Inpatient Experience with Remifentanil
1999; Lippincott Williams & Wilkins; Volume: 89; Issue: 4S Linguagem: Inglês
10.1097/00000539-199910001-00004
ISSN1526-7598
Autores Tópico(s)Epilepsy research and treatment
ResumoOpioids provide the analgesia required in balanced and total IV anesthesia (TIVA) techniques to block autonomic nervous system and somatic responses to noxious surgical stimuli. Thus, they help to maintain hemodynamic stability during surgery by attenuating the surgical stress. Despite adequate levels of the hypnotic component of the anesthetic, patients may respond to stimuli with tachycardia and/or an increase in arterial blood pressure. This is particularly the case in surgical procedures with high levels of intraoperative stress, such as cardiac and major abdominal surgery. Large doses of opioids will blunt or, in some cases, eliminate these sympathetic responses. For example, a dose of fentanyl of 100 μg/kg abolishes the catabolic responses to cholecystectomy (1). The obvious penalty for this perceived benefit is prolonged respiratory depression and the need for ventilatory support. For major cardiac and vascular categories, this inevitable respiratory depression has, until recently, been relatively unimportant. However, changes in this approach have been brought about by alterations in medical practice, partly as a result of fiscal, as opposed to medical or patient-derived, pressures. The introduction of managed care and other aspects of cost-control has sparked a renewed interest in establishing spontaneous ventilation in the early hours after cardiac surgery. The μ-opioid receptor agonists are the most commonly used analgesics during surgery. Alfentanil was the shortest-acting opioid available in anesthesia, but the recent introduction of remifentanil hydrochloride, a rapid-acting μ-opioid that can be closely titrated to patient need, may provide new methods of combining large-dose opioid anesthesia with risk reduction strategies and cost-containment. Several studies, which are summarized in this article, have compared alfentanil or fentanyl with remifentanil administered as a continuous infusion during balanced and TIVA for inpatients. These opioids were compared for their potential to reduce responses to surgical stimulation and with respect to their recovery profiles in terms of times to adequate respiration, extubation, and response to verbal command. Throughout these studies, response to surgical stimulation or inadequate anesthesia was defined as an increase in systolic blood pressure >15 mm Hg from baseline for ≥1 min, heart rate >90 bpm for ≥1 min, patient movement, eye opening, sweating, or tearing. Abdominal Surgery In a double-blind, randomized study (2), continuous infusions of remifentanil were compared with alfentanil during N2O/O2/isoflurane anesthesia in benzodiazepine-premedicated patients undergoing major, nongynecological, abdominal surgery. Patient groups were comparable with respect to age (18–65 yr), weight, ASA physical status, and duration of surgery. After a bolus of 1 μg/kg, remifentanil was administered as an infusion of 0.5 μg · kg−1 · min−1 to 116 patients and compared with alfentanil (25-μg/kg bolus followed by an infusion of 1 μg · kg−1 · min−1 to 118 patients). Propofol dosing was titrated to loss of consciousness (LOC). After vecuronium administration and intubation, the infusion rates were reduced by half in both groups, and anesthesia was maintained with 0.5% isoflurane (end-tidal) in 66% nitrous oxide in oxygen. Response to surgical stimuli was treated with a bolus of study drug (remifentanil 1 μg/kg, alfentanil 5 μg/kg) followed, if needed, by doubling of the infusion rate of the opioid. If required, this sequence was repeated and, if control of the response was not achieved after 5 min, the isoflurane concentration was increased in 0.2% increments. IV crystalloid replacement therapy was initiated to treat hypotension. If unsuccessful, isoflurane was reduced in 0.1% decrements (maximum of three decrements), followed by the administration of vasopressors or anticholinergic drugs and a decrease of the opioid infusion rate by 50%, if needed. Results A larger proportion of alfentanil-treated versus remifentanil-treated patients showed responses to endotracheal intubation (28% vs 15%;P= 0.014) and to skin incision (17% vs 8%;P= 0.037) (Table 1). Muscle rigidity was observed during the induction phase in nine patients (8%) receiving remifentanil and in six patients (5%) receiving alfentanil. The incidence of hypertensive or tachycardic responses to surgical stimuli was significantly higher in the alfentanil group compared with the remifentanil group (72% vs 57%;P= 0.016). Somatic and/or autonomic responses were recorded in <10% of patients. Requirements for additional boli and changes in infusion rate were less frequent in the remifentanil group (42% vs 63%;P= 0.002). The proportions of