1 Department of Anesthesiology, 3C444, University of Utah Health Sciences Center, 30 North 1900 East, Salt Lake City, UT 84132, USA. 2 Clinical Pharmacology, Glaxo Research Institute (now GlaxoSmithKline)
*Corresponding author. E-mail: talmage.egan@hsc.utah.edu Declaration of interest. Dr Egan has received research funding, consultancy fees and speaking honoraria from GlaxoWellcome (the original developers of remifentanil; now GlaxoSmithKline) and Abbott Laboratories (the current marketers of remifentanil in the USA). The work, supported in part by a grant from GlaxoWellcome Research Institute administered through the Utah Pain Research Foundation, was performed entirely at the University of Utah Health Sciences Center, Salt Lake City, UT.
Accepted for publication: September 9, 2003
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. Using a randomized, double-blind, placebo-controlled, dose-escalation, crossover study design, 64 subjects (16 over 60 years old) received remifentanil or placebo by bolus injection in a fixed unit dose separated by a 1 h washout period. Respiratory effects were assessed using a respiratory intervention scale. Analgesic effects were assessed using pressure algometry. A population pharmacokinetic model was constructed using non-linear, mixed-effects modelling techniques based on arterial blood samples. Computer simulations were performed to illustrate the clinical application of the pharmacokinetic model.
Results. Dose-related increases in both respiratory and analgesic effects were observed. In general, the respiratory depression observed was mild and easily treated with requests to breathe or the administration of oxygen, although the older cohort (and some younger subjects) experienced more substantial respiratory depression at lower doses. The pharmacokinetics of bolus-dose remifentanil were adequately described by a two-compartment model. The pharmacokinetic simulations illustrated the potential utility of bolus-dose remifentanil.
Conclusions. Bolus injection could potentially be a safe and effective means of administering remifentanil in clinical situations requiring a brief period of intense analgesia. Because some subjects, both old and young, experienced significant respiratory depression even at low doses, careful monitoring of respiratory function is essential.
Br J Anaesth 2004; 92: 33543
Keywords: anaesthetic techniques, i.v. bolus; anaesthesia, geriatric; analgesics opioid, remifentanil; pharmacodynamics; pharmacokinetics
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Because of its short-acting pharmacokinetic profile, remifentanil may be well suited for clinical situations in which a brief period of intense analgesia is desirable such as during painful diagnostic and therapeutic procedures performed outside the operating room. In such settings, practitioners may find the gathering of the necessary equipment and the setting up of an infusion pump apparatus excessively inconvenient and therefore unappealing. If remifentanil could be safely and efficaciously administered by bolus injection in such situations, practitioners may find the ease and simplicity of the technique more appropriate for the out-of-operating-room setting.
To date, there is very little information describing the clinical pharmacology of remifentanil by bolus injection in awake subjects breathing room air. In fact, the current product labelling in the USA recommends bolus dosing of remifentanil only in patients who are undergoing general anaesthesia.
The primary aim of this observational study was to examine the safety of single bolus doses of remifentanil in conscious, healthy, adult volunteers breathing room air, particularly in terms of respiratory effects. Secondary aims included the evaluation of remifentanil pharmacokinetics and analgesic effects after bolus injection and a comparison of these aspects of remifentanils clinical pharmacology in younger and older adults (over 60 yr). We hypothesized that remifentanil would be well tolerated in younger adults in bolus doses up to 200 µg and that older subjects would exhibit more substantial respiratory effects at all doses.
![]() |
Methods and materials |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Only English-speaking volunteers 1859 yr (younger group) and 60 yr and over (older group) who were generally healthy (ASA III) were eligible for enrolment. All volunteers were required to be within 50% of their ideal body weight based on criteria described by Abernethy and Greenblatt.3 Female volunteers were required to be non-lactating and to be either sterile (i.e. post-menopausal or surgically sterilized) or using an effective method of contraception. Potential subjects were excluded if they had a history of alcohol abuse or illegal drug use, a history of hypersensitivity to opioids, or a record of significant psychiatric illness that might impair their capacity to give informed consent. Volunteers with renal or hepatic disease were also excluded, as were volunteers whose concurrent medications included drugs that are known to interact significantly with opioids (including oral opioid analgesics).
