BJA Advance Access originally published online on April 10, 2007
British Journal of Anaesthesia 2007 98(5):598-603; doi:10.1093/bja/aem069
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Low-dose remifentanil to suppress haemodynamic responses to noxious stimuli in cardiac surgery: a dose-finding study
Division of Cardiothoracic and Vascular Anaesthesia and Intensive Care, University Hospital Vienna, Vienna, Austria
* Corresponding author: Division of Cardiothoracic and Vascular Anaesthesia and Intensive Care, University Hospital Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. E-mail: barbara.steinlechner{at}meduniwien.ac.at
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Abstract |
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Background: High-dose remifentanil (1–5 µg kg–1 min–1), commonly used for cardiac surgery, has been associated with muscle rigidity, hypotension, bradycardia, and reduced cardiac output. The aim of this study was to determine an optimal lower remifentanil dose, which should be accompanied by fewer adverse events, that still effectively suppresses haemodynamic responses to typical stressful stimuli (i.e. intubation, skin incision, and sternotomy).
Methods: Total i.v. anaesthesia consisted of a target-controlled propofol (2 µg ml–1) and a remifentanil infusion. Forty patients were allocated to receive either a constant infusion of remifentanil at 0.1 µg kg–1 min–1 or up-titrations to 0.2, 0.3, or 0.4 µg kg–1 min–1, respectively, 5 min before each stimulus. Subsequently, changes in heart rate and mean arterial blood pressure were recorded for 8 min. Increases exceeding 20% of baseline were considered to be of clinical relevance. Patients who exhibited these alterations were termed responders.
Results: The number of responders was less with the two higher remifentanil dosages (P < 0.05) while propofol target doses could either be kept at the same level or even be reduced without affecting the plane of anaesthesia. Although single phenylephrine bolus had to be applied more frequently in these two groups (P < 0.05), no severe haemodynamic depression was observed.
Conclusions: Remifentanil at 0.3 and 0.4 µg kg–1 min–1 in combination with a target-controlled propofol infusion in the pre-bypass period is well tolerated. It appears to mitigate potentially hazardous haemodynamic responses from stressful stimuli equally well as higher doses when compared with data from the literature.
Keywords: anaesthetic techniques, i.v. infusion; analgesics opioid, remifentanil; cardiovascular anaesthesia; monitoring, bispectral index; stress
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Introduction |
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Many patients undergoing cardiac surgery do not tolerate unstable haemodynamics that can be precipitated by various noxious stimuli in the precardiopulmonary bypass period. Particularly, tachycardia that is strongly linked to the degree of sympathetic stimulation is a risk factor for perioperative myocardial ischaemia/infarction, especially in patients with coronary artery disease and those with a hypertrophic left ventricle. Concomitant rises in blood pressure increase wall stress and may also cause decompensation in heart failure patients. Attenuation of neurohumoural responses to surgical stress has always been a main focus of cardiac anaesthesia and is predominantly managed by administration of high-dose opioids in order to avoid extensive cardiodepression by anaesthetics. Immediate on- and offset of the analgesic effect of remifentanil makes it a perfect agent to instantly control painful stimuli during surgery.1 2 Remifentanil can easily be adjusted to each patient's analgesic needs without compromising recovery. Therefore, remifentanil is frequently used for cardiac surgery to facilitate fast-track protocols.3 4 The high dosages, however, that are commonly applied for adult and paediatric cardiac surgery (1–5 µg kg–1 min–1) are frequently associated with severe adverse effects, which may be just as hazardous for the patient as the sympathetic activation one aims to mitigate. Declining cardiac output accompanied by hypotension and reduced coronary perfusion and muscle rigidity that impairs oxygenation have been observed, which often necessitated decreases in the remifentanil infusion rate.5–9 Geisler and colleagues5 reported a high incidence of adverse effects and suggested that ‘further studies are required to show if a lower dose of remifentanil in combination with the same or probably higher dose of propofol can be used as safely’. At our institution, much lower doses (i.e. those recommended for general anaesthesia in combination with propofol10) have been used for a long time.4 Although our patients do not appear to lack adequate intraoperative analgesia, the dosage that selectively blunts intraoperative sympathetic stimulation in an efficient way has not been studied systematically in this low-dose remifentanil range.
