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Anesth Analg 2003;96:33-38
© 2003 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Target-Controlled Infusion for Remifentanil in Vascular Patients Improves Hemodynamics and Decreases Remifentanil Requirement

Victor De Castro, MD, Gilles Godet, MD, Gonzalo Mencia, MD, Mathieu Raux, MD, and Pierre Coriat, MD

Department of Anesthesiology, Pitié-Salpêtrière Hospital, Paris, France

Address correspondence and reprint requests to Gilles Godet, MD, Département d’Anesthésie-Réanimation, Hôpital Pitié-Salpêtrière, 47-83 Bd de l’Hôpital, 75013, Paris, France. Address e-mail to gilles.godet{at}psl.ap-hop-paris.fr


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Remifentanil is a potent ultra-short-acting opioid, which permits rapid emergence. However, remifentanil is expensive and may have detrimental effects on hemodynamics in case of overdose. Target-controlled infusion (TCI) permits adapting infusion to pharmacokinetic models. In this prospective randomized study, we compared intra- and postoperative hemodynamics, remifentanil requirement during anesthesia, and postoperative morphine requirement in patients scheduled for carotid surgery, and receiving either continuous IV weight-adjusted infusion of remifentanil (RIVA) or TCI for remifentanil (TCIR). Forty-six patients were enrolled in this study: all were anesthetized by using TCI for propofol. Twenty-three received RIVA (0.5 µg · kg-1 · min-1) for the induction of anesthesia and endotracheal intubation, with the infusion rate decreased to 0.25 µg · kg-1 · min-1 after intubation, then adapted by step of 0.05 µg · kg-1 · min-1 according to hemodynamics. Twenty-three patients received TCIR (Minto model, Rugloop), with an effect-site concentration at 4 ng/mL during induction, then adapted by step of 1 ng/mL according to hemodynamics. All patients received atracurium and a 50% mixture of N2O/O2. Hemodynamic variables were recorded each minute. The number and duration of hemodynamic events were collected, and total doses of anesthetics (remifentanil and propofol) and vasoactive drugs were noted in both groups of patients. Data were analyzed by using unpaired t-tests. RIVA was significantly associated with more frequent episodes of intraoperative hypotension (16 versus 6, P < 0.001) and more frequent episodes of postoperative hypertension and/or tachycardia requiring more frequent administration of ß-adrenergic blockers (16 vs 10, P < 0.04) in comparison with TCIR. The need for morphine titration was not significantly different between groups. TCIR led to a significantly smaller requirement of remifentanil (700 ± 290 versus 1390 ± 555 µg, P < 0.001) without difference in propofol requirement. This prospective randomized study demonstrated that, during carotid endarterectomy, in comparison with patients receiving remifentanil using continuous RIVA, TCI results in less hypotensive episodes during the induction of anesthesia, in fewer episodes of tachycardia and/or hypertension and a smaller ß-adrenergic blocker requirement during recovery, and a decrease in remifentanil requirement. Recommendations to prefer TCI for remifentanil administration during carotid endarterectomy may be justified.

IMPLICATIONS: Remifentanil for intraoperative analgesia in carotid artery surgery is associated with a better stability in perioperative hemodynamics when administered in target-controlled infusion compared with continuous weight-adjusted infusion. This may be related to a smaller requirement of this drug when using target-controlled infusion, as well as a smooth mode of administration.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Because of its original metabolism independent of kidney and liver functions (1–3), remifentanil has a very short context-sensitive half-time (4,5), allowing rapid emergence even after prolonged infusion. This synthesized 4-anilido-piperidine with an ester side chain hydrolyzed by blood and tissue nonspecific esterase, is also one of the most potent opioids and permits a profound blockade of sympathetic system response to nociceptive stimulation. As a result of its pharmacokinetics, bolus administration alone is impossible and continuous infusion is required, the most common modality of which is a weight-adjusted administration associated with boluses if necessary. An alternative, as with propofol, is a target-controlled infusion (TCI) for remifentanil using a computer-driven infusion device that adapts infusion to pharmacokinetic models (6). TCI allows an accurate adaptation of the analgesia level and fewer overdose-linked adverse effects. The combination of opiates and hypnotics is well known. Numerous studies have reported potentiation with either volatile or IV hypnotics when associated with remifentanil (7–10). However, remifentanil is expensive and may have detrimental effects on hemodynamics in the case of overdose1 (11–13).

Hypotension occurs frequently during carotid surgery, mainly in relation to the induction of anesthesia, and hypertension and/or tachycardia is a common event during recovery of such patients. Unfortunately, a coronary artery disease is common in patients undergoing vascular surgery, in particular carotid artery surgery. In such patients, these hemodynamic events may be a trigger for coronary or neurologic ischemic events with potential catastrophic consequences.

