1 Department of Anaesthesia, Erasme Hospital, 808 route de Lennik, 1070, Anderlecht, Belgium. 2 Faculty of Medicine, Free University of Brussels, 808 route de Lennik, 1070, Anderlecht, Belgium. 3 Glasgow Royal Infirmary, Alexandra Parade, Glasgow, UK
Corresponding author. E-mail: lbarvais@ulb.ac.be
Accepted for publication: April 28, 2003
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Abstract |
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Methods. Anaesthesia was induced with propofol TCI to obtain loss of consciousness (LOC) in 12 ASA I/II patients. Thereafter, remifentanil CeT was titrated by increments of 1 up to 5 ng ml1. In the awake state, at LOC and at each plateau level of remifentanil CeT, arterial pressure, heart rate, and BIS (A2000) were recorded. Pupil size and dilatation after a 100 Hz tetanic stimulation (T100) were measured at LOC and at each plateau level of remifentanil CeT.
Results. LOC was observed at a mean propofol CeT of 3.53 (SD 0.43) µg ml1. Arterial pressure and heart rate decreased progressively from LOC to 5 ng ml1 remifentanil CeT without any statistical difference between each incremental dose of remifentanil. Mean BIS values decreased from 96 (2) in the awake state, to 46 (12) at LOC (P<0.05) and then remained unchanged at all remifentanil CeT. Pupil dilatation in response to 100 Hz tetanic stimulation decreased progressively from 1.55 (0.72) to 0.01 (0.03) mm and was more sensitive than pupil diameter measured before and after 100 Hz tetanus. An inverse correlation between pupil dilatation in response to 100 Hz tetanus and an increase in remifentanil CeT from 0 to 5 ng ml1 was found (R2=0.68).
Conclusions. During propofol TCI in healthy patients, the decrease in pupil response to a painful stimulus is a better measurement of the progressive increase of remifentanil CeT up to 5 ng ml1 than haemodynamic or BIS measurements.
Br J Anaesth 2003; 91: 34752
Keywords: anaesthetics i.v., propofol; analgesics opioid, remifentanil; eye, pupil size; eye, reflexes
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Introduction |
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Larson and colleagues2 have demonstrated that alfentanil does not diminish the light reflex but blocks reflex pupillary dilatation in response to noxious stimulation. These workers reported a good correlation between plasma alfentanil concentration and the magnitude of pupil dilatation. Remifentanil is an opioid drug with a short onset and duration of action. Minto and colleagues described the pharmacokinetics and pharmacodynamics of remifentanil in 65 healthy adult volunteers, using the electroencephalogram to measure the opioid effect.3 The predictive performance of their population pharmacokinetic set had an acceptable accuracy.3
TCI systems calculate and target the effect compartment concentration (CeT) of i.v. anaesthetic drugs.4 5 Recently, an accurate and easy to use pupillometer has been marketed, which allows measurement of pupil size without any influence on the light reflex (Colvard infrared pupillometer; OASIS Medical Inc., Glendora, CA, USA). The aim of this study was to investigate the relationship between calculated CeT of remifentanil and pupil size or dilatation in response to repetitive, standard noxious stimulation. The changes in BIS and haemodynamic measurements were also recorded and compared with remifentanil CeT.
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Methods |
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A software system, called TOOLBOX, designed in the Department of Computer Sciences of our faculty, was used to infuse propofol and remifentanil.5 This TCI system allows the CeT of i.v. anaesthetic drugs to be targeted. The software is programmed in Visual Smalltalk, one object orientated language (VisualAge for Smalltalk version 6.0, IBM) and is run on a Windows-based PC. It has been implemented with the same algorithms as those proposed by Shafer.4
Induction of anaesthesia was obtained by increasing propofol CeT progressively until loss of consciousness (LOC) using the population pharmacokinetic set of Schnider.6 This set was selected because a propofol TCI, which controlled the effect site rather than the plasma drug concentration, more accurately produced the desired effect.7 In all patients, the initial Ce was 2 µg ml1, which was progressively increased by steps of 1 µg ml1 until LOC. Thereafter, the propofol CeT associated with LOC was maintained at the same level during the whole study period and cisatracurium 0.15 mg kg1 was administered.
The CeT of propofol was titrated without any restriction on the peak plasma concentration, using propofol 1% and a maximum pump flow rate of 1200 ml h1. Figure 1 describes the progressive increase in the CeT of propofol in a 40-yr-old patient with a weight of 70 kg and a height of 170 cm using the pharmacokinetic set of Schnider,6 with a T1/2keo of 1.8 min. In this patient, the initial target CeT of 2 µg ml1 is generated by a bolus of 38 mg administered over 10 s, which is associated with a short peak plasma overshoot of 8 µg ml1.
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All data are given as mean (SD). Statistical analysis was performed using analysis of variance for repeated measures across all measurements. P<0.05 was considered as statistically significant. When a P value <0.05 was obtained, a Tukey post hoc analysis was performed to compare individual points.
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Results |
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Systolic arterial pressure decreased progressively from the awake state to a remifentanil CeT of 5 ng ml1. Compared with the value at LOC, systolic arterial pressure decreased significantly at a remifentanil CeT of 3, 4, and 5 ng ml1 (Table 2). No statistical difference between each successive plateau level of remifentanil CeT was found.
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Compared with the heart rate values recorded at LOC, a significant decrease was measured at a remifentanil CeT of 4 and 5 ng ml1. Compared with the values at a remifentanil CeT of 1 ng ml1, a significant decrease in heart rate was only measured at 5 ng ml1 (Table 2).