Volunteers reported to the study site having abstained from tobacco products for 12 h, from solid food intake for 8 h and from clear fluid intake for 4 h. Instrumentation included an 18 G i.v. catheter in an arm (with normal saline infusing at 100 ml h1) in all subjects and a 20 G radial artery catheter in subjects in whom blood samples for remifentanil concentration measurement were to be obtained (see below). Also, a nasal cannula was applied to each subject at the beginning of the experiment in preparation for the possible administration of oxygen after drug administration.
Safety monitoring included a finger pulse oximeter (SpO2), a three-lead continuous ECG and an automated arterial pressure cuff attached to the arm opposite the i.v. catheter. As a means of measuring ventilatory frequency, expired carbon dioxide was continuously measured (sampled through the nose).
In a randomized, double-blind, crossover manner, subjects received either remifentanil or placebo as the first treatment in a fixed unit dose (i.e. not weight adjusted) by bolus injection as rapidly as clinically feasible (i.e. 23 s). After a 1 h washout period, the second treatment was injected in a similar fashion, completing the crossover. Each dose was diluted in 8 ml of normal saline; each injection was immediately followed by a flush of normal saline (10 ml). Beginning with a unit dose of 25 µg, six subjects were studied at each dose level. The dose was increased in increments of 25 µg until a total of four out of six subjects in one dosage group experienced significant respiratory depression (see below) or until a maximum dose of 200 µg was reached.
Respiratory depression effects were measured using the respiratory intervention scale (RIS) as shown in Table 1. In brief, the RIS is an observer assessment that quantifies the degree of respiratory depression by incorporating the SpO2 and the subjects responsiveness into a graded score reflecting the degree of intervention necessary to normalize the subjects oxygenation status as assessed by pulse oximetry. The maximum RIS score was the primary end-point for the measurement of respiratory depression (i.e. the RIS is a one-time measurement). Significant respiratory depression was arbitrarily defined as a RIS score of 3 or more; once four of six subjects in a single dosage group reached a RIS score of 3 or more, the dosage escalation was stopped. The RIS methodology has been described in more detail elsewhere.4 As the primary respiratory effect measure, the maximum RIS score during the first 15 min after each injection was recorded. Episodes of apnoea and respiratory depression were also recorded as they occurred. Apnoea was defined as no breath for 15 s or longer and respiratory depression was defined as an SpO2 less than or equal to 85% for longer than 5 s or a ventilatory frequency of less than or equal to 8 bpm for 1 min or longer.
|
Safety and drug effect measurements were made at preset intervals, with initial baseline measurements being made 15 min before the first treatment. The SpO2, ventilatory frequency, heart rate and systolic, diastolic and mean arterial pressures were recorded every minute during the first 15 min after drug administration and then every 15 min during the 45 min washout phase.
Other adverse events such as episodes of nausea, vomiting and muscle rigidity were recorded as they occurred. In order to capture these events, volunteers were instructed to report spontaneously any concerns or disturbing symptoms to the investigator; volunteers were asked How do you feel? by the investigators 15 min after each injection.
The analgesic response (i.e. the maximal algometry pressure tolerated) and the respiratory depression responses (i.e. the maximal RIS score and the minimum SpO2), were compared between different doses within each subject group (i.e. older vs younger) using the KruskalWallis test corrected for multiple comparisons. These effects were also compared between subject groups using the MannWhitney rank sum test. P<0.05 was considered significant.
In subjects who received 75 µg or more, arterial blood samples of 3 ml were obtained at preset intervals with the most rapid sampling immediately after treatment injection (samples were obtained during both the placebo and remifentanil limbs to maintain blinding). Samples were collected into heparinized tubes at baseline and at 1, 2, 4, 6, 8, 10, 15, 20, 30, 45 and 60 min after injection of the study drug (both remifentanil and placebo). To prevent continued metabolism of remifentanil after sample collection, the drawn blood was immediately transferred into previously prepared glass tubes containing citric acid, and frozen at 70°C until the time of assay.
