If blood pressure fell rapidly, the opioid maintenance infusion rate decrease could be accompanied by simultaneous administration of vasopressors.
Further vasopressor treatment was to be used if these interventions were not successful. The propofol infusion rate could be adjusted accordingly if additional sedation was required. If additional analgesia was required a bolus dose of open label morphine could be administered at the minimum dose necessary to provide patient comfort according to standard local practice and this was recorded as rescue treatment. The down titration period started 30 min later as long as the patient still met the criteria for weaning from study opioid.
If additional analgesia was required during this period, an open label bolus dose of morphine minimum dose 0. If the patient had not met the criteria for beginning the extubation sequence by 4. Patients were eligible for transfer from ICU if stable conditions continued. Vital signs were recorded immediately before induction of anaesthesia baseline values and at regular intervals throughout surgery and in the ICU.
MSEs were defined as intubation, sternal skin incision, sternotomy, maximal sternal spread MSS , and sternal wire placement. Arterial pressure was recorded at the start of cardiopulmonary bypass and every 15 min until the patient went off bypass. Vital signs and pain and sedation scores were also recorded at 15, 30, 45, 60, 90, and min after discontinuation of study opioid infusion. The primary efficacy endpoint was response to MSS. Secondary efficacy endpoints included responses to intubation, sternal skin incision, sternotomy, and sternal wire placement.
Efficacy was evaluated by the number of patients who showed signs of inadequate anaesthesia and by the number of treatments for responses indicative of inadequate or excessive anaesthesia. Overall use of study drug, propofol and other medications were noted. Patients were continually assessed for occurrence of adverse events including negative cardiac outcomes throughout the perioperative period and up to the end of postoperative day 5 or up to hospital discharge if this occurred earlier.
To compensate for withdrawals and to obtain additional safety data, up to randomized patients were to be included in the study. The study was stopped when patients had been recruited because of time restriction. The hidden entry envelopes were allocated sequentially to each subject eligible for study entry and the corresponding treatment allocation and drug preparation was performed by a named person, independent to the conduct of the study.
In most instances this was the hospital pharmacist. Logistic regression analyses were used to analyse the proportions of patients with responses to MSS. The weighted mean pain and sedation scores during the ICU down titration were analysed using the Wilcoxon rank sum test. The treatment differences in overall use of alternate analgesics until extubation, were analysed using logistic regression analysis.
The two groups were well matched with regard to gender, ethnic origin, age, height, weight, and ASA status distribution Table 1. The mean ejection fraction was similar in the remifentanil 0. Two patients in each group had previous CABG surgery. The median durations of surgery, of bypass, and of aortic cross clamping were comparable between the two groups.
The median sd time from the start of study drug to skin closure was 3. The median sd durations of bypass and of aortic cross clamping were 1. The mean remifentanil infusion rate at the time of MSS was 1. In the fentanyl group, the cumulative fentanyl bolus dose administered at this point was Fentanyl F cumulative bolus doses were 7. Propofol varied between R 2. Figures 1 and 2 present the SBP and HR profiles during key stages during surgery for both treatment groups.
Table 2 summarizes the postoperative recovery times in the remifentanil and fentanyl anaesthesia groups. The median times to eligibility for, and for actual transfer from the ICU to less intense monitoring were similar in the remifentanil and fentanyl groups. Pain and sedation scores were assessed at scheduled times during the ICU down titration period and following discontinuation of study drugs.
During the ICU transition period, the weighted mean sedation score was slightly but significantly higher in the remifentanil group score 3. Both anaesthetic regimens were well tolerated. Both of these events were most commonly reported during the ICU period. A total of 13 patients remifentanil five, fentanyl eight were withdrawn from the study because of adverse events. In these patients anaphylactic reaction and bleeding from the chest wall, respectively, were given as the reason for patient withdrawal.
Neither of these events was assessed as related to study drug. In a further three patients the phase of the adverse event was not specified. The events leading to withdrawal in these three cases were postoperative haemorrhage, left ventricular failure, and case of bleeding leading to haemodynamic instability, respectively. In the latter case, the event was considered possibly related to study drug. This article has been cited by other articles in PMC.
