1Klinik für Anaesthesiologie und Intensivmedizin, Universitätskliniken des Saarlandes, D-66421 Homburg, Germany. 2Klinik für Anaesthesiologie und operative Intensivmedizin, Klinikum Leverkusen, Dhünnberg 60, D-51375 Leverkusen, Germany*Corresponding author
Accepted for publication: January 3, 2001
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Br J Anaesth 2001; 86: 7638
Keywords: analgesics opioid, sufentanil; analgesics opioid, remifentanil; recovery, neurological
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
As remifentanil is metabolized by non-specific esterases, it is eliminated very quickly and independently of liver or kidney function. The context-sensitive half time is 34 min and is independent of the duration of infusion.3
The present investigation was performed to study the effects of remifentanil administered in combination with a hypnotic to provide analgesia and sedation in ICU patients. We wanted to investigate if it was possible to: (1) provide adequate analgesia with remifentanil and (2) achieve complete emergence from analgesia and sedation (neurological recovery) within minutes after termination of the remifentanil infusion. As morphine and fentanyl4 have unfavourable pharmacokinetics if administered as a continuous infusion, we chose sufentanil for comparison with remifentanil. Sufentanil has a context-sensitive half time of 34 min after 4 h infusion.3 Since its introduction in the 1980s, sufentanil has been frequently used for postoperative analgesia and sedation in ICU patients.58
![]() |
Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Patients received either balanced anaesthesia with isoflurane, nitrous oxide, and fentanyl in the operating theatre (elective surgery) or a fentanyl/midazolam anaesthesia in the emergency room (trauma). On transfer to and after arrival at the ICU, all patients received midazolam and fentanyl before the trial was started. Details of the patients and the amounts of fentanyl and midazolam administered before the onset of the trial are listed in Table 1. For every patient, the study started during the first 24 h of their study on the ICU.
|
Propofol was administered with an initial dose of 2 mg kg1 h1 as the sedative component. In addition, patients initially received either remifentanil 5 µg kg1 h1 or sufentanil 0.5 µg kg1 h1. The aim was to achieve a Ramsay score adapted to the patients individual demand ranging from 2 (e.g. weaning from artificial ventilation) to 5 (e.g. in case of severe respiratory failure) together with complete pain relief. In case of pain or inadequate sedation, the dose of the drugs was adjusted stepwise according to the following procedure.
In case of inadequate sedation, the propofol infusion was increased to 2.5 mg kg1 h1 and if sedation remained insufficient 15 min after the first adjustment, the propofol infusion was increased to 3.0 mg kg1 h1 and likewise increased, if necessary, every 15 min. To facilitate procedures such as washing, punctures, etc., additional boli of propofol (2050 mg) were permitted. When sedation was excessive (Ramsay score 6), the infusion of propofol was decreased by 0.5 mg kg1 h1 and, if necessary, 15 min later, again by 0.5 mg kg1 h1. Afterwards the dose of the analgesic was reduced by 2.5 µg kg1 h1 for remifentanil and by 0.25 µg kg1 h1 for sufentanil, respectively.
In case of insufficient analgesia, the dose of the opioid was doubled (remifentanil 10 µg kg1 h1 or sufentanil 1.0 µg kg1 h1), and if the pain remained 15 min after the first adjustment, the dose was increased to remifentanil 15 µg kg1 h1 or sufentanil 1.5 µg kg1 h1, and likewise increased, if necessary, every 15 min.
The degree of sedation and the pain score was assessed every 2 h and the dose of propofol and/or the opioid was adjusted accordingly. In case of inadequate sedation (Ramsay score <2), or spontaneous complaint of pain between scheduled observation intervals, drug doses were adjusted as described.
Patients were ventilated to normocapnia (mandatory minute ventilation by respirator EVITA 24, Draeger Werke AG, Lübeck, Germany).
Measurements
The continuous analgesic and sedative medication was temporarily stopped after 24 h. Immediately before and 10 and 30 min after the following parameters were determined: systolic (SAP) and diastolic (DAP) invasive arterial pressure, heart rate, arterial carbon dioxide, oxygen and pH, spontaneous ventilation as a percentage of respiratory minute volume, degree of sedation, and pain score. Drug administration was recommenced after the 30 min measurement or immediately (together with a bolus of propofol) if the patient complained of pain or had a Ramsay score of <2.
The values for the sedation score and fraction of spontaneous ventilation are expressed as median (25th, 75th percentile), values for the pain score are expressed as frequencies. The data for arterial pressure, heart rate, pH, arterial carbon dioxide and oxygen are reported as their mean (SD). The Wilcoxon signed-ranks test was used to determine the effect of remifentanil (0, 10 min) and Friedman test followed by Dunns method was conducted to determine the effect of sufentanil (0, 10, 30 min) on HR, SAP, DAP, pH, PaCO2, degree of sedation, pain score and fraction of spontaneous ventilation. The MannWhitney U-test was used to evaluate differences between groups (0, 10 min). Statistical analysis was performed with the software package Sigma Stat for Windows Version 2.03 (SPSS Inc., USA). P<0.05 was considered significant for all tests.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
To achieve adequate analgesia and sedation, patients in the remifentanil group required mean doses of remifentanil 10.6 µg kg1 h1 and propofol 2.1 mg kg1 h1 and, in the sufentanil group, sufentanil 0.5 µg kg1 h1 and propofol 1.3 mg kg1 h1. The propofol dose was significantly higher in the remifentanil group (P=0.012).