Under target-controlled propofol anaesthesia, we used increases in heart rate (HR) and mean arterial pressure (MAP) to determine the effectiveness of four different dose regimens of remifentanil to suppress haemodynamic consequences of stressful manipulations at bispectral index (BIS) values representing adequate anaesthesia.11
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Methods |
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After approval by the local ethics committee and having obtained written informed consent, 40 patients of either gender, ASA physical status
IV, undergoing elective cardiac surgery for the first time were included in our study. Patients were excluded if there was evidence of hypersensitivity to opioids, a history of substance abuse, mental impairment, congestive heart failure (left or right ventricular ejection fraction < 40%), or participation in another clinical trial.
Protocol
The patients' medication was not discontinued before surgery. Patients were premedicated with midazolam 7.5 mg orally given 90 min before surgery. To monitor the depth of anaesthesia, ZipprepTM electrodes (Aspect Medical System, Newton, MA, USA) were placed according to the recommendations of the manufacturer, and the BIS index was displayed continuously using an Aspect A-2000 EEG analyser (A 2000, Aspect Medical Systems) throughout surgery. Routine monitoring included electrocardiogram, arterial and central venous pressures, pulse oximetry, and capnometry (9000 XL; Siemens Medical Solutions Inc., Sweden).
Anaesthesia was induced by targeting a propofol plasma concentration of 2 µg ml–1 (Master TCI infusion system, Fresenius, Bad Homburg, Germany). If loss of consciousness (i.e. loss of response to verbal commands and loss of the eyelash reflex) was not obtained with this target plasma concentration, the anaesthetist in charge was authorized to increase the rate in 0.2 µg ml–1 increments. Subsequently, the target plasma concentration was titrated to maintain BIS values between 40 and 50 throughout surgery that has been associated with an adequate depth of anaesthesia.11 Patients were randomly assigned to receive remifentanil (ULTIVA®, GlaxoSmithKline Pharma GmbH, Vienna, Austria) at one of four infusion rates (i.e. 0.1, 0.2, 0.3, or 0.4 µg kg–1 min–1 with 10 patients per group) that was started with the induction of anaesthesia. The patients were subsequently ventilated with 40% oxygen in air to maintain a PE'CO2 between 30 and 40 mm Hg. Intubation was facilitated by 0.2 mg kg–1 cisatracurium. Eight minutes after intubation, the remifentanil infusion rate was set in all groups to 0.1 µg kg–1 min–1 again. Five minutes before skin incision and sternotomy, rates were increased again to 0.1, 0.2, 0.3, or 0.4 µg kg–1 min–1, respectively. After skin incision and sternotomy, an observation period of 8 min followed. Remifentanil infusions had been prepared before surgery by an anaesthetist of the study group who also changed the infusion rates before the interventions. However, the anaesthetist taking care of the patient was blinded to the remifentanil infusion rate.
Pre-cardiopulmonary bypass (CPB) period end-points included MAP and HR as markers of the sympathetic response to surgical stress.5 6 12 The incidence of intraoperative bradycardic, tachycardic, hyper- and hypotensive events, and the dosage of the cardiovascular ‘rescue’ medication were also recorded. Heart rate, MAP, and BIS level were determined at baseline over 5 min (i.e. before induction of anaesthesia and before skin incision and sternotomy) and recorded continuously thereafter. An increase in HR, MAP, or both of more than 20% above baseline during the first 8 min after each stimulus was considered to be clinically relevant.13 Those patients were termed ‘responders’ (to painful stimuli). The acceptable range for MAP was set at 
60–120 mm Hg. If MAP increased above 120 mm Hg or decreased below 60 mm Hg, either nitroprusside (0.02 mg i.v.) or phenylephrine bolus (0.02 mg i.v.) was administered. Bradycardia (35 min–1) or tachycardia (110 min–1) was treated with atropine (0.5 mg i.v.) or esmolol (0.05 mg kg–1 i.v.), respectively.