Abstract Introduction This double-blind, randomized, multicentre study was conducted to compare the efficacy and safety of remifentanil and fentanyl for intensive care unit ICU sedation and analgesia. Results The mean percentages of time in optimal sedation were Conclusion Analgesia based sedation with remifentanil titrated to response provided effective sedation and rapid extubation without the need for propofol in most patients.
Keywords: analgesia, analgesia based sedation, critical care, fentanyl, propofol, remifentanil, renal function, sedation. Introduction The provision of effective analgesia and sedation for patients in the intensive care unit ICU is important in controlling pain, relieving agitation and anxiety, and aiding compliance with mechanical ventilation, and thereby maintaining patient comfort. Methods The study was conducted in accordance with good clinical practice and with the guidelines set out in the Declaration of Helsinki.
Treatment protocol The aim of the study was to achieve optimal sedation and patient comfort by maintaining an optimal SAS score of 4, without clinically significant pain, until the start of the extubation process or for 72 hours, whichever occurred first. Table 1 The Sedation—Agitation Scale. Score Description Example 7 Dangerous agitation Pulling at endotracheal tube, trying to remove catheters, climbing over bedrails, thrashing from side to side, striking at staff 6 Very agitated Patient does not calm down in response to verbal instructions or reassurance, requires physical restraint, biting endotracheal tube 5 Agitated Anxious or agitated but calms down in response to verbal instructions or reassurance 4 Calm, cooperative Calm, easily rousable, follows commands 3 Sedated Difficult to rouse, awakens to verbal stimuli or gentle shaking but drifts off again, will follow simple commands 2 Very sedated Can be roused by physical stimuli but does not communicate or follow commands, may move spontaneously 1 Not rousable May move or grimace minimally to stimuli but does not communicate or follow commands.
Open in a separate window. Figure 1. Dosing algorithm: maintenance phase. Patient monitoring In addition to SAS and PI scale scores, mean arterial pressure MAP and heart rate HR were recorded at baseline, and approximately every 20 min from the start of study drug administration for the first 6 hours, then every hour until extubation, and immediately before and 10 min after changes in study opioid or propofol dose.
Study end-points The primary efficacy end-point was the between-patient variability about the mean percentage of hours of optimal sedation i.
Results A total of patients remifentanil, 81 fentanyl were evaluable for safety. Table 2 Patient demographic and clinical characteristics. Table 3 Duration of study periods. Table 4 Mean percentage of hours of optimal sedation intent to treat population. Table 5 Exposure to study opioids and propofol during the maintenance phase intent to treat population.
Safety Both treatment regimens were well tolerated. Table 6 Haemodynamic parameters during the study period safety population. Conclusion In conclusion, initiation and titration of remifentanil before administration of propofol allowed effective provision of optimal sedation and rapid extubation without the need for propofol in the majority of patients with normal renal function or mild renal impairment. Synergistic sedation with propofol and midazolam in intensive care patients after coronary artery bypass grafting.
Crit Care Med. Propofol vs midazolam in short-, medium- and long-term sedation of critically ill patients. Pharmacokinetics of remifentanil GIB and its major metabolite GR in patients undergoing elective surgery. Measured context-sensitive half-times of remifentanil and alfentanil. Remifentanil in the critically ill — what will its place be?
Br J Intensive Care. Sedation in the critically ill patient. Curr Opin Anaesthesiol. Remifentanil in intensive care medicine. J Anasth Intensivbehandl. Remifentanil in anesthesia and intensive care. Minerva Anestesiol. Learning to use remifentanil routinely in the critically ill.
Care Crit Ill. The use of remifentanil in the critically ill. Sedation and analgesia in the critically ill patient using remifentanil: frequently asked questions and their answers. Improving sedation and analgesia in the critically ill. Safety and feasibility of continuous infusion of remifentanil in the neurosurgical intensive care unit. A remifentanil-based technique for analgesia and sedation in ICU patients with neurotrauma: preliminary data [abstract A] Intensive Care Med.
