“Decreased duration of mechanical ventilation when comparing analgesia-based sedation using remifentanil with standard hypnotic-based sedationfor up to 10 days in intensive care unit patients: a randomised tria l” Dr Peter Sherren
Analgesia Blunting or absence of sensation of pain or noxious stimuliSedation 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
Item Description ScoreFacial expression Relaxed 1 Partially tightened 2 Fully tightened 3 Grimacing 4Upper limbs No movement 1 Partially bent 2 Fully bent with finger flexion 3 Permanently retracted 4Compliance with ventilation Tolerating movement 1 Coughing but tolerating ventilation for most of the time 2 Fighting ventilator 3 Unable to control ventilation 4Source: 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 aninadequate 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 recovery from 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.
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.
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.
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.
Remifentanil (n =Characteristic 57) Comparator (n = 48) PNumber (%) of patients 29 (51%) 16 (33%)extubatedTime from start of study 83.0 98.0 0.523drugs to weaning (h) Difference (95% CI) -15.0 (-61.8 to 31.8)Time from start of study 94.0 147.5 0.033drugs to extubation(h) Difference (95% CI) -53.5 (-111.4 to 4.4)Time from weaning time 0.9 27.5 <0.001until extubation (h) Difference (95% CI) -26.6 (-40.8 to -12.4)Time from start of studydrugs 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
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 doseSource: Crit Care. 2005; 9(3): R200–R210
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 studys 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/cc23983. 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: 10.1097/00000542-200409000-000124. 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.