Statistical analysis
Differences in categorical data were evaluated using the Chi-square test. According to our power calculation, a number of 10 patients per group will detect relevant changes in MAP, as the primary end-point, with a power of 90% and an 
-level of 0.05. The changes in MAP and HR were analysed using a repeated measures analysis of variance followed by the Dunnett's method to account for multiple comparisons. The P-level was set at 0.05.
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Demographic characteristics and intraoperative data of the 40 patients are shown in Table 1. Eight women and 32 men with a mean (SD) age of 65 (9) yr were studied. Coronary artery bypass grafting was performed in 30 patients. In 6 patients an aortic valve replacement was done and 2 patients had combined coronary bypass and aortic valve replacement surgery. A myxoma of the right atrium was removed in another 2 patients. The preoperative left ventricular ejection fraction was 57 (9)%. Twenty-seven patients were on ß-blockers, 24 were treated with nitrates, and 16 were treated with ACE inhibitors. The time after completion of surgery to extubation was 2.7 (3.7) h. There were no statistically significant differences in patient characteristics data between the four treatment groups.
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Changes in HR and MAP averaged over 8 min after each stimulus and the corresponding baseline values in all the four treatment groups are given in Table 2. These data show that especially increases in MAP but also in HR after intubation could be better prevented by timed remifentanil dose adjustments to 0.3 and 0.4 µg kg–1 min–1.
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To keep the BIS level between 40 and 50, the highest cumulative propofol dose from induction of anaesthesia to intubation was required in the remifentanil 0.1 µg kg–1 min–1 group (163 mg). It was 140 mg in the remifentanil 0.2 µg kg–1 min–1 group, and even lower (118 and 121 mg propofol) in the remifentanil 0.3 and 0.4 µg kg–1 min–1 groups, respectively (P < 0.05). Eight patients in the remifentanil 0.4 and 0.3 µg kg–1 min–1 groups, six patients in the remifentanil 0.2 µg kg–1 min–1 group but only three patients in the remifentanil 0.1 µg kg–1 min–1 group required single phenylephrine bolus applications to keep MAP
60 mm Hg (P < 0.05). The cumulative phenylephrine dose for each group is also shown in Table 1. Muscle rigidity and bradycardia requiring the application of atropine have not been observed during up-titrations of remifentanil independent of the given dose. The number of patients who showed haemodynamic responses (i.e. increases in either HR or MAP > 20% of baseline) to intubation, skin incision, or sternotomy is given in Table 3. Heart rate and MAP increases occurred more frequently in the two groups that received the two lower remifentanil doses (i.e. 0.1 and 0.2 µg kg–1 min–1). However, this reached statistical significance only at the time points ‘after intubation’ and ‘after skin incision’. In contrast, the mean target propofol dose in the highest remifentanil dose group was consistently lower as compared with the other three groups (P < 0.05). BIS values over time in the four groups are presented in Figure 1. They ranged between 40 and 50 throughout the observation period. As can be seen, they were not different among groups at any point in time. No incidence of recall has been reported.
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Discussion |
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In adult and paediatric cardiac surgery, high-dose remifentanil regimes are frequently associated with severe, potentially harmful adverse effects.5–7 14 We therefore assessed the appropriate remifentanil dosage in a low-dose range that in combination with propofol will still effectively blunt stress responses to typical intraoperative noxious sympathetic stimuli in the pre-bypass period during cardiac surgery.