Our hypothesis is that the incidence and the severity of hypotension during the induction of anesthesia are closely related to the dose of anesthetics used and to its mode of administration. In this prospective randomized study, we compared hemodynamics during the induction of anesthesia in patients receiving either continuous IV weight-adjusted infusion of remifentanil (RIVA) or TCI for remifentanil (TCIR). A secondary end point was to compare remifentanil requirement between both groups, because the larger requirement may be the cause of a rapid development of acute opioid tolerance in close relation with increased postoperative pain (14,15).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
After approval of the study by the Ethics Committee for Human Research of our institution, 46 patients scheduled for carotid endarterectomy surgery were included in this prospective randomized study. All patients were ASA physical status II or III, and gave informed consent. Patients with severe heart failure (stages III–IV of the New York Heart Association) or severe renal insufficiency (creatinine plasma level >200 µmol/L) were excluded.

Patients were all premedicated with midazolam 5 mg given orally 1 h before surgery. They received their cardiovascular medication on the morning before the operation, except converting enzyme inhibitors and angiotensin II antagonists, which were discontinued the day before (16,17). Standard monitoring included electrocardiogram with continuous ST-T analysis (leads D2, CS5, and V4; Marquette monitor, Milwaukee, WI), pulse oximetry, and invasive blood pressure with a radial catheter inserted before induction under local anesthesia. Baseline systolic arterial blood pressure (SBP) was defined as the average of 3 repeated measures on the day before surgery, and heart rate (HR) was calculated as the mean of 3 successive measurements taken after a 5–10 min period of stabilization. Depth of anesthesia was monitored by using bispectral index installed before induction.

After a 10 mL/kg crystalloid infusion over 10–15 min, and denitrogenation with pure O2, patients were anesthetized by using TCI for propofol (central nervous system target at 3 µg/mL then 1.6 after intubation, the infusion pump being programmed using actual body weight) adjusted to obtain a bispectral index value between 40 and 60. According to the randomization group of the patient defined by a computer-generated list compiled before the start of the study, the patients were included in 1 of the 2 groups for intraoperative analgesia: in Group I (n = 23), patients received continuous RIVA (RIVA group). They received 0.5 µg · kg-1 · min-1 over 60 s for induction, then the infusion rate decreased to 0.25 µg · kg-1 · min-1 for intubation, then adapted by step of 0.05 µg · kg-1 · min-1 according to hemodynamics. In Group II (n = 23), patients received TCIR (TCIR group). They received remifentanil with an effect-site concentration at 4 ng/mL during induction then adapted by step of 1 ng/mL according to hemodynamics (Minto model, Rugloop).

All patients received atracurium 0.5 mg/kg and a mechanical ventilation was performed by using a mixture of 50% N2O in O2. Approximately 30 min before the end of surgery, patients in both groups received proparacetamol 2 g and morphine 0.1 mg/kg. Propofol and remifentanil infusions (RIVA and TCI) were stopped at skin closure.

Hemodynamic variables were recorded each minute, from 10 min before starting the induction of anesthesia. Hemodynamic events were defined as: hypotension = SBP value <80 mm Hg lasting >1 min, hypertension = SBP value >160 mm Hg lasting >1 min, tachycar-dia = HR value >90 bpm lasting >1 min, and bradycardia = HR value <40 bpm lasting >1 min.

Intraoperatively, the anesthesiologist was required to maintain SBP and HR within 30% of baseline values by using fluid administration and vasoconstrictive drugs (ephedrine, phenylephrine, or terlipressin).

Postoperatively, patients were transferred to our recovery room. Hemodynamic events such as hypertension (>130% of control value) were treated with a bolus of nicardipine 1 mg, or titrated esmolol or propanolol when associated with increased HR (>85 bpm) or clonidine. Postoperative myocardial ischemia, defined as an ST depression >1 mm at 60 ms after the J point, was treated with diltiazem, or nitrates in case of poor left ventricular function. Postoperative analgesia included morphine titration as needed (when visual analog score was >30). Pain, morphine titration requirements, and number and duration of hemodynamic events were recorded, and total doses of vasoactive drugs were noted in each group of patients, and the hemodynamic study ended at discharge from the recovery room.

Postoperative cardiac complications were defined as: congestive heart failure, pulmonary edema, cardiac death, supraventricular arrhythmia, ventricular arrhythmia, new Q-wave or ST-T depression longer than 48 h on twice-daily 12-lead electrocardiogram, associated or not with clinical findings such as circulatory failure with the need for catecholamines, or a decrease in global or regional function on echocardiography, or an increase of cardiac Troponin I. Troponin I was measured at recovery and on the first, second, and third postoperative days, by using an immunoenzyme fluorometric assay on a Stratus autoanalyzer (Dade Behring Holding GmbH, Liederbach, Germany). Normal values are <0.2 ng/mL.