patients requiring either a dose increase or a dose change in end-tidal isoflurane were similar in both groups. Both systolic blood pressure and heart rate were significantly lower in the remifentanil-treated patients, with a higher incidence of hypotension (53% vs 39%;P< 0.001) and bradycardia (10% vs 3%;P= 0.027). Table 1: Responses to Stimulation, Side Effects, and Median Recovery Times After Remifentanil and Alfentanil in Major Abdominal SurgeryThe alfentanil infusion was discontinued 15 min before the anticipated end of surgery. Responses to skin closure occurred in 16% and 21% of patients treated with remifentanil and alfentanil, respectively. Median time to spontaneous respiration, time to adequate respiration, and time to response to verbal command did not differ between groups (Table 1). Median time from end of infusion to extubation was, however, significantly shorter in patients treated with remifentanil. One patient in the remifentanil group had possible recall of events during surgery. Total Abdominal Hysterectomy and Spinal Surgery Methods Remifentanil and alfentanil were compared during balanced anesthesia in 35 patients scheduled for total abdominal hysterectomy in a double-blind, randomized study (3). Patients were randomized to receive an infusion of either remifentanil (0.25 or 0.5 μg · kg−1 · min−1) or alfentanil (0.5 μg · kg−1 · min−1). The infusion was started after induction with thiopental and vecuronium, and a loading dose of the opioid. Alfentanil was administered as a bolus of 50 μg/kg, followed by an infusion of 0.5 μg · kg−1 · min−1. Nitrous oxide 66% in oxygen was given concurrently with the opioid infusion for maintenance of anesthesia. Responses to surgical stimuli were treated with either intermittent boli of alfentanil (7 μg/kg) or remifentanil (1 μg/kg), and/or infusion rate increases ≤4 μg · kg−1 · min−1 alfentanil or ≤2 μg · kg−1 · min−1 remifentanil. Results The incidence of hemodynamic, somatic, or autonomic responses was significantly lower in the 0.5 μg · kg−1 · min−1 remifentanil group (38%) compared with alfentanil (50%) and the 0.25 μg · kg−1 · min−1 remifentanil group (92%) (Table 2). Similar median times to spontaneous respiration (4.5 and 3 min, respectively) and extubation (7 and 8 min, respectively) were observed for the smaller and larger doses of remifentanil. These were significantly shorter than those for the alfentanil patients (spontaneous respiration 13.5 min, extubation 14.5 min). Table 2: Remifentanil Versus Alfentanil in Total Abdominal HysterectomySimilar recovery characteristics were observed after prolonged administration of the same (0.25 or 0.5 μg · kg−1 · min−1) remifentanil doses for 3- to 6-h spinal surgery, with spontaneous respiration and extubation occurring 2–7 min after infusion termination (4). No differences were found between alfentanil and remifentanil with regard to recovery from anesthesia. In these clinical trials, doses of remifentanil up to the 90% effective dose (ED90) were compared with the recommended doses (approximately ED50) for alfentanil. More patients in the alfentanil group had one or more responses involving inadequate anesthesia. Remifentanil provided more stable analgesia during surgery than alfentanil, but remifentanil-treated patients had a significantly higher incidence of excessive anesthesia, in the form of hypotension, in the presence of isoflurane 0.5% and nitrous oxide. Despite the higher infusion rate of either remifentanil or alfentanil, responses to endotracheal intubation were also more common in alfentanil-treated patients. Thoracic, Intraabdominal, and Orthopedic Surgery Methods Higher and lower infusion rates of remifentanil were studied in a double-blind, randomized manner for the management of intraoperative responses during TIVA in 178 patients scheduled for major thoracic, intraabdominal, and orthopedic surgery (5). A bolus dose of 1 μg/kg remifentanil was followed by either a small dose (0.5 μg · kg−1 · min−1) or a large dose ( 1 μg · kg−1 · min−1) infusion until tracheal intubation. Propofol was administered 3 min later as bolus of 1 mg/kg, followed by a continuous infusion of 75 μg · kg−1 · min−1. Vecuronium was administered to facilitate endotracheal intubation. After intubation, the infusion rates of remifentanil were reduced by 50%. Signs of inadequate anesthesia were treated with bolus doses of remifentanil (1 μg/kg) and/or infusion rate increases, allowing for a maximum of five bolus doses and two infusion rate increases in a 5-min period for a given response. The maximal infusion rates were 2 μg · kg−1 · min−1 (smaller-dose group) and 4 μg · kg−1 · min−1 (larger-dose group). If insufficient, propofol doses of 20 mg were administered (maximum of five doses at 1-min intervals) followed by an increase of the propofol infusion rate to 125 μg · kg−1 · min−1 if needed. Results Of the patients in the lower-dose group, 7% lost