The BIS decreased statistically from 95.6 (2.3) in the awake state to 45.5 (11.5) at LOC and remained low, varying little at the increasing levels of remifentanil CeT (Table 2).
In the absence of any noxious stimulus and compared with the reference size at LOC (4.14 (1.42) mm), pupil size was statistically decreased from remifentanil CeT of 2 ng ml1 (2.07 (0.48) mm) (Fig. 3A). Compared with the pupil size at 1 ng ml1 (3.02 (1.24) mm), the pupil size before 100 Hz tetanic stimulus was statistically smaller at remifentanil CeT of 3, 4, and 5 ng ml1 (Fig. 3A). Compared with the pupil diameter after T100 at LOC (5.69 (1.42) mm) and at a remifentanil CeT of 1 ng ml1 (4.25 (1.21) mm), all subsequent measurements of the pupil size after T100 were less than 2.5 mm and statistically significantly smaller (Fig. 3B).
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Discussion |
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Noxious stimulation dilates the pupil in both unanaesthetized and anaesthetized humans and is mediated primarily by the sympathetic system in the awake state. However, during desflurane anaesthesia, pupil dilatation in response to a noxious stimulus appears to involve either inhibition of the pupilloconstrictor nucleus located in the central pathway as high as the rostral mesencephalon, or a previously undescribed non-cholinergic, non-adrenergic synapse with neuromuscular junctions within the iris.9 The halogenated agents (halothane, isoflurane, sevoflurane, desflurane), the catecholamines and atropine provoke mydriasis.10 11 Propofol, thiopental, lidocaine, and the neuromuscular blocking agents do not alter pupil reactivity.12 13 The neuroleptic and opioid drugs have a pupilloconstriction effect.
During isoflurane anaesthesia, alfentanil did not diminish the light reflex but produced a substantial dose-dependent depression of pupillary dilatation after a noxious stimulus. Dilatation was reduced to 50% of control values at alfentanil concentrations around 20 ng ml1, and was almost abolished at concentrations approaching 100 ng ml1.2 Larson and colleagues10 have demonstrated that pupil dilatation is a more sensitive measure of noxious stimulation than the commonly used variables of arterial pressure and heart rate during isoflurane and propofol anaesthesia. The effect of opioids on pupil dilatation in response to a painful stimulus is not mediated via the 2 receptors.14
TCI propofol combined with a continuous opioid infusion has become the standard European technique for total i.v. anaesthesia. Synergy between propofol and the opioid drugs permits administration of lower doses of each.15 Adjustments of the hypnotic or analgesic components are made in response to the intensity of the surgical stimulus, to the haemodynamic changes that occur during surgery, and also according to the respective pharmacokinetic profiles and duration of infusion of each drug.15
As yet, there have been only two clinical reports of improving opioid titration and decreasing the variability in individual responsiveness during adequate administration of propofol.17 18 BIS variability in response to a nociceptive input has been shown to decrease when opioid doses were increased in healthy volunteers.17 BIS is as sensitive as haemodynamic responses after a painful stimulus for detecting deficits in the analgesic component of anaesthesia,18 and it may help to monitor depth of anaesthesia in patients who are incapable of heart rate and arterial pressure responses because of cardiovascular medication.18 But the BIS index cannot help the anaesthetist to titrate remifentanil analgesia during propofol TCI.
During general anaesthesia, pupillary changes to light or a painful stimulus are rarely studied because of the lack of a convenient and accurate method of recording pupillary activity in the operating room. As a new portable and easy to use pupillometer has been marketed and validated,19 this clinical study was undertaken to evaluate the relationship between the remifentanil effect site concentration and haemodynamic responses, changes in BIS, and pupil dilatation to a noxious and repetitive stimulus.
In the 12 patients studied, systolic and diastolic arterial pressures and heart rate decreased progressively from the awake state until a remifentanil Ce of 5 ng ml1, without any statistical difference between each successive plateau level of remifentanil (Table 2). This decrease in arterial pressure may not be related to the progressive increase in remifentanil Ce and is probably caused by the delayed effects of propofol combined with a dose-dependent, synergistic action of remifentanil. Kazama and colleagues20 have compared the effect site equilibration constants (keo) of propofol with BIS and arterial pressure in elderly and younger patients. They demonstrated that the decrease in arterial pressure is delayed compared with EEG depression, independently of the age of the patient.20
A linear relationship between pupil dilatation in response to T100 and the calculated remifentanil Ce using the population pharmacokinetic data set of Minto3 was demonstrated clearly in this study. This relation is similar to the results of Larson and colleagues who measured reflex pupil dilatation and plasma alfentanil concentrations.2 To exclude any reduction in pupil dilatation caused by the repetition of the same noxious stimulus, we studied a control group of five ASA I patients anaesthetized with the same propofol effect site TCI profile without any opioid administration. Pupillary dilatation was evaluated five times every 2 min after the same tetanic stimulus of 100 Hz. No sign of fade of pupil dilatation in response to 100 Hz tetanus was detected.
In conclusion, during propofol TCI anaesthesia in young healthy patients, the addition of remifentanil up to a 5 ng ml1 effect site concentration produces a dose-dependent depression in pupil dilatation after a noxious stimulus. Pupil dilatation in response to 100 Hz tetanus is a more sensitive measurement of remifentanil Ce than arterial pressure, heart rate, or BIS variations.
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References |
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