Immediately before terminating the continuous infusion, there was no difference between groups with respect to the degree of sedation as indicated by the Ramsay score (median: 3 in both groups, Fig. 1). During the first 10 min after stopping the administration of the infusions, in the sufentanil group the Ramsay score (median) remained unchanged (3) compared with the control and decreased significantly (2, P<0.05), 30 min after terminating the infusion. In the remifentanil group the Ramsay score significantly (P=0.002) decreased from 3 (control) to 1.5, 10 min after stopping the analgesic and sedative infusion. The difference between groups at the 10-min time point was significant (P=0.015 for remifentanil versus sufentanil, Fig. 1). During the following 20 min of the scheduled observation period, nine patients in the remifentanil group emerged from analgesia and sedation (Ramsay score <2) and measurements were stopped and infusion was recommenced. Subsequently, valid data are available only for one patient in the remifentanil group at 30 min. In the sufentanil group, the continuous infusion had to be restarted only once before completing the 30 min evaluation interval.
|
|
Mean systolic and diastolic invasive arterial pressure significantly increased in the remifentanil group 10 min after terminating infusion compared with baseline values (SAP P=0.002, DAP P=0.002) and were significantly elevated compared with the values obtained in the sufentanil group (SAP P=0.002, DAP: P=0.013). In the sufentanil group, mean systolic and diastolic arterial pressure increased significantly 30 min after discontinuing the infusion (SAP: P<0.05; DAP: P<0.05, values shown in Table 3). No significant changes in heart rates were observed in or between groups.
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We were aware of the difficulty of separating sedation and analgesia in an intubated and deeply sedated patient. Another major problem of our study was differentiating between the effects of propofol and the opioids, as both drugs possess sedative qualities and act synergistically. Using a fixed dose of propofol, the comparison between groups would have been possible under standardized conditions. However, with administration of a fixed high propofol dose, sufficient for all patients, the dose of the opioid would have to be reduced to such a degree that emergence from analgesia-sedation would mainly reflect emergence from propofol sedation and differences between the duration of effect of the opioids would have been concealed. On the other hand, some patients clearly had no pain during the study, but were anxious and agitated (Ramsay 1). Increasing the dose of the analgesic would not have changed this state. These patients would have suffered discomfort without a deeper degree of sedation. Therefore, the study design had to permit an increase of the dose of propofol because of ethical considerations.
Remifentanil has previously been proven to be effective in postoperative pain management after abdominal, spine and thoracic surgery or joint replacement using a mean dose of 6 µg kg1 h1.10 It is well known that the amount of analgesics required by ICU patients is lower than the dose necessary to provide analgesia during surgery. Nevertheless, the initial dose of 5 µg kg1 h1 in our study was not sufficient and had to be increased in most of the patients. The mean remifentanil dose finally required by our patients (10.6 µg kg1 h1) has been reported to provide adequate analgesia during several surgical procedures.11
By contrast, compared with data published by other authors, the mean sufentanil dose required by the patients in our study (0.5 µg kg1 h1) was rather low.5 8 Wappler and colleagues8 used 0.41.5 µg kg1 h1 sufentanil in combination with midazolam for analgesia and sedation of mechanically ventilated ICU patients and Hofbauer and colleagues5 administered 0.751.0 µg kg1 h1 sufentanil combined with midazolam in ICU patients requiring mechanical ventilation for more than 96 h. Nevertheless, the scheduled initial dose in the present study proved sufficient. In addition, in many cases the supplementary dose of 2 mg kg1 h1 propofol initially set in our study could even be reduced. Once adjusted by clinical assessment of pain, neither the dose of remifentanil or sufentanil had to be reduced in any of the patients during the 24 h observation period. This pattern suggests that neither remifentanil or sufentanil accumulated after a 24 h infusion period, although it has been demonstrated for sufentanil, that the context-sensitive half time increases continuously after 25 min of continuous infusion.3 12 13 By contrast, Egan and colleagues3 determined the context-sensitive half time for remifentanil to be 34 min, independent of the duration of infusion.
Patients in the remifentanil group required significantly more propofol than patients in the sufentanil group. Therefore, it may be that the analgesic dosages used in our study were not equivalent and differences in the pharmacodynamic effects of remifentanil and sufentanil may be responsible for the different propofol requirements. Sufentanil has a greater hypnotic potency than other opiates, for example, morphine, fentanyl, alfentanil or remifentanil, and has been proven to be suitable as monoanaesthetic for analgesia and sedation in ICU patients.7 8 1416 As no patient complained of pain during continuous infusion of remifentanil, the higher dosage of propofol needed in this group is most probably a result of a less pronounced hypnotic potency of remifentanil, rather than an insufficient analgesic effect provided by the chosen dose of remifentanil. However, there surely exists a drug interaction between propofol and both opioids. So one must be aware of the difficulty of separating the clinical effects of analgesia and sedation at such high levels of drug effect.
