This randomized trial compared analgesia-based sedation using remifentanil versus standard hypnotic-based sedation for up to 10 days in intensive care unit patients requiring mechanical ventilation. It found that remifentanil reduced the duration of mechanical ventilation and improved the weaning process compared to standard sedation. Specifically, remifentanil decreased the time from starting treatment to extubation by an average of 53.5 hours and decreased the time from starting weaning to extubation by 26.6 hours on average. Remifentanil also required less sedative medication compared to standard therapy. The adverse event profiles were similar between the two groups.

1. “Decreased duration of mechanical ventilation when comparing analgesia-
based sedation using remifentanil with standard hypnotic-based sedation
for up to 10 days in intensive care unit patients: a randomised tria l”
Dr Peter Sherren

2. Analgesia
 Blunting or absence of sensation of pain or noxious stimuli
Sedation
 Complex neurophysiologic condition
• Anxiolysis
• Hypnosis (minimal motor activity; physically similar to sleep)
• Amnesia
 Needs for sedation vary widely
 Target level: Sedation scoring

3. • Riker Sedation-Agitation Scale (SAS)
• Motor Activity Assessment Scale (MAAS)
• Ramsay Scale
• Homerton’s own

4. • Self Reporting- Gold standard
• Numerical Rating Scale (NRS)
• Behavioural Pain Scale (BPS)

5. Item Description Score
Facial expression Relaxed 1
Partially tightened 2
Fully tightened 3
Grimacing 4
Upper limbs No movement 1
Partially bent 2
Fully bent with finger flexion 3
Permanently retracted 4
Compliance with ventilation Tolerating movement 1
Coughing but tolerating ventilation for
most of the time 2
Fighting ventilator 3
Unable to control ventilation 4
Source: Ahlers et al. Critical Care 2008 12:R15 doi:10.1186/cc6789

6.  Anxiety
• Fear, apprehension
• Multi-factorial: inability to communicate, continuous lightingand stimulation, sleep
deprivation, fight or flight.
 Agitation
• Physiological disturbance (Hypoxemia/tension/glycaemia, Biochemical, Pyrexia,
Bacteraemia etc)
• Multi-factorial: pain, withdrawal, delirium, adverse drug effects, extreme anxiety
 Pain
• ITU environment (Sleeplessness, tubes, lack of control and autonomy, lack of information,
immobilisation, dressings etc)
• Underlying Pathology
• Trauma and surgical procedures (major and minor)
• Cytokine Overload (TNF, IL-1/6/8 +++)
 To allow ITU intervention and expedite care

7. Causes/consequences of an
inadequate analgesia/sedation

10. • The time for the drug concentration to decrease
a set percentage varies according to the duration
of infusion
• “Context-sensitive half-time” is the time taken for
the plasma concentration to decrease by 50%,
following an infusion, of a given duration.
• A 50% reduction is necessary for recovery
from most IV anesthetics

12.  Phenanthrene, Vd 3.5, T1/2 180 min
 Pharmacologic effects of δ/μ/κ-receptor agonists
 Analgesia, respiratory depression, GI effects, orthostatic
hypotension, sedation and altered mentation
 Metabolism
• Glucuronide conjugation; active metabolite, morphine-6-
glucoronide (5-10%) and renally eliminated
• Prolonged effects in renal/hepatic failure
 Adverse effects
• Histamine release (allergic rxns, hypotension)
• N&V, Pruritis

13.  Synthetic anilino-piperidine opoid-like agonist
• Vd 4, T ½ β 350min
• 100x more potent than morphine, μ agonist
• Lipophilic 580x morphine: rapid (lipophilic)
 CV stable
• No histamine release, no hypotension
• Bradycardia
 Metabolism
• No active metabolites, dealkylation to nor fentanyl-> hydroxylation ->
Excreted renally
• Clearance affected by age, obesity, plasma protein content, liver
disease, renal insufficiency
• 2+ compartment model pharmacokinetics, context sensitive T ½, both
an α and β T ½, plasma 13 min, Terminal 350 min

14.  Anilo-piperidine analogue of fentanyl
• 20x potency of morphine, μ agonis
• Onset 90 seconds due to pKa
• Vd 0.8, pKa 6.5, Plasma T ½ 13, terminal T ½ 90 min
 Pharmacological effects
• Hypotension, bradycardia and obtunds hypertensive response to
laryngoscopy
• Chest wall rigidity
• Minimal histamine release
 Metabolism
• Hepatic N dealkylation to noralfentanil, inactive metabolite
• Virtually no accumulation or prolonged terminal half life due to lower
lipid solubility

15.  Synthetic anilino-piperidine opoid without methyl ester
linkage
• Potent μ agonist, 100x morphine
• 50x relative lipid solubility to morphine, rapid onset/offset
• Vd 0.35, T ½ 15 min
 Similar effect to alfentanil
 Metabolism
• independent of hepatic and renal function
• de-esterification by non specific plasma and tissue esterases to
inactive metabolites

16.  Optimal analgesia to alleviate anxiety and distress
 Need to improve weaning/extubation times
 Time on ITU
 Adverse Events
 Sedative requirements
 Ideal analgesic agent
 Does not negate good ITU practice, sedation breaks
etc. Simply an adjunct to best practice.