In order to investigate the effect of different remifentanil dosages on pain-induced alterations of haemodynamics, we had to guarantee an adequate depth and the same plane of anaesthesia in all four study groups. Therefore, we employed target-controlled propofol anaesthesia to keep the BIS index between 40 and 50. BIS index is a useful neurophysiologic variable to monitor the level of anaesthesia during cardiac surgery.8 11 15 16 Similar BIS values have already been applied by Bauer and colleagues11 during propofol–remifentanil anaesthesia in patients undergoing elective on-pump coronary artery bypass grafting in hypothermia. Bauer and colleagues kept the remifentanil dose constant at 0.3 µg kg–1 min–1 and used higher target propofol plasma concentration (3 vs 2 µg ml–1 before CPB). Propofol–remifentanil anaesthesia at these dosages completely blunted the release of epinephrine and cortisol during surgery and guaranteed stable haemodynamics. In contrast to this investigation, our patients were managed with normothermic bypass at a lower propofol and remifentanil dose whereby remifentanil was adjusted according to the patient's need. Our intention was to avoid excessive cardiovascular depression resulting from excessive anaesthesia. Nevertheless, because of moderate hypotension, single phenylephrine bolus still had to be administered, particularly in our two high-dose remifentanil groups. In contrast, the majority of patients (almost 90%) in the study by Geisler and colleagues5 needed to be treated with fluids and vasopressors to stabilize blood pressure again, and more than 50% of patients presented with more than five hypotensive episodes. The incidence of bradycardia ranged between 13 and 23% in patients receiving 1 and 2 µg kg–1 min–1, respectively. Consequently, propofol had to be decreased in almost 50% of the patients in Geisler and colleagues' study and in 20% of patients, the remifentanil dosage was decreased as well. The mean haemodynamic response rate in this investigation was 30, 8, and 10% after intubation, skin incision, and sternal spread, respectively.5 Similar rates of pain-induced hypertension (10–25%) have been reported by Howie and colleagues6 after intubation and sternotomy. Tachycardia was consistently less common. Howie and colleagues, however, used a primary opioid protocol using remifentanil at 1–5 µg kg–1 min–1 with isoflurane only given as a rescue medication.
Heart rate, myocardial wall stress, and contractility are key determinants of myocardial oxygen demand. Catecholamine-mediated stress responses lead to sympathetic activation reflected by increases in HR and MAP, which is associated with an increase in myocardial oxygen demand. Anaesthetics and opioids are frequently applied guided by variables such as MAP and HR. In this study, propofol was titrated to keep BIS values in the designated range between 40 and 50 during each of the four different remifentanil infusion regimes. Under these circumstances, haemodynamic responses, here defined as increases in HR and MAP > 20% of baseline, would clearly indicate a deficit in the analgesic component of anaesthesia. Responses to noxious stimuli occurred more frequently in the two lower remifentanil dose groups of our study (0–90%) compared with those in the high remifentanil dose groups (0.3 and 0.4 µg kg–1 min–1) where they were noted in only 0–20% (see Table 3). The attenuation was dose dependent. It is comparable with the findings reported in heart surgery patients managed with a high-dose remifentanil regime.5 6 Haemodynamic alterations mostly presented as changes in MAP and less often as increases in HR, which may be because of the effect of the preoperative ß-blocker treatment (>50% of patients in each group). Additionally, propofol consumption was highest in the group with the lowest remifentanil dose rate. However, thereby increases in the BIS index during noxious stimuli could be prevented successfully.
The effect of opioids on the BIS during general anaesthesia is controversial. Some investigators have reported the BIS index to be insensitive to opioids,17 whereas others have found decreases accompanied by decrease in HR and MAP at higher opioid doses.18 The findings by Mustola and colleagues19 suggest that remifentanil infusion started before induction of propofol anaesthesia significantly accelerates the hypnotic onset of propofol. Remifentanil at different infusion doses (placebo, 0.01, 0.05, or 0.1 µg kg–1 min–1) combined with a target-controlled infusion of propofol 2 µg ml–1 was also shown to reduce BIS.20 Guignard and colleagues21 evaluated the effect of remifentanil at various target effect site concentrations (0, 2, 4, 8, or 16 ng ml–1) on the BIS index and haemodynamic responses to laryngoscopy and tracheal intubation in ASA I patients undergoing non-cardiac surgery. Propofol was maintained at a comparatively high effect-site concentration of 4 µg ml–1 throughout the study. Under these conditions, the addition of remifentanil affected BIS only when a painful stimulus was applied. Moreover, remifentanil attenuated or completely abolished increases in BIS and MAP after tracheal intubation in a dose-dependent fashion.