consciousness before propofol administration, compared with 5% of patients in the higher-dose group. A lower incidence of hemodynamic response to intubation was seen with the higher-dose remifentanil infusion (6% vs 25%;P= 0.003), whereas the incidence of response to skin incision was similar (11% vs 16%) (Table 3). Approximately half of the patients in the two groups demonstrated a response to surgical stimuli after skin incision until the end of surgery. Fewer patients in the larger-dose group required an opioid bolus dose (42% vs 54%) or an increase of opioid infusion rate (39% vs 54%) to control these events. The median percentage of surgical time without responses was high (93% and 92%, respectively). The weighted mean remifentanil infusion rate was 0.4 μg · kg−1 · min−1 in the smaller-dose group and 0.53 μg · kg−1 · min−1 in the larger-dose group. Only 19% and 23% of patients in the smaller-dose and larger-dose groups, respectively, required propofol rescue. Incidences of intraoperative hypotension (27% and 30%, respectively) and bradycardia (7% and 9%, respectively) were similar in both groups. Table 3: Remifentanil Dosing and Response to Stimuli and Muscle RigidityThe median time to spontaneous respiration (3 and 3.5 min, respectively), to adequate respiration (6.5 and 6 min, respectively), to response to verbal command (5 min in both groups), or to extubation (6 min and 7 min, respectively) did not differ between doses. One patient in this study reported intraoperative recall without pain when queried after surgery. There was a 5- to 10-min interruption in the remifentanil infusion during this patient's procedure. Thus, the large proportion of patients not requiring remifentanil dose adjustments or propofol supplements suggests that the combination of remifentanil with propofol and vecuronium for TIVA provided easy titratability for intraoperative stress events. Higher infusion rates were significantly more efficient in controlling response to intubation, but they induced a higher incidence of muscle rigidity and hypotension. A remifentanil maintenance infusion rate of 0.5 μg · kg−1 · min−1 seems appropriate as analgesic background for TIVA with propofol. However, propofol infusion rates >75 μg · kg−1 · min−1 should be used to avoid the occurrence of awareness in some patients. Cardiopulmonary Bypass Surgery In patients requiring revascularization, the challenge is to reduce to a minimum the myocardial metabolic demand. Hyperdynamic ischemia or "demand-induced ischemia" will be avoided if hypertension, which leads to increased wall tension or afterload, and tachycardia, the most potent stimulus to ischemia (shown as ST segment changes), are prevented (6). A number of studies have been performed in Europe and North America to investigate these possibilities. The major focus of these studies has been to demonstrate efficacy and safety for regulatory and registration purposes. This must be borne in mind when considering the data in more clinically relevant scenarios. Studies with remifentanil in patients undergoing coronary artery bypass grafting (CABG) have addressed three questions: Is remifentanil useful as a sole drug to induce anesthesia? Will remifentanil produce good intraoperative sympathetic control when used as part of a TIVA technique? Can the patient achieve controlled return of spontaneous ventilation within an acceptable time after the reduction or discontinuation of the remifentanil infusion? Extracorporeal Circulation and Pharmacokinetics of Remifentanil The rate of metabolism of remifentanil could be expected to be reduced in patients subjected to a period of relative hypothermia, hemodilution, and nonpulsatile perfusion. Two pilot studies investigated the effects of the period of extracorporeal support on the kinetics of remifentanil. In the first study (7), larger doses than are clinically recommended were used to study the pharmacokinetics and pharmacodynamics of remifentanil. Single IV bolus doses (2 μg/kg in nine and 5 μg/kg in eight patients) were assessed in patients undergoing elective CABG surgery with induced hypothermia. Each injection was given over 1 min, and the patient was scheduled to receive three bolus doses: one at prebypass with the patient normothermic, the second during hypothermic (28–30°C) bypass, and a third during normothermic bypass. The clearance of remifentanil decreased an average of 20% during the hypothermic period, which resulted in an increase in clearance half-time. Both doses of remifentanil caused a decrease in blood pressure when patients were normothermic before bypass but changed little during hypothermia (Figure 1). The remifentanil was administered in addition to fentanyl/isoflurane/propofol. Figure 1: Effects of a bolus injection of remifentanil 2 μg/kg or 5 μg/kg given over 1 min on mean arterial pressure. The start of the injection was taken as time zero. This bolus was