Remifentanil blood concentrations were measured by a high-pressure liquid chromatography method employing ultraviolet detection. The assay was validated between 0.1 and 100 ng ml1 with an interassay coefficient of variation of less than 15% for concentrations greater than 0.1 ng ml1. The sample preparation and assay methodology are described in detail elsewhere.6
The raw concentration vs time data were analysed using several techniques. First, as an exploratory manoeuvre, each individual subjects pharmacokinetic parameters were estimated using standard compartmental modelling techniques. Guided by the results of this preliminary analysis, a mixed-effects population model was constructed. Finally, to help bring clinical meaning to the pharmacokinetic analysis, computer simulations were performed using the mixed-effects population pharmacokinetic model. Because it had been previously demonstrated for the remifentanil dose range employed in this study, linear pharmacokinetics were assumed for the purposes of this analysis.7
Using the two-stage approach implemented on WinNonlin (version 3.0, Pharsight Corporation, Mountain View, CA, USA), both two- and three-compartment mamillary models were fitted to the raw concentration vs time data to estimate each individuals pharmacokinetic parameters. These biexponential and triexponential disposition equations were parameterized in terms of clearances and apparent distribution volumes. Initial parameter estimates were obtained from our previous work.8 Because the magnitude of the errors between the measured concentrations (Cm) and the concentrations predicted (Cp) by the model were presumed to be proportional to the predicted concentration, a proportional (1/Cp2) variance model was used for each fit.
Guided by the results of the individual compartmental analysis in terms of the number of compartments and the initial parameter estimates, a mixed-effects model was built using WinNonmix (version 2.0, Pharsight Corporation, Mountain View, CA, USA), a mixed-effects modelling program. Mixed-effects modelling simultaneously analyses an entire populations data and provides estimates of typical values for the parameters, along with an estimate of the parameters interindividual variability within the population studied.
Interindividual error on each parameter was modelled using a log-normal error model:
individual =
typical e
individual
where individual is the true value in the individual,
typical is the population mean estimate and
individual is a random variable whose distribution is estimated by WinNonmix with a mean of 0 and a variance of
2. The estimates of
obtained with WinNonmix are similar to the coefficient of variation (CV) often used in standard descriptive statistics. Residual intra-individual error was modelled assuming a constant coefficient of variation. The two-compartment model was parameterized in terms of distribution volumes and clearances.
The performance of the population model constructed using WinNonmix was assessed in terms of the ability to predict the measured blood concentrations. This was accomplished by plotting the observed concentrations against the predicted concentrations and by plotting the weighted residuals (WRs) as computed by WinNonmix against the predicted concentrations. These plots were then examined for accuracy and bias.
Computer simulations using the mixed-effects model were performed to illustrate the clinical implications of the pharmacokinetic analysis. The simulations predict the effect-site concentrations that would result from two alternative remifentanil dosing regimens that might be applied in clinical situations requiring a brief period (15 min) of intense analgesia (i.e. a 100 µg bolus followed by a 50 µg bolus every 2.5 min, and a 100 µg bolus followed by a 25 µg bolus every 1.5 min). The simulations were designed to target effect-site concentrations that are associated with analgesia and spontaneous ventilation (36 ng ml1).9 The rate constant characterizing the equilibration between the plasma and the effect site concentrations (ke0) used for these simulations was obtained from our previous work.10
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
Older subjects experienced more significant respiratory depression at lower doses than did the younger groups, with an average RIS score of 4 in the 75 µg dose group of the older cohort (further dosage escalation was therefore not undertaken). In fact, all four of the older subjects who received 75 µg exhibited a RIS score of 4. However, as with the younger cohort, the respiratory depression observed in the older subjects was short lived and easily managed as specified by the RIS.