As compared with our study, Albertin and colleagues22 administered a larger mean targeted plasma concentration of propofol (3.4 µg ml–1) in younger patients undergoing elective abdominal surgery under propofol–remifentanil anaesthesia to obtain stable BIS values in the same range as applied here. In this setting, remifentanil target effect-site concentrations of 5 and 2 ng ml–1 blunted sympathetic responses (defined as increases in either HR or MAP 15%) to tracheal intubation and skin incision. These were achieved and maintained with a computer-assisted target-controlled infusion. In contrast, we used conventional weight-adjusted administration. For ‘practical purposes’ Albertin and colleagues suggested to give a remifentanil 0.5 µg kg–1 bolus followed by a continuous infusion of 0.2 µg kg–1 min–1 for tracheal intubation and a 0.35 µg kg–1 bolus followed by 0.08 µg kg–1 min–1 for skin incision. Our results were obtained in elderly ASA III and IV patients undergoing cardiac surgery, however, where dosages should be reduced.8 They indicate that remifentanil doses exceeding 0.3 µg kg–1 min–1 for intubation and skin incision were generally associated with a higher incidence of hypotensive episodes, but were hardly ever required.
We deliberately focused on haemodynamic alterations during the pre-bypass period, as these should have a greater impact on cardiac morbidity than those occurring after surgical correction of the cardiac pathology. In addition, haemodynamics on and after CPB are frequently affected by the application of catecholamines and volume status and may not reflect stress responses.
In conclusion, this study shows that temporarily up-titrating the remifentanil infusion from 0.1 to 0.3 or 0.4 µg kg–1 min–1 provided a potent antinociceptive effect. They better suppressed haemodynamic responses from typical noxious stimuli during cardiac surgery than the two lower doses (0.1 and 0.2 µg kg–1 min–1). At the same time, propofol target doses were either equal in two higher dose groups or could even be decreased without affecting the level of anaesthesia. However, superior attenuation of hypertension and tachycardia because of sympathetic stimulation goes along with a higher vasoconstrictor usage. In spite of mild hypotension, remifentanil, even at these two higher dosages, did not compromise cardiac pump function, as is the case with propofol and a high-dose remifentanil protocol.
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References |
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1 Egan TD. Remifentanil pharmacokinetics and pharmacodynamics. A preliminary appraisal. Clin Pharmacokinet (1995) 29:80–94.[Web of Science][Medline]
2 Patel SS, Spencer CM. Remifentanil. Drugs (1996) 52:417–27.[Web of Science][Medline]
3 Olivier P, Sirieix D, Dassier P, D'Attellis N, Baron JF. Continuous infusion of remifentanil and target-controlled infusion of propofol for patients undergoing cardiac surgery: a new approach for scheduled early extubation. J Cardiothorac Vasc Anesth (2000) 14:29–35.[CrossRef][Web of Science][Medline]
4 Steinlechner B, Koinig H, Grubhofer G, et al. Postoperative analgesia with remifentanil in patients undergoing cardiac surgery. Anesth Analg (2005) 100:1230–5.
5 Geisler FEA, de Lange S, Royston D, et al. Efficacy and safety of remifentanil in coronary artery bypass graft surgery: A randomized, double-blind dose comparison study. J Cardiothorac Vasc Anesth (2003) 17:60–8.[CrossRef][Web of Science][Medline]
6 Howie MB, Michelsen LG, Hug CC, et al. Comparison of three remifentanil dose-finding regimens for coronary artery surgery. J Cardiothorac Vasc Anesth (2003) 17:51–9.[CrossRef][Web of Science][Medline]
7 Kazmaier S, Hanekop GG, Buhre W, et al. Myocardial consequences of remifentanil in patients with coronary artery disease. Br J Anaesth (2000) 84:578–83.