injected at three time points: before bypass with the patient normothermic (upper panel), during hypothermic (temperature 28–30°C) bypass (middle panel), and normothermic bypass (temperature approximately 37°C). Data show a decrease in mean pressure before bypass only. Bars indicate 95% confidence interval.A second study of remifentanil 1 μg · kg−1 · min−1 administered to eight patients by continuous infusion during CABG reported similar findings (8). Eight male patients received large-dose lorazepam premedication, followed by remifentanil-based anesthesia. The anesthetic protocol included sufentanil, thiopentone, and isoflurane. Compared with prebypass values, the blood concentration of remifentanil increased by approximately 30% during hypothermia and decreased by the same amount after bypass. The changes reported in these studies are thought to reflect the influence of temperature on the metabolism of remifentanil. Efficacy and Tolerability Studies with Remifentanil-Based TIVA The efficacy and tolerability of remifentanil at three doses have been assessed in patients undergoing hypothermic CABG. In the European multicenter study (9), remifentanil was administered as a 1-, 1.5-, or 2-μg · kg−1 · min−1 continuous infusion in combination with propofol 3 mg · kg−1 · h −1 in 132 patients undergoing elective primary CABG in nine centers. Induction of Anesthesia During the early part of the study, the remifentanil infusion was administered alone in an attempt to achieve LOC, which was reported in 6 of 29 (21%), 3 of 29 (10%), and 7 of 32 (22%) patients for each infusion rate (overall 16 of 90 [18%]). Moderate to severe rigidity was reported in 4 of 29 (14%), 2 of 29 (7%), and 8 of 32 (25%) patients (overall 14 of 90 [16%]). The protocol was modified to a propofol induction followed by remifentanil infusion. Moderate to severe rigidity was not reported in 42 patients with this technique (9). Suppression of Sympathetic Hemodynamic Changes During surgery, responses to intubation, incision, sternotomy with or without maximal sternal spread (S/MSS), aortic cannulation, and chest drain placement were recorded. The response to S/MSS was the primary study end point. At each dose, remifentanil-based anesthesia provided highly effective suppression of responses to these stimuli (Figure 2). Criteria for a sympathetic response were defined as follows: hypertension = systolic blood pressure >15 mm Hg above baseline or ≥140 mm Hg for ≥1 min or mean arterial pressure ≥75 mm Hg on bypass; tachycardia = heart rate >20% above baseline or ≥90 bpm. Figure 2: Data shown are the proportion of patients without significant heart rate or blood pressure response, as defined in the text, to skin incision (upper panel), sternotomy with or without maximal sternal spread (middle panel), and insertion of the aortic cannula (lower panel) in patients undergoing elective myocardial revascularization. Data are for three infusion rates of remifentanil in combination with propofol 3 mg · kg−1 · h−1. Data show excellent cardiovascular stability and lack of a dose-response effect with this total IV anesthetic technique. See Reference 10 for details.Of patients at the primary end point, 125 of 132 (95%) required no change in the anesthetic or no more than a single additional bolus of remifentanil to ablate the response compared with 95 of 132 (72%) when all stressful periods were combined (9). Figure 3 summarizes these observations compared with data from other studies using alfentanil (5–10 mg) (10), fentanyl (100 μg/kg), or sufentanil (15 μg/kg) (11) and the end points of LOC, rigidity at induction, and suppression of sympathetic hemodynamic responses. Figure 3: Comparison of four μ-opioid agents on ability to induce loss of consciousness (LOC) as a sole agent; incidence of clinically significant muscle and chest wall rigidity; and ability to prevent a >15% increase from baseline in systolic blood pressure (SBP) at the time of sternotomy with or without maximal sternal spread in patients undergoing elective myocardial revascularization. See References 10–12 for details.In a separate multicenter study from North America, remifentanil blunted the catecholamine response to major surgical stimuli in patients undergoing CABG. The concentrations of adrenaline and noradrenaline in blood taken from 40 patients who had received an infusion of remifentanil at one of three dose rates were significantly lower than preanesthesia levels after sternotomy. Catecholamine levels only increased above this baseline at the end of bypass surgery in patients receiving the lowest of these three infusion rates (12). Patients in these studies received anesthesia based on remifentanil together with IV lorazepam (50 μg/kg) and isoflurane during maintenance. With this technique, LOC was recorded 1–8 min after the start of the infusion of remifentanil (13). The patients showed hemodynamic responses to intubation