%Dex

• Withdrawal– Stop infusion if no further analgesia– Reduce by 25% every 15min if alt analgesic

Start Anxiolysis propofol or midazolam

Patient needs analgesia/sedation

Patient needs further analgesia/sedation

Not For Remifentanil

Patient paralysed/ encephalopathic

6mcg/kg/h Remifentanil

Increase Remifentanil 1.5 mcg/kg/h

At 12mcg/kg/h Remifentanil

Patient still needs analgesia/sedation

If remains in pain increase remifentanil 15mcg/kg/h + propofol or midazolam AND D/W Doctor

Case Study 1

• 72 yr man, alcoholic liver disease• Urinary obstruction and sepsis• Acute on chronic renal failure• Agitated & Hypoxic ?? needs CVVH, • Ventilated 40 hours• Renal function improves without CVVH• Remifentanil and propofol stopped • Extubated & sent to ward next day

Case Study 2

• 38 yr woman, Tracheal reconstruction surgery. Surgeons want sedated 48hrs

• Remifentanil peri-op

• Taken back to theatre day 1

• Remifentanil & propofol continued 48 h

• Controlled titration of remifentanil until patient awake and not agitated / coughing

Summary: Remifentanil on ICU

• Short acting opioid for analgesia & sedation

• Useful in renal patients

• May facilitate early extubation

• Take care when stopping infusions

• Staff training was essential

• Start Pain Scores

nfusion rates of remifentanil by body weight using a 100μg/mL solution Body

weight (kg)

6 μg/kg/h(mL/h)

9 μg/kg/h (mL/h)

12 μg/kg/h (mL/h)

15 μg/kg/h (mL/h)

40 2.4 3.6 4.8 6.0

45 2.7 4.1 5.4 6.8

50 3.0 4.5 6.0 7.5

55 3.3 5.0 6.6 8.3

60 3.6 5.4 7.2 9.0

65 3.9 5.9 7.8 9.8

70 4.2 6.3 8.4 10.5

75 4.5 6.8 9.0 11.0

80 4.8 7.2 9.6 12.0

85 5.1 7.7 10.2 12.8

90 5.4 8.1 10.8 13.5

95 5.7 8.6 11.4 14.3

100 6.0 9.0 12.0 15.0

105 6.3 9.5 12.6 15.8

110 6.6 9.9 13.2 16.5

115 6.9 10.4 13.8 17.3

120 7.2 10.8 14.4 18.0

• Key messages In neurotrauma patients requiring intensive care for up to 5 days, analgesia-based sedation using remifentanil compared with a standard hypnotic-based technique provided the following:

• • a significant reduction in the mean time taken to wake the patient for assessment of neurological function;• a significantly reduced mean between-patient variability in the time to wake-up, making the performance of this assessment more predictable;• a significantly shorter time to extubation than with a hypnotic-based regimen using morphine as the analgesic;• no clinical differences in pain and sedation scores;• a trend towards reduced dosing with propofol;• comparable haemodynamic and cerebral haemodynamic stability;• higher user satisfaction rating by physicians and nurses;• a similar safety profile.