We observed pronounced differences between the groups with respect to time required for recovery. We assume that, even at the 10-min time point, a substantial sedative effect of propofol no longer existed in any patient because, in the remifentanil group, no sedative effect of propofol was present 10 min after terminating the infusion in spite of the higher propofol dose in this group. Therefore, we attribute the poorer recovery in the sufentanil group to the sedative effect of sufentanil.
In most patients on the ICU it would not be of particular advantage to decrease the emergence from analgesia and sedation to a few minutes. Thus, the use of an expensive analgesic drug like remifentanil may still remain the exception rather than the rule in the future. It might even be more comfortable for the patient to be treated with longer acting opioids as analgesia does not fade immediately after stopping their administration. This might be one of the reasons why morphine and fentanyl were recommended as the preferred analgesic agents for the critically ill by a consensus conference of 40 experts in 1995.4
However, there are situations requiring regular neurological assessment by clinical signs and remifentamil may be advantageous in these cases.17
In conclusion, the use of remifentanil combined with propofol up to 24 h postoperation provides adequate analgesia in patients with no intracranial pathology, after elective maxillo-facial surgery or severe trauma. A more rapid emergence from analgesia and sedation with remifentanil compared with sufentanil is indicative of the pharmacokinetic properties of remifentanil. Despite high cost and rapid termination of effect, the use of remifentanil may be particularly advantageous in patients suffering from severe intracranial disease or head trauma because it allows intermittent and rapid neurological assessment by clinical examination.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Bonica JJ. Current status of postoperative pain therapy. In: Yokata T, Dubner R, eds. Current Topics in Pain Research and Therapy. Amsterdam: Exerpta Medica, 1983; 169
3 Egan TD, Lemmens HJM, Fiset P, et al. The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology 1993; 79: 88192[ISI][Medline]
4 Shapiro BA, Warren J, Egol AB, et al. Practice parameters for intravenous analgesia and sedation for adult patients in the intensive care unit: an executive summary. Society of Critical Care Medicine. Crit Care Med 1995; 23: 15961600[ISI][Medline]
5 Hofbauer R, Tesinsky P, Hammerschmidt V, et al. No reduction in the sufentanil requirement of elderly patients undergoing ventilatory support in the medical intensive care unit. Eur J Anaesthesiol 1999; 16: 7027[ISI][Medline]
6 Kremer MJ, Bachenberg KL. Sedation by infusion: a clinical trial in cardiac surgery patients. AANA J 1993; 61: 2736
7 Kroll W, List WF. Is sufentanil suitable for long-term sedation of a critically ill patient? Anaesthesist 1992; 41: 2715[ISI][Medline]
8 Wappler F, Scholz J, Prause A, et al. Level concept of analgesic dosing in intensive care medicine with sufentanil. Anästhesiol Intensivmed Notfallmed Schmerzther 1998; 33: 826[Medline]
9 Ramsay MA, Savege TM, Simpson BR, Goodwin R. Controlled sedation with alphaxalone-alphadalone. BMJ 1974; 2: 6569[ISI][Medline]
10 Bowdle TA, Camporesi EM, Maysick L, et al. A multicenter evaluation of remifentanil for early postoperative analgesia. Anesth Analg 1996; 83: 12927[Abstract]
11 Wilhelm W, Biedler A, Larsen R. Remifentanil. Early clinical experiences with 3100 patients. Anaesthesist 1997; 46: 9927[ISI][Medline]
12 Egan TD. Remifentanil pharmacokinetics and pharmaco dynamicsa preliminary appraisal. Clin Pharmacokinet 1995; 29: 8094[ISI][Medline]
13 Hughes MA, Glass PSA, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology 1992; 76: 33441[ISI][Medline]
14 Coda BA, OSullivan B, Donaldson G, et al. Comparative efficacy of patient-controlled administration of morphine, hydro morphone or sufentanil for the treatment of oral mucositis pain following bone marrow transplantation. Pain 1997; 72: 33346[ISI][Medline]
15 Ellmauer S. Sufentanil. An alternative to fentanyl/alfentanil? Anaesthesist 1994; 43: 14358[ISI][Medline]
16 Rathgeber J, Burchardi H. Analgo-sedation during mechanical ventilationnew concepts for new ventilatory modes? Intensivmed 1996; 33: 22734
17 Warner DS, Hindman BJ, Todd MM, et al. Intracranial pressure and hemodynamic effects of remifentanil versus alfentanil in patients undergoing supratentorial craniotomy. Anesth Analg 1996; 83: 34853[Abstract]