and surgery in keeping with those reported in the European studies (13,14). Postoperative Recovery and Tracheal Extubation The use of large doses of traditional opioids to provide adequate intraoperative analgesia during cardiac surgery inevitably results in prolonged or occasionally recurrent respiratory depression that requires assisted ventilation and monitoring. In the European studies using remifentanil-based anesthesia, all patients received an obligatory, protocol-defined infusion of 1 μg · kg−1 · min−1 remifentanil for the first 3 h postoperatively in the intensive care unit. The protocol also called for a controlled weaning process with reductions in infusion rate every 15–30 min before the return of spontaneous ventilation and tracheal extubation. When patients were deemed eligible for an attempt at tracheal extubation, they were given morphine sulfate 100 μg/kg IV. Thirty minutes after this injection, the process of controlled weaning was begun. Investigators were allowed to give additional doses of morphine if the patient had insufficient analgesia, midazolam if the patient was thought to be anxious, or small-dose infusions of propofol if sedation was deemed necessary. Treatment with nonsteroidal antiinflammatory drugs (NSAIDs) was also allowed, and these were used in approximately 50% of patients. Controlled tracheal extubation was achieved in approximately 40% of patients with the use of no further therapy or additional analgesia alone. Of the remaining 60%, half received anxiolytic and half received some sedation to achieve successful extubation. Analgesic regimens after successful discharge from the intensive care unit were as practiced in each of the individual centers. Of 132 patients, 94 were eligible for early tracheal extubation within 3–5 h after surgery (15). These patients had a median total duration of remifentanil administration of 530 min, with a median postoperative duration of 287 min. The median times after the end of surgery to obey command, have adequate respiration, and be tracheally extubated were 3.8, 4.9, and 5.6 h, respectively. The time to eligibility for intensive care unit discharge (18.5 ± 6.5 h after surgery) was significantly shorter (P< 0.001) in those patients eligible for early tracheal extubation than those not eligible, who were tracheally extubated later that day (43.8 ± 38.8 h). If the time from discontinuation of the remifentanil infusion to adequate respiration is compared with the total duration of administration of remifentanil, then the relationship is as shown in Figure 4(15). Remifentanil infusion time was 6–11 h. As predicted from the known pharmacokinetics of remifentanil, recovery time was not related to the infusion time. The line was fitted by linear regression analysis. This analysis suggests that, patients will have return of adequate spontaneous respiration approximately 15–30 min after discontinuation of the remifentanil infusion independent of the duration of the infusion. Figure 4: Time from discontinuation of the remifentanil infusion to return of adequate spontaneous ventilation versus the total duration of remifentanil infusion. Line is linear regression and shows that recovery time is unrelated to duration of infusion. Negative values on vertical axis show patients breathing adequately while receiving remifentanil by infusion. See Reference 16 for details.Conclusions These studies have differences in design with respect to the effective remifentanil infusion rate for treating signs of inadequate anesthesia, (i.e., prevention of movement and hemodynamic changes at skin incision and during surgery). Although infusion rates >0.4 μg · kg−1 · min−1 provide satisfactory analgesia throughout surgery, they may induce a significant incidence of hypotension, particularly when combined with isoflurane and propofol infusions. The prolonged use of remifentanil infusions for several hours of surgery did not induce a risk of delayed recovery or respiratory depression. In all studies, awakening was fast, and spontaneous respiration returned after a mean time of 3–11 min. The patients could be tracheally extubated after median times of 5–16 min. This is consistent with the pharmacokinetics and the context-sensitive half-time of remifentanil. Remifentanil does not seem to be suitable as a sole induction drug. Despite the modest reduction in the clearance of remifentanil during periods of induced hypothermia, it can be used safely in patients requiring anesthesia for myocardial revascularization. Remifentanil-based anesthesia may provide significant benefits, both to patients with cardiac disease and during cardiac surgery, by minimizing intraoperative stress and providing hemodynamic stability. These potential benefits are associated with the ability to plan and control the period of recovery of spontaneous ventilation and extubation.
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