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Pharmacology

Effects of remifentanil on pharyngeal swallowing

A double blind randomised cross-over study in healthy volunteers

Savilampi, Johanna; Omari, Taher; Magnuson, Anders; Ahlstrand, Rebecca

Author Information
European Journal of Anaesthesiology: September 2016 - Volume 33 - Issue 9 - p 622-630
doi: 10.1097/EJA.0000000000000461
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Abstract

Introduction

Postoperative lung complications are common and may prolong hospital stay and increase mortality.1,2 Patients who are breathing spontaneously and require analgesia may be particularly vulnerable to silent pulmonary aspiration.3 Opioid agonists are widely used in such a setting and we have previously shown, in healthy volunteers, that the incidence of pulmonary aspiration increases following exposure to remifentanil.4 However, the underlying mechanisms predisposing to aspiration in this experimental setting were not determined. Perturbation of the complex motor-sensory neural circuitry governing pharyngeal swallowing efficiency and/or airway protection appear the most likely causes.5,6 Advanced age is also a known risk factor for postoperative lung complications.1 Diminished swallowing functional reserve, which occurs as part of the normal aging process, may provide an explanation for this. Hence, even though elderly patients may present preoperatively without any overt symptoms of dysphagia5,7 loss of swallowing reserve may nevertheless render them at risk of aspiration when depressants such as sedation/anaesthesia are applied.

The primary aim of this study was to measure directly the effect of remifentanil on pharyngeal swallowing physiology. Our secondary aims were to compare the effects of remifentanil with morphine, and to examine if age-related factors exacerbated these effects. To address these aims, we used a nonradiological technique, combining high-resolution impedance manometry with a novel analytical approach called automated impedance manometry pressure-flow analysis (AIM analysis).8 Finally, any subjective difficulty with swallowing was recorded during the experiment.

Methods and materials

Study participants

Twenty healthy volunteers [12 young (8 male) <30 years, mean (± SD) age 23 ± 3 years, and 8 older (5 male) >65 years, mean age 73 ± 4 years] were invited to participate in a double-blind, randomised, placebo-controlled, cross-over study. The study was conducted in the Department of Anaesthesiology, University Hospital of Örebro, Sweden, and the study protocol was approved by the central Ethics Review Board (Uppsala, Sweden). Written informed consent was obtained from the volunteers after they had received full details of the study. The volunteers also received financial compensation. The volunteers were non-smokers, had no history of dysphagia symptoms or upper gastrointestinal diseases, and were not taking any medication that could affect pharyngeal or oesophageal function. The exclusion criteria included pregnancy, breastfeeding and previous participation in a medical study. Volunteers were recruited by means of notices on university and hospital bulletin boards.

Treatment

There were two study treatments given at least 3 days apart: a target-controlled i.v. infusion of remifentanil (Target controlled infusion, Minto Model, Alaris PK syringe pump; Alaris Medical Nordic AB, Sollentuna, Sweden) with an effect-site target concentration of 3 ng ml−1 for young volunteers and