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Department of Anesthesia and Intensive Care, Pitie-Salpetriere University Hospital, and the *Department of Anesthesia and Intensive Care, St. Antoine University Hospital, Paris, France
Address correspondence to Pierre Coriat, MD, Chairman, Département d’Anesthésie-Réanimation, Hôpital Pitié-Salpêtrière, 47, Boulevard de l’hôpital, 75651 Paris Cédex 13, France.
Several new anesthetics, related drugs, and technologies have become available in recent years that inevitably have made new approaches with patient management possible. Will these new anesthetics, which often appear expensive at first glance, have benefits that outweigh their direct cost (1)? In parallel to these new developments, there have appeared real opportunities to apply novel physiologic and pharmacologic concepts that may redefine our clinical practice. Exciting new investigations have thus been spurred in the fields of surgery, epidemiology, and economics in addition to other disciplines. Fast-tracking, which emphasizes the major role of anesthetic management in postoperative outcome, is one such line of investigation.Fast-tracking after cardiac surgery was first introduced in an attempt to decrease the time to tracheal extubation and thereby reduce expensive time in intensive care unit (ICU) areas (2,3). Large doses of opioids have been clearly identified as a factor in delaying weaning from mechanical ventilatory support after cardiac surgery. Thus, early investigations emphasized the importance of limiting the dose of potent opioid analgesics during the intraoperative period to achieve early recovery (3,4). Supplementation with hypnotic drugs allows reduction of the opioid dose, enabling earlier extubation without compromising hemodynamic stability (5,6). Subsequent, well designed, prospective, randomized trials have demonstrated that fast-track anesthesia is easy to implement, safe (probably even beneficial for patients in certain circumstances) and leads to potentially significant cost savings as compared to conventional large-dose opioid anesthesia (3,6,7).
The studies of Cheng et al. (8), and Howie et al. (9), presented in this issue of Anesthesia & Analgesia offer new insights into the effects of different opioids on the intraoperative course and recovery after CABG (coronary artery bypass graft) surgery. These studies were performed to determine whether the fast-track process could be improved by using the short-acting opioid remifentanil (e.g., to shorten the time to extubate patients and the length of ICU stay). In a prospective, randomized, double-blinded protocol, fentanyl 10 µg/kg bolus at induction of anesthesia followed by 1 µg/kg maintenance doses was compared to remifentanil 1 µg/kg bolus at induction of anesthesia followed by a titration of up to 4 µg · kg-1 · min-1 continuous infusion and 1 µg/kg boluses. Both analgesics were supplemented with propofol and isoflurane. Results of these studies showed that, even after stratification by preoperative risk scores and age, both techniques allowed for similar times to tracheal extubation and ICU and hospital discharge.
At a first glance these results seem surprising. What was noteworthy about these studies was the strict control of conditions of the double-blinded drug administration. A very sophisticated protocol was used including double-blinded induction/maintenance infusion, double-blinded induction and preextubation boluses, and simultaneous double-blinded/double-dummy bolus/infusion rate changes for hemodynamic control. Although this methodology provides very useful information regarding the pharmacologic properties of the opioids investigated, the very tightly controlled environment the authors built into these studies limits our ability to generalize their results. To make the investigators truly blinded, the opioid administration did not mimic the usual clinical practice, thus precluding translation of the results into the clinical setting without some restrictions. In relation to study design, several years ago, Mc Peek (10) summarized the dilemma of efficacy versus effectiveness and the need for the ability to generalize (10). For a study to have meaningful practical conclusions, it is important that the control group follow a course that conforms to routine clinical practice (11). The most useful trials allow other clinicians to be confident in applying research findings in their own practices (10,12).
The design of the current studies may explain some of the differences observed in previous reports. For instance, using the combination of propofol and remifentanil in a descriptive noncomparative evaluation in cardiac surgical patients, Olivier et al. (13) observed a faster rate of recovery and a shorter time to extubation in patients after arrival in the ICU when compared with the remifentanil group in the present studies (1). Furthermore, in a different unblinded comparison in cardiac surgery patients, the use of a combined remifentanil and propofol regimen led to a significant reduction in the time to extubation and the ICU length of stay compared to a combination of fentanyl and propofol (14). It therefore appears prudent that controlled, double-blinded investigations should be followed by observational evaluations, performed in accordance with usual clinical practice. This would serve to establish the clinical significance of the studies’ conclusion (12). In the context of fast changing attitudes, as in the field of cardiac anesthesia, it has recently been advocated to perform "tracker trials" in which the content of the trial tracks changes in patients’ treatment or clinician’s beliefs (15). In their recommendations, the authors advocated that "tracker trial" investigators should be guided by flexible clinical practice protocols to provide easily comprehended and meaningful conclusions.
A possible misinterpretation of the two studies published in this issue of Anesthesia & Analgesia would be to conclude that remifentanil does not have any place in anesthesia for cardiac surgery. The choice of an intraoperative opioid usually relates to factors other than the ability to fast track and includes speed of action, ease of administration, and tolerance. From this perspective, Howie et al. (9) observed significantly more patients in the fentanyl regimen experiencing substantial changes in systemic arterial pressure. The efficacy of remifentanil infusion to provide tight control of hemodynamic variables during cardiac surgery has been emphasized (13,16).