A summary of RIS scores for both the younger and older cohorts is displayed in Table 4. No subject in either group at any dose required more than administration of nasal canula oxygen (2 litre min1) and verbal prompting to breathe to restore oxygenation to satisfactory levels (i.e. no subject achieved a RIS score greater than 4).
|
The most serious respiratory events were episodes of apnoea, occurring in four subjects (a 68-yr-old male receiving 75 µg, a 36-yr-old male receiving 150 µg, a 27-yr-old female receiving 75 µg and a 21-yr-old male receiving 200 µg). All of these apnoeic episodes occurred within the first 5 min after injection and lasted for 1 min or less. An additional subject (a 26-yr-old male receiving 175 µg) experienced an episode of respiratory depression that lasted for 1 min. Although these events were obviously regarded as serious, they were easily managed.
There was a clear pattern of gradually increasing analgesia as the dose was increased, although subjects receiving 25 µg or less had algometry responses not significantly different from placebo (P<0.05), particularly for the older group. As with the respiratory effects, the algometry effects were rapid in onset and short-lived, with the maximal effects typically occurring within 12 min and lasting on average about 8 min. A summary of the analgesic response (i.e. onset, duration, maximal and time to maximal) as measured by pressure algometry for selected doses is displayed in Table 5. The maximum percent algometry increase for each dosage level is displayed in Figure 1.
|
|
The drug administration scheme applied in this protocol resulted in concentration vs time curves characteristic of bolus injections. The raw concentration vs time data are displayed in Figure 2. The raw concentration vs time data were adequately described by a two-compartment model. The average two-stage parameter estimates were a central clearance of 4.3 (SD 1.4) litre min1, an intercompartmental clearance of 3.5 (2.5) litre min1, a central distribution volume of 9.1 (7.1) litre and a peripheral distribution volume of 13.4 (7.1) litre. These parameter values were used as initial estimates for the mixed-effects population analysis. The final data set for mixed-effects population analysis consisted of 273 measured blood concentrations and 48 dosing records. The mixed-effects, two-compartment model parameter estimates were a central clearance of 4.1 litre min1 (CV 16.4%), an intercompartmental clearance of 1.5 litre min1 (CV 21.9%), a central distribution volume of 5.6 litre (CV 26.5%) and a peripheral distribution volume of 10.9 litre (CV 21.2%).
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The use of bolus-dose remifentanil is not new. Several investigators have examined the pharmacodynamics of bolus-dose remifentanil in various clinical settings. For example, remifentanil by bolus injection has been shown to be effective in preventing an untoward haemodynamic response to laryngoscopy and tracheal intubation.1113 Bolus-dose remifentanil has been used successfully in combination with propofol for orotracheal intubation without muscle relaxants.14 15 Remifentanil by intermittent bolus injection has also been used successfully as a means of controlling undesirable increases in heart rate and arterial pressure during craniotomy procedures.16
We studied remifentanils effects when given by fixed dose bolus injection to adults breathing room air. The study was primarily aimed at assessing the potential safety of remifentanil injection for procedures that might take place in various locations outside the operating room where patients will be breathing spontaneously without an artificial airway. Overall, the study confirmed that bolus doses of up to 200 µg are well tolerated by younger adults breathing room air, in terms of both respiratory and haemodynamic effects. Significant respiratory depression is to be expected, but it can typically be managed with supplemental oxygen administered by nasal canula and prompting to breathe.