Statistical analysis was performed by using NCSS 6.0 software (Kaysville, UT). Prospective power analysis was based on hemodynamic variables. This showed that a sample size of 23 patients per group would have 90% power at the 5% significance level to detect a difference in hemodynamic variable variations of 30%.

After data had been checked for normality by using the Kolmogorov-Smirnov test, clinical characteristics of the patients, hemodynamic events, medication requirements, and use of vasoactive drugs were analyzed by using unpaired t-test or {chi}2 test when appropriate. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patient demographic characteristics were similar between the two groups in terms of age, sex ratio, actual body weight, ASA physical status, and associated morbidity (Table 1). The duration of anesthesia (Group 1: 113 ± 23 min versus Group 2: 123 ± 33 min) and surgery (Group 1: 82 ± 22 min versus Group 2: 90 ± 30 min) were identical between both groups, and no patient required postoperative ventilation in our study.


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  		Table 1. Clinical Characteristics of the Patients
 
At the start of the study, arterial blood pressure was identical between groups. Hemodynamic events are summarized in Table 2. In comparison with TCIR, RIVA was significantly associated with more frequent episodes of intraoperative hypotension (P < 0.001), but the use of vasoactive drugs was equal in both groups. For other hemodynamic events, such as hypertension, brady- or tachycardia, no intraoperative significant difference was found between groups.


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  		Table 2. Hemodynamic Events
 
Anesthetic requirements are shown in Table 3. TCIR led to a significantly smaller requirement of remifentanil but without a difference in propofol requirement (P < 0.001).


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  		Table 3. Anesthesia Characteristics
 
During recovery, morphine titration was necessary in a few cases, and no significant difference between groups was observed in pain scores. In contrast, RIVA was associated with more frequent episodes of hypertension and/or tachycardia, requiring more frequent administration of ß-blockers (P < 0.04) than TCIR, during the period in the recovery room. During the period of the study, none of the patients developed myocardial ischemia, and/or neurologic or surgical postoperative complication.


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
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References
 
Whatever the kind of surgery, remifentanil improves intraoperative hemodynamic stability compared with other opioids. In a large-scale study including 2438 patients, Twersky et al. (18) confirmed better hemodynamic control by using remifentanil compared with fentanyl. In this study, remifentanil-treated patients exhibited lower SBP and diastolic blood pressure (by 10–15 mm Hg) and slower HR (by 10–15 bpm) intraoperatively compared with the fentanyl-treated patient, a difference that promptly disappeared on emergence. It confirms the results of many others studies including more restricted populations. In microsuspension laryngoscopy, with high-risk patients undergoing brief and very high reflexogenic surgery, remifentanil is associated with significantly fewer episodes of tachycardia and hypertension compared with fentanyl (19). Prakash et al. (20) also found attenuated hemodynamic response to rigid bronchoscopy using remifentanil compared with fentanyl. Nevertheless, one study reported deleterious effects of remifentanil used as intraoperative analgesic (21). This prospective study included 40 patients with ischemic heart disease randomly assigned to one of the two following groups: patients in Group 1 received sevoflurane and remifentanil for the induction of anesthesia; patients in Group 2 received etomidate and fentanyl for induction. This study had to be rapidly terminated because of a frequent incidence of bradycardia and asystolic episodes in the remifentanil group. Unfortunately, patients in the sevoflurane-remifentanil group were significantly more chronically treated with ß-adrenergic blockers and had a slower preinduction HR. Moreover, remifentanil for induction was used at the dose of 0.5 µg · kg-1 · min-1 over 90 seconds after inspired 5% sevoflurane.

Concerning carotid artery surgery, there are two references. In a prospective randomized study including 56 endarterectomy patients undergoing general anesthesia with remifentanil versus sufentanil for analgesia, Mouren et al. (22) concluded that remifentanil was more effective in blunting the increase of blood pressure and HR associated with intubation without increasing the blood pressure-decreasing effect of induction or the blood pressure response to recovery, and that remifentanil was associated with a decrease in intraoperative drug requirement. Doyle et al. (23) showed that hemodynamic variables are equivalent during balanced anesthesia for carotid endarterectomy using remifentanil compared with fentanyl, but in this study, the fentanyl-treated group had delayed recovery in relation to continuous intraoperative fentanyl infusion. Our results confirm that hypotension occurs frequently during carotid surgery, mainly in relation to the induction of anesthesia, and that hypertension and/or tachycardia is a common event during recovery of such patients. TCIR improves hemodynamic behavior when compared with RIVA.