The use of short-acting opioids with fast onset, predictable recovery, and minimal postoperative effects, such as remifentanil, teaches us how to better control postoperative pain because a specific analgesic regimen is necessary for these patients. In high-risk cardiac patients, the problem of postoperative pain control can be overcome by administering a mixture of nonopioids and long-acting opioids before remifentanil discontinuation. Thoracic epidural analgesia or intrathecal morphine also effectively controls pain after cardiac surgery in patients who received remifentanil (17,18). In the study by Cheng et al. (8), remifentanil infusion was continued in the ICU until criteria for extubation were achieved. The patients received parenteral ketorolac as continuation of the analgesic management. No information was given concerning the need for opiate administration in the ICU and the effectiveness of pain relief was not part of the criteria for eligibility for ICU discharge. Howie et al. (9) administered ketorolac and a bolus of fentanyl (2 µg/kg) before discontinuation of the remifentanil infusion. The majority of patients (88%) needed supplemental repeat boluses of either morphine or fentanyl during their ICU stay. In the study by Olivier et al. (13), despite the administration of 0.1 mg/kg morphine before discontinuing remifentanil, a majority of patients (72%) also experienced significant pain (visual analog scale score >4) and required morphine supplementation. Obviously, the need to administer long-acting opiates postoperatively may offset the pharmacokinetic advantage of the intraoperative use of remifentanil and could potentially greatly influence the recovery process and the overall length of stay in ICU. This variable should be considered in future investigations.
Resource utilization and time spent in the ICU were similar between patients receiving remifentanil infusion and those on the small dose fentanyl regimen. With studies designed to evaluate the impact of a given technique on personnel costs and ICU discharge, it is essential to be able to alter work patterns (e.g., discharge policies) to exploit all the benefits afforded by the use of short-acting drugs.
Notably, some patients who were tracheally extubated within the first hour after arrival in the ICU remained there <8 h after surgery regardless of which opioid they received. Thus, if we accept that anesthetic management is a major determinant in the success of the fast-track process, the conditions of the present studies may be very close to reaching the upper limit of positive influence on postoperative outcome. Indeed, although it is possible to extubate most patients quickly after a cardiac procedure, a minimal delay appears prudent to avoid the risk of mediastinal bleeding, hypothermia, hemodynamic instability, hypoxemia, or shivering (2). All these factors are potential sources of delay in the time to extubation. Consequently, the rate-limiting step in the fast-track process may be the patient’s preoperative physical status rather than the intraoperative anesthetic management. Risk factors for delayed extubation and prolonged ICU stay after CABG related mostly to patient status (increased age, female gender, postoperative use of the intraaortic balloon pump, inotropes, bleeding, and atrial arrhythmias) (19). From this perspective, it is likely that efforts are better focused on the perioperative care of high-risk patients rather than on methods to further reduce the already short duration of postoperative ventilatory support in low-risk patients. Aside from its relation to the anesthetic management, future developments in the fast-track concept may concentrate on better preoperative patient selection (20) and the further development of minimally invasive cardiac surgical techniques (21).
In conclusion, these two studies, which were subject to strictly controlled methodology, provided further interesting information on the pharmacologic properties of remifentanil. They illustrate the problem of differentiating between effectiveness and efficacy in a trial, as well as suggest that observational studies might be necessary to evaluate the usefulness of a particular health care protocol. In future studies aimed at evaluating the potential clinical benefits of new anesthetics, it will be as important to pose meaningful questions as it is to have the correct answers.
References
This article has been cited by other articles:
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  K. Rauf, A. Vohra, P. Fernandez-Jimenez, N. O'Keeffe, and M. Forrest Remifentanil infusion in association with fentanyl-propofol anaesthesia in patients undergoing cardiac surgery: effects on morphine requirement and postoperative analgesia Br. J. Anaesth., November 1, 2005; 95(5): 611 - 615. [Abstract] [Full Text] [PDF]
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A. Ouattara, G. Boccara, S. Lemaire, U. Kockler, M. Landi, E. Vaissier, P. Leger, and P. Coriat Target-controlled infusion of propofol and remifentanil in cardiac anaesthesia: influence of age on predicted effect-site concentrations{dagger} Br. J. Anaesth., May 1, 2003; 90(5): 617 - 622. [Abstract] [Full Text] [PDF]
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 J. Reis, J.C. Mota, P. Ponce, A. Costa-Pereira, and M. Guerreiro Early extubation does not increase complication rates after coronary artery bypass graft surgery with cardiopulmonary bypass Eur. J. Cardiothorac. Surg., June 1, 2002; 21(6): 1026 - 1030. [Abstract] [Full Text] [PDF]
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 S. Mouren, G. De Winter, S. P. Guerrero, C. Baillard, M. Bertrand, and P. Coriat The Continuous Recording of Blood Pressure in Patients Undergoing Carotid Surgery Under Remifentanil Versus Sufentanil Analgesia Anesth. Analg., December 1, 2001; 93(6): 1402 - 1409. [Abstract] [Full Text] [PDF]
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