Recovery after remifentanil and sufentanil for analgesia and sedation of mechanically ventilated patients after trauma or major surgery. Br J Anaesth. The offset of pharmacodynamic effects of remifentanil in ICU patients is not affected by renal impairment [abstract A] Intensive Care Med. Pharmacokinetics and pharmacodynamics of remifentanil in persons with renal failure compared with healthy volunteers. Remifentanil as an analgesic in the critically ill.
The use of remifentanil in critically ill patients. An initial clinical experience report. Experience with remifentanil in the intensive care unit. A low-dose remifentanil infusion is well tolerated for sedation in mechanically ventilated, critically ill patients. Can J Anesth. In contrast, the German Society of Anaesthesiology and Intensive Care Medicine opted not to recommend the use of morphine when opioids are needed for longer than 24 hours [ 5 ].
These agents are synthetic opioids of the 4-anilidopiperidine group and they are commonly used in the operating room. These opioids also undergo hepatic metabolism, and their continuous infusion can lead to accumulation as well as prolonged drug effects. This is especially so in critically ill patients, in whom drug clearance may be substantially reduced because of illness, organ dysfunction, or concomitant therapy.
Therefore, use of fentanyl, alfentanil, and sufentanil as well as morphine in ICU patients is always accompanied by concerns regarding drug accumulation, which potentially can lead to prolonged respiratory depression and delayed and unpredictable recovery. Fentanyl is available worldwide, but alfentanil is not commonly used in North America [ 4 ], and neither alfentanil nor sufentanil are licensed for use in ICU patients in many countries.
When these opioids are compared, alfentanil is the drug with the most rapid onset of action and the shortest duration of effect. However, alfentanil is a substrate for different cytochrome PA enzymes, and its metabolism and offset of effect can underly interindividual variability due to polymorphic enzyme expression and can markedly be inhibited by different drugs, including antibiotics and antifungal medication [ 6 ].
Thus, although single bolus injections of alfentanil are short acting, the effects of an infusion of alfentanil in ICU patients are much less predictable, and so this drug is not the ideal short-acting opioid for use in the ICU. Since intensivists identified the potentially devastating impact of accumulation of analgesic and sedative drugs on patient outcomes, various attempts have been made to limit such accumulation. Means include daily interruption of infusion of sedatives and analgesics [ 7 ], intermittent bolus injections rather than continuous infusions [ 8 ], and selecting ventilatory support that permits more spontaneous than controlled ventilation [ 9 ], among many others.
These techniques are discussed in detail in the other reviews included in this supplement. However, these techniques at best only limit the effects of drug accumulation, but they do not solve the problem itself. Therefore, a totally different approach is needed, one that involves a drug that undergoes rapid and complete metabolism, independent of the duration of infusion or any organ insufficiency.
In remifentanil received approval from the European Medicines Agency for provision of analgesia for a duration of up to 3 days in mechanically ventilated ICU patients, aged 18 years or older. However, in contrast to fentanyl and its congeners, remifentanil is completely metabolized by unspecific esterases.
In principle, esterases are enzymes that break down esters into their alcohol and acid components. The term 'unspecific' means that one enzyme not only catalyzes a specific reaction but is also able to break down other ester linkages, for example, that of remifentanil.
Because unspecific esterases are involved in multiple steps in the metabolism of the living human cell, no ICU disease or organ failure has yet been identified that can cause reduced breakdown of remifentanil. The clearance of RA is reduced in patients with impaired renal function, and the half-life of RA increases to 14 to 32 hours in these patients [ 14 , 15 ].
Because of its unique pharmacokinetic profile, remifentanil is characterized by a rapid and uniform clearance and a highly predictable onset and offset of effect [ 11 ].
Remifentanil has a terminal half-life of approximately 10 to 20 minutes [ 16 ], and its context-sensitive half-time is 3 to 4 minutes, regardless of the duration of infusion [ 10 ].