8 Quattara A, Boccara G, Lemaire S, et al. Target-controlled infusion of propofol and remifentanil in cardiac anaesthesia: influence of age on predicted effect-site concentrations. Br J Anaesth (2003) 90:617–22.
9 Chanavaz C, Tirel O, Wodey E, et al. Haemodynamic effects of remifentanil in children with and without intravenous atropine. An echocardiographic study. Br J Anaesth (2005) 94:74–9.
10 Servin F. Remifentanil: when and how to use it. Eur J Anaesth (1997) 14((Suppl. 15)):41–4.[Medline]
11 Bauer M, Wilhelm W, Kraemer T, et al. Impact of bispectral index monitoring on stress response and propofol consumption in patients undergoing coronary artery bypass surgery. Anesthesiology (2004) 101:1096–104.[CrossRef][Web of Science][Medline]
12 Matute E, Alsina E, Roses R, Blanc G, Perez-Hernandez C, Gilsanz F. An inhalation bolus of sevoflurane versus an intravenous bolus of remifentanil for controlling hemodynamic responses to surgical stress during major surgery: a prospective randomized trial. Anesth Analg (2002) 94:1217–22.
13 Djian MC, Blanchet B, Pesce F, et al. Comparison of the time to extubation after use of remifentanil or sufentanil in combination with propofol as anesthesia in adults undergoing nonemergency intracranial surgery: a prospective, randomized, double-blind trial. Clin Ther (2006) 28:560–8.[CrossRef][Web of Science][Medline]
14 Weale NK, Rogers CA, Cooper R, Nolan J, Wolf RA. Effect of remifentanil infusion rate on stress response to the pre-bypass phase of paediatric cardiac surgery. Br J Anaesth (2004) 92:187–94.
15 Forestier F, Hirschi M, Rouget P, et al. Propofol and sufentanil titration with the bispectral index to provide anesthesia for coronary artery surgery. Anesthesiology (2003) 99:334–46.[CrossRef][Web of Science][Medline]
16 Heck M, Kumle B, Boldt J, Lang J, Lehmann A, Saggau W. Electroencephalogram bispectral index predicts hemodynamic and arousal reactions during induction of anesthesia in patients undergoing cardiac surgery. J Cardiothorac Vasc Anesth (2000) 14:693–7.[CrossRef][Web of Science][Medline]
17 Lysakowski C, Dumont L, Pellegrini M, Clergue F, Tassonyi E. Effects of fentanyl, alfentanil, remifentanil and sufentanil on loss of consciousness and bispectral index during propofol induction of anaesthesia. Br J Anaesth (2001) 86:523–7.
18 Koitabashi T, Johansen JW, Sebel PS. Remifentanil dose/electroencephalogram bispectral response during combined propofol/regional anesthesia. Anesth Analg (2002) 94:1530–3.
19 Mustola ST, Baer GA, Neuvonen PJ, Toivonen KJ. Requirements of propofol at different end-points without adjuvant and during two different steady infusions of remifentanil. Acta Anaesthesiol Scand (2005) 49:215–21.[CrossRef][Web of Science][Medline]
20 Strachan AN, Edwards ND. Randomized placebo-controlled trial to assess the effect of remifentanil and propofol on bispectral index and sedation. Br J Anaesth (2000) 84:489–90.
21 Guignard B, Menigaux C, Dupont X, Fletcher D, Chauvin M. The effect of remifentanil on the bispectral index change and hemodynamic responses after orotracheal intubation. Anesth Analg (2000) 90:161–7.
22 Albertin A, Casati A, Federica L, et al. The effect-site concentration of remifentanil blunting cardiovascular responses to tracheal intubation and skin incision during bispectral index-guided propofol anesthesia. Anesth Analg (2005) 101:125–30.
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