Dr Peter Sherren

“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 trial”

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

• Riker Sedation-Agitation Scale (SAS)

• Motor Activity Assessment Scale (MAAS)

• Ramsay Scale

• Homerton’s own

• Self Reporting- Gold standard

• Numerical Rating Scale (NRS)

• Behavioural Pain Scale (BPS)

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

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

Causes/consequences of an Causes/consequences of an inadequate analgesia/sedationinadequate analgesia/sedation

• 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 recoveryfrom most IV anesthetics

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

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

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

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

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.

CitationBreen 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

BackgroundSedation 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.

ObjectiveThis 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.

DesignThis study was a randomised, open-label, multicentre, parallel-group.

Setting10 countries and 15 medical centres.

SubjectsPatients 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.

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.

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.

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 ± 1.1aBaseline 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.

CharacteristicRemifentanil (n = 57)

Comparator (n = 48) P

Number (%) of patients extubated

29 (51%) 16 (33%)

Time from start of study drugs to weaning (h)

83.0 98.0 0.523

 Difference (95% CI) -15.0 (-61.8 to 31.8)

Time from start of study drugs to extubation(h)

94.0 147.5 0.033

 Difference (95% CI) -53.5 (-111.4 to 4.4)

Time from weaning time until extubation (h)

0.9 27.5 <0.001

 Difference (95% CI) -26.6 (-40.8 to -12.4)

Time from start of study drugs until ICU discharge (h)

187.3 209.8 0.326

 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

Source: Crit Care. 2005; 9(3): R200–R210

Kaplan–Meier survival plot of time to extubation (days)

Source: Crit Care. 2005; 9(3): R200–R210

Median time to offset of effects as measured by the time to therapeutic

intervention

Source: Crit Care. 2005; 9(3): R200–R210

Mean total midazolam dose

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

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.

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.

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.

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.

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.