Examining the pharmacokinetic simulations is perhaps the best way to understand the studys clinical implications. As demonstrated by the simulations in Figure 4, frequent small bolus doses of remifentanil can be expected to produce a concentration vs time curve in the site of action (i.e. effect site) that is a reasonable approximation of a steady-state infusion. Additional clinical study and computer simulation investigation will be necessary to identify the optimal dosage regimen for various clinical applications. It is important to recognize that the current study did not examine the safety of repeated bolus doses of remifentanil, although the fact that remifentanils pharmacokinetics are linear suggests that pharmacokinetic simulation is a valid and useful way of exploring the clinical implications of new dosage regimens.7 Although not presented here, comparison of the pharmacokinetic simulations shown in Figure 4 with simulations using the remifentanil pharmacokinetic parameters published by Minto and colleagues17 were substantially similar, suggesting that kinetic parameters for remifentanil estimated from bolus injection administration are not markedly different from those estimated from continuous infusion administration. This issue has been a concern for some i.v. anaesthetics such as propofol.18
In order to safely use remifentanil by bolus injection in patients breathing room air, it is important to understand not only the magnitude of the expected respiratory effects but also the time course of these effects. Babenco and colleagues19 studied the time course of respiratory depression induced by remifentanil (by bolus injection) using a carbon dioxide rebreathing technique in healthy volunteers. They observed peak respiratory depression at 2.5 min after injection with substantial recovery at 6 min and essentially complete recovery by 15 min after injection. Although we did not study the time course of remifentanils respiratory effects in the same way because our respiratory depression end-point was a one-time maximal score (i.e. the RIS), in general our findings are consistent with the more detailed observations of Babenco and colleagues; that is, the respiratory depression we observed was maximal in the first few minutes after injection, substantially recovered within 6 min and essentially resolved within 15 min after injection.
Several nuances relating to the respiratory depression observed in this study deserve highlighting. For example, it is important to note that some of the subjects who experienced the most severe respiratory events in this study had received doses that were substantially less than the maximum dose studied. It is also very important to emphasize that the older subjects in this study clearly exhibited more pronounced respiratory depression than younger subjects. In older patients with certain co-morbidities (e.g. coronary artery disease), the degree of respiratory depression we observed after bolus remifentanil injection would certainly be viewed as serious and clinically very significant.
The limited literature addressing the hazards of bolus-dose remifentanil in terms of respiratory depression is certainly a cause for concern. In studying the safety and efficacy of bolus-dose remifentanil (with an ongoing continuous infusion) for pain management in the immediate postoperative period, several investigators have observed a high incidence of potentially life-threatening respiratory events (e.g. apnoea).2022 Although perhaps not entirely relevant to most clinical settings because of the intermittent nature of the pain, similarly serious adverse respiratory events have been observed when bolus-dose remifentanil has been employed as an analgesic for the relief of labour pain.23 24
Because the degree of respiratory depression subjects experienced was highly variable and was occasionally significant even at relatively low remifentanil doses, careful monitoring of respiratory function would be critical in the clinical setting when using remifentanil by bolus injection. Although all episodes of respiratory depression observed in the 64 subjects enrolled in this study were successfully treated with verbal prompting to breathe and the supplementation of inspired oxygen by nasal cannula, skills in the recognition and treatment of inadequate respiration would be obligatory when using bolus-dose remifentanil. Appreciation of the substantial respiratory depression synergy between opioids and sedatives would also be essential. Because of these dangers, it would be prudent for clinicians to gain experience with the clinical pharmacology of remifentanil by infusion before considering the use of remifentanil by bolus injection.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Remifentanil approved for anesthesia use. Am J Health Syst Pharm 1996; 53: 2250