17.  Citation
Breen D, Karabinis A, Malbrain M, Morais R, Albrecht S, Jarnvig I-L, Parkinson P, Kirkham AJT:
Decreased time on mechanical ventilation when comparing analgesia-based sedation
using remifen-tanil versus standard hypnotic-based sedation for up to 10 days in ICU
patients: a randomised trial. [ISRCTN47583497].
Crit Care 2005, 9:R200-R210
 Background
Sedation and analgesia on the ITU is a complex balancing act. At all times trying to
ensure optimal patient comfort in a group that have a variety of problems and
organ dysfunction as well as often quite protracted length of stay. All of which in
combination with the various drug interactions can alter the pharmacological effect
of all our therapies. Remifentanil in some respects ticks most of the boxes of an
ideal opioid, bar cost. Its use on the ITU seems to have a great deal of potential.

18.  Objective
This study aimed to assess the efficacy and safety of a prolonged infusion
of remifentanil in critically ill patients for up to 10 days in comparison
with a standard sedative regime of midazolam plus a traditional opioid.
 Design
This study was a randomised, open-label, multicentre, parallel-group.
 Setting
10 countries and 15 medical centres.
 Subjects
Patients requiring long-term mechanical ventilation for medical reasons.
Post-op patients requiring extended mechanical ventilation as a result of
post-surgical complications were also included. Patients were eligible if
they were more than 18 years old, had been admitted to the intensive care
unit (ICU) within the previous 30 hours, were expected to require
mechanical ventilation for longer than 96 hours and required analgesia
and sedation.

19.  Exclusion Criteria
• Pregnant females
• Patients with condition preventing sedation assessment
• If likely to require tracheostomy/surgery during treatment
• If NMJ blocking agents required by infusion
• Epidural analgesia
• Anaesthetic agents beyond the specified
• Sensitivity to any of the specified drugs
• History of alcohol or drug abuse
 Intervention
• 105 patients were randomised in a 1:1 ratio to receive either a
remifentanil-based regime or a comparator hypnotic-based regime
using midazolam with either morphine or fentanyl for analgesia.

20.  Study End points
• The primary endpoint was the time from the start of study drug to
extubation. Secondary endpoints were the time from start of study
drug until start of weaning, the time from start of weaning until
extubation, the time from start of study drug to ICU discharge.
• The safety endpoints were the offset of pharmacodynamic effects of
study drugs after permanent discontinuation, haemodynamic effects,
clinical adverse events and the requirement for re-intubation.
• Serious adverse events were defined as adverse events that resulted
in any of the following outcomes: death, life-threatening event,
prolongation of hospitalisation, or a disability or incapacity.
 Statistics
• The time to event endpoints were analysed with the generalised
Wilcoxon test with a two-sided α level of 5% judged to indicate a
statistically significant difference between the treatment groups.

21. Characteristic Remifentanil Comparator
Number of patients treated 57 48
Medical (%)/post-surgical (%) 49 (88)/7 (13) 44 (92)/4 (8)
Emergency (%)/elective (%) 27 (84)/5 (16), n = 32 21 (91)/2 (9), n = 23
Age (years) 52.2 ± 18.4 57.3 ± 18.1
Male (%)/female (%) 39 (68)/18 (32) 32 (67)/16 (33)
Height (cm) 171.2 ± 9.7 169.0 ± 7.9
Weight (kg) 78.6 ± 13.41 76.3 ± 15.50
SAPS II on admission 43.0 ± 15.6 43.3 ± 11.2
MAP (mmHg)a 88.8 ± 16.5 88.9 ± 14.8
Heart rate (b.p.m.)a 98.9 ± 20.1 95.9 ± 15.5
SAS scorea 3.3 ± 1.3 3.3 ± 1.4
PI scorea 2.0 ± 1.2 2.1 ± 1.1
aBaseline values. Where errors are given, results are means± SD. MAP, mean arterial pressure; PI, pain intensity; SAS,
Sedation–Agitation Scale.
Crit Care. 2005; 9(3): R200–R210.