In contrast, continuous infusions of the other 4-anilidopiperidine opioids result in accumulation and considerable prolongation of effect with increased duration of infusion [ 10 ], making these opioids intermediate-acting or long-acting agents during prolonged infusion Figures 1 and 2. Context-sensitive half-times of remifentanil and the other 4-anilido-piperidine opioids. Remifentanil has a context-sensitive half-time of 3 to 4 minutes, regardless of the duration of infusion, whereas continuous infusion of the other opioids results in accumulation and considerable prolongation of effect, making these opioids intermediate-acting or long-acting agents, depending on the duration of infusion.
Anesthesiology , — Decline of effect site concentrations of different opioids after 24 hours of infusion. The findings are expressed as percentage of the individual maximum effect site concentration. This figure was calculated using Stanpump simulation software by Shafer S, University of Stanford, CA, USA for a female individual age 80 years, height cm, body weight 80 kg and the following infusion rates: remifentanil 0.
Although remifentanil is not licensed for applications for longer than 3 days, several of the reports reviewed here and in other reviews included in this supplement have addressed its use for longer periods. The first experiences with the use of remifentanil in ICU patients were reported shortly after remifentanil became available for use in the operating room. In a case series of six patients, Evans and Park [ 17 ] reported successful use of remifentanil for analgesia and sedation during mechanical ventilation for 3 to 33 days.
The infusion rate ranged from 0. After 24 hours of remifentanil infusion at a mean rate of 0. In another study conducted in 46 ICU patients aged Extubation times after remifentanil infusion. Shown are extubation times in 46 intensive care unit patients after sedation with a remifentanil infusion mean duration 9. Clinical findings and early experience. Anaesthesist , — Within the ICU, remifentanil has been compared with various other opioids in the management of critically ill patients requiring mechanical ventilation.
Dahaba and colleagues [ 20 ] evaluated 40 mechanically ventilated patients who received a blinded infusion of either remifentanil 0. Initially, the opioid infusion was titrated to reach an optimal level of sedation defined as Sedation Agitation Scale score of 4 , and a midazolam infusion was added only if further sedation was deemed necessary.
Although adverse events were seldom and comparable in both groups, fewer infusion rate adjustments were necessary in the remifentanil group, and the percentage of time spent in optimal sedation was greater for remifentanil than for morphine.
Most important, the mean duration of mechanical ventilation was significantly shorter with remifentanil Opioid infusion rates could be adjusted to reach an optimal level of sedation defined as Sedation Agitation Scale score of 4 , and propofol 0. Of note, recovery times were similar in both groups 1. Patients received either remifentanil 0. Baillard and colleagues [ 23 ] compared remifentanil starting dose 0. It must be emphasized that the midazolam doses used in this investigation were relatively high, and this may in part explain the long weaning times in both groups, especially with remifentanil.
In patients with traumatic brain injury it has been demonstrated that remifentanil can provide effective sedation during transient painful procedures for example, endotracheal suctioning and physiotherapy , and no significant changes in mean arterial blood pressure, intracranial pressure, or cerebral blood flow velocity were observed [ 24 ]. In another study of remifentanil in severely head injured patients [ 25 ], reduction in coughing due to endotracheal suctioning was dose dependent, but most patients needed vasopressors to maintain cerebral perfusion pressure.
One of the most important issues in neuroanesthesia and neurocritical care is neurologic assessment. Therefore, cessation of analgesic and sedative infusions should be accompanied by rapid and predictable awakening, thus allowing clear differentiation between brain dysfunction and over-sedation. Two studies have been conducted [ 26 , 27 ] that compared remifentanil with fentanyl or morphine in neurologic ICU patients.
In a randomized multicenter study, Karabinis and coworkers [ 26 ] investigated mechanically ventilated patients who had suffered acute brain injury or had undergone neurosurgery.
A total of 84 patients received remifentanil, with a median weighted mean infusion rate of 0. When fentanyl was used for analgesia, the median weighted mean infusion rates were 3. More Information. National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services.
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Breast Disease Anesthesia Inflammatory Response. Drug: Remifentanil Drug: Fentanyl. Not Applicable. Study Type :. Interventional Clinical Trial.
Actual Enrollment :. This is a single-blind, randomized control trial. The opioid selection disguised to the patient. Actual Study Start Date :. Actual Primary Completion Date :.
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