3 Abernethy DR, Greenblatt DJ. Pharmacokinetics of drugs in obesity. Clin Pharmacokinet 1982; 7: 10824[ISI][Medline]
4 Bailey PL, Rhondeau S, Schafer PG, et al. Dose-response pharmacology of intrathecal morphine in human volunteers [see comments]. Anesthesiology 1993; 79: 4959[ISI][Medline]
5 Shapira SC, Magora F, Chrubasik S, Feigin E, Vatine JJ, Weinstein D. Assessment of pain threshold and pain tolerance in women in labour and in the early post-partum period by pressure algometry. Eur J Anaesthesiol 1995; 12: 4959[ISI][Medline]
6 Selinger K, Lanzo C, Sekut A. Determination of remifentanil in human and dog blood by HPLC with UV detection. J Pharm Biomed Anal 1994; 12: 2438[ISI][Medline]
7 Egan TD, Lemmens HJ, Fiset P, et al. The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology 1993; 79: 88192[ISI][Medline]
8 Egan TD, Huizinga B, Gupta SK, et al. Remifentanil pharmaco kinetics in obese versus lean patients. Anesthesiology 1998; 89: 56273[ISI][Medline]
9 Egan TD, Muir KT, Hermann DJ, Stanski DR, Shafer SL. The electroencephalogram (EEG) and clinical measures of opioid potency: defining the EEG-clinical potency relationship (fingerprint) with application to remifentanil. Int J Pharm Med 2001; 15: 1120[CrossRef]
10 Egan TD, Minto CF, Hermann DJ, Barr J, Muir KT, Shafer SL. Remifentanil versus alfentanil: comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers. Anesthesiology 1996; 84: 82133[CrossRef][ISI][Medline]
11 Hall AP, Thompson JP, Leslie NA, Fox AJ, Kumar N, Rowbotham DJ. Comparison of different doses of remifentanil on the cardiovascular response to laryngoscopy and tracheal intubation. Br J Anaesth 2000; 84: 1002[Abstract]
12 OHare R, McAtamney D, Mirakhur RK, Hughes D, Carabine U. Bolus dose remifentanil for control of haemodynamic response to tracheal intubation during rapid sequence induction of anaesthesia. Br J Anaesth 1999; 82: 2835
13 Thompson JP, Hall AP, Russell J, Cagney B, Rowbotham DJ. Effect of remifentanil on the haemodynamic response to orotracheal intubation. Br J Anaesth 1998; 80: 4679[CrossRef][ISI][Medline]
14 Alexander R, Olufolabi AJ, Booth J, El-Moalem HE, Glass PS. Dosing study of remifentanil and propofol for tracheal intubation without the use of muscle relaxants. Anaesthesia 1999; 54: 103740[CrossRef][ISI][Medline]
15 Stevens JB, Wheatley L. Tracheal intubation in ambulatory surgery patients: using remifentanil and propofol without muscle relaxants. Anesth Analg 1998; 86: 459[Abstract]
16 Gesztesi Z, Mootz BL, White PF. The use of a remifentanil infusion for hemodynamic control during intracranial surgery. Anesth Analg 1999; 89: 12827
17 Minto CF, Schnider TW, Egan TD, et al. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology 1997; 86: 1023[ISI][Medline]
18 Schnider TW, Minto CF, Gambus PL, et al. The influence of method of administration and covariates on the pharmaco kinetics of propofol in adult volunteers. Anesthesiology 1998; 88: 117082[ISI][Medline]
19 Babenco HD, Conard PF, Gross JB. The pharmacodynamic effect of a remifentanil bolus on ventilatory control. Anesthesiology 2000; 92: 3938[CrossRef][ISI][Medline]
20 Yarmush J, DAngelo R, Kirkhart B, et al. A comparison of remifentanil and morphine sulfate for acute postoperative analgesia after total intravenous anesthesia with remifentanil and propofol. Anesthesiology 1997; 87: 23543[CrossRef][ISI][Medline]
21 Schuttler J, Albrecht S, Breivik H, et al. A comparison of remifentanil and alfentanil in patients undergoing major abdominal surgery [see comments]. Anaesthesia 1997; 52: 30717[ISI][Medline]
22 Bowdle TA, Camporesi EM, Maysick L, et al. A multicenter evaluation of remifentanil for early postoperative analgesia. Anesth Analg 1996; 83: 12927[Abstract]
23 Volmanen P, Akural EI, Raudaskoski T, Alahuhta S. Remifentanil in obstetric analgesia: a dose-finding study. Anesth Analg 2002; 94: 91317
24 Olufolabi AJ, Booth JV, Wakeling HG, Glass PS, Penning DH, Reynolds JD. A preliminary investigation of remifentanil as a labor analgesic. Anesth Analg 2000; 91: 6068