Maintaining adequate cerebral perfusion and continually adjusting cardiovascular variables to reduce the risk of potential adverse neurologic or cardiovascular events are the major goals of anesthetic management. It is why the results of our study may be of particular interest in patients undergoing carotid endarterectomy.

Another important aspect of anesthesia, enhanced in carotid artery surgery, concerns the recovery period and the neurologic examination. Remifentanil is associated in all studies with faster recovery and extubation (23), and earlier successfully performed neurologic tests when compared with fentanyl administration (24). When propofol is used as a hypnotic, for elective cardiac surgery, hemodynamic stability and good postoperative analgesia are achieved (25). Twersky et al. (18) confirmed with a large cohort of patients, significantly faster emergence and faster discharge from the recovery room and from the hospital in remifentanil-treated than in fentanyl-treated patients.

Hemodynamic stability, recovery, and discharge may be improved by using TCI (26). Adaptation of infusion rates allows achievement of a defined effect-site target by integration of the duration of infusion, the pharmacokinetic properties of remifentanil, and the patients’ characteristics (sex, age, height, body weight). That permits a reduction of fluctuating drug concentrations and drug effects and seems particularly interesting because of the adverse effects of remifentanil that mainly occur in cases of overdose. The better hemodynamic stability obtained in our study in the TCIR group was attributed to a decreased cumulative dose of remifentanil in this group, but also probably to its slower administration. Moreover, to decrease the requirement of an expensive drug obviously has a favorable cost impact. This type of finding is clearly demonstrated when using TCI for propofol and when considering both the direct and indirect costs of anesthesia regimens: TCI is associated with an increased intraoperative cost (26), but this type of anesthetic regimen may be an important step toward fast-track eligibility and shortening of postanesthetic care unit time. However, determining this cost-reducing factor is relatively straightforward.

Concerning postoperative pain, rapid development of acute opioid tolerance is well established, particularly when large doses of short-acting drugs like remifentanil are used (14,15). In healthy volunteers undergoing general anesthesia using remifentanil, other studies found no evidence concerning this phenomenon (27–29). However, postoperative pain in carotid artery surgery is not influenced by the opioid used intraoperatively, the visual analog score remaining comparable with remifentanil or fentanyl (23). The lack of difference in our study between the TCIR and RIVA groups concerning intensity of postoperative pain and postoperative morphine requirement does not confirm this secondary hyperalgesia phenomenon, carotid endarterectomy remaining a surgery associated with moderate pain. Two other hypotheses could explain our results. The central nervous system target for remifentanil used in our study is nearly twofold less than in the Guignard et al. study (14), and we could have been under a trigger value necessary for secondary hyperalgesia. Duration of infusion is insufficient to induce clinically relevant postoperative hyperalgesia; this tolerance is appreciable with remifentanil only when infusion exceeds two hours according to Vinik and Kissin (15).

Many problems remain to be solved when using TCIR. The most important is the choice of the pharmacokinetic model to use. According to target in plasma or at effect site, the emergence and the delay before emergence are predictable knowing the concentration needed for loss of consciousness and the drugs’ pharmacokinetics. The three-compartmental Minto’s pharmacokinetic model is often used (30,31), but the biexponential decay curve (32) and other three-compartmental models (33,34) have been described, none of them including remifentanil pharmacodynamic variability linked to duration of infusion (15), or the synergistic hypnotic-opioid interaction occurring during balanced anesthesia. The best described interaction concerns propofol-remifentanil synergistic interaction (35,36).

The problem of the target to use remains easy to resolve by titration of the patient’s requirement according to clinical variables. In the literature, a study concerning intraabdominal surgery showed adequate intraoperative plasma concentrations by using TCIR in the range of 4.1–7.5 ng/mL according to a 2-compartment model with lean body mass as a significant covariate (37). In our study, in a much less painful surgery, the target achieved before first laryngoscopy was 4 ng/mL in the central nervous system, and the intraoperative requirements were in the range of 2–5 ng/mL.

In summary, we have found that remifentanil for intraoperative analgesia in carotid artery surgery is associated with a better stability in perioperative hemodynamics when administered in TCI compared with continuous RIVA. This is probably because less of this drug is required when using TCI, as well as its smooth mode of administration. Minto’s pharmacokinetic model seems to be adapted to TCIR for surgery of intermediate time duration.


   Footnotes
 
1Pitts MC, Palmore MM, Salmenpera MT, et al. Pilot study: hemodynamic effects of intravenous GI87084 in patients undergoing elective surgery [abstract]. Anesthesiology 1992;77:A101. Back


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Accepted for publication September 30, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press