22. Remifentanil (n =
Characteristic 57) Comparator (n = 48) P
Number (%) of patients
29 (51%) 16 (33%)
extubated
Time from start of study
83.0 98.0 0.523
drugs to weaning (h)
Difference (95% CI) -15.0 (-61.8 to 31.8)
Time from start of study
94.0 147.5 0.033
drugs to extubation(h)
Difference (95% CI) -53.5 (-111.4 to 4.4)
Time from weaning time
0.9 27.5 <0.001
until extubation (h)
Difference (95% CI) -26.6 (-40.8 to -12.4)
Time from start of study
drugs until ICU discharge 187.3 209.8 0.326
(h)
Difference (95% CI) -22.5 (-201.5 to 156.5)
Point estimates are 75th centiles. CI, confidence interval.
Source: Crit Care. 2005; 9(3): R200–R210

23. Kaplan–Meier survival plot of time to
extubation (days)
Source: Crit Care. 2005; 9(3): R200–R210

24. Median time to offset of effects as measured
by the time to therapeutic intervention
Source: Crit Care. 2005; 9(3): R200–R210

25. Mean total midazolam dose
Source: Crit Care. 2005; 9(3): R200–R210

26.  Matching
• The two treatment groups were well matched in terms of patient characteristics
and baseline clinical assessments.
 Efficacy
• Fewer than 50% of patients were extubated during the 10-day treatment period
(45 of 105). There was no difference in the time to the start of the weaning
process. There was a statistical and clinically significant difference between the
two groups in the study's primary endpoint of time of starting the drug to
extubation. A Kaplan–Meier plot analysing the duration of mechanical
ventilation, the time difference was 53.5 hours, being shorter in the remifentanil
group (P = 0.033). The time from the start of the weaning process to extubation
was also significantly different at 26.6 hours, also in favour of remifentanil (P <
0.001).
• The median percentage time of optimal analgesia/sedation was comparable for
both groups (remifentanil 96.9%, comparator 97.8%, median difference -0.3,
95% confidence interval -2.7 to 0.2; P = 0.16).
 Safety
• Comparable

27.  Exposure to Study drugs
• Of the patients treated with remifentanil, 26% (15 of 57) did not receive any
midazolam during the study. There was nearly a ninefold difference in mean
total midazolam requirements in the fentanyl group compared with the
remifentanil group, and a fourfold difference in the morphine group compared
with the remifentanil group.

28.  Analgesia-based sedation with remifentanil was well
tolerated; it reduces the duration of mechanical ventilation
and improves the weaning process compared with standard
hypnotic-based sedation regimes in ICU patients requiring
long-term ventilation for up to 10 days.
 Reminfentanil is sedative sparing and has a very rapid offset
even after a 10-day infusion, with no evidence of
accumulation.
 The adverse event profile was similar in remifentanil-based
and other hypnotic-based regimes.

29.  One particular concern was that the titration of remifentanil was based on
a fixed protocol, but the titration of the comparator benzodiazepine
infusion was not.
 There was no statistical difference in the time from start of study drug to
the beginning of the weaning process, however, this process was begun in
the remifentanil group an average of 15 hours earlier.
 The authors do mention that the sedation levels were matched in both
groups, during treatment and in the post-treatment period, and that the
differences were due to the drug per se and not the level of sedation. In
an unblinded trial, if no reason for the delay is offered, the potential for
bias is there.
 Competing interest with funding from GSK to some of the centres
involved.

30.  The technique of using remifentanil as the primary sedative
and analgesic, with the addition of traditional sedatives such
as propofol or midazolam only if necessary, has been
studied in ICU patients for up to 3 days (1,2,3) and in
neurosurgical patients studied for up to 5 days, with good
results (4).
 The end of Fentanyl infusions?
 Clearly a rigorous double blinded RCT is needed.
 Of particular interest is in the cost/benefit ratio of alfentanil
vs remifentanil, as pharmacokinetically alfentanil and
remifentanil demonstrate similar profiles.

31. 1. Breen, D; Wilmer, A; Bodenham, A; Bach, V; Bonde, J; Kessler, P; Albrecht, S; Shaikh, S. Offset of
pharmacodynamic effects and safety of remifentanil in intensive care unit patients with various
degrees of renal impairment. Crit Care. 2004;8:R21–R30. doi: 10.1186/cc2399.
2. Muellejans, B; Lopez, A; Cross, MH; Bonome, C; Morrison, L; Kirkham, AJT. Remifentanil versus
fentanyl for analgesia based sedation to provide patient comfort in the intensive care unit: a
randomised control trial [ISRCTN43755713]. Crit Care. 2004;8:R1–R11. doi: 10.1186/cc2398
3. Dahaba, AA; Grabner, T; Rehak, PH; List, WF; Metzler, H. Remifentanil versus morphine
analgesia and sedation for mechanically ventilated critically ill patients: a randomised double
blind study. Anesthesiology. 2004;101:640–646. doi: 10.1097/00000542-200409000-00012
4. Karabinis, A; Mandragos, K; Stergiopoulos, S; Komnos, A; Soukup, J; Speelberg, B; Kirkham,
AJT. Safety and efficacy of analgesia-based sedation using remifentanil versus standard
hypnotic-based regimens in intensive care unit patients with brain injuries: a randomised,
controlled trial [ISRCTN50308308]. Crit Care. 2004;8:R268–R280. doi: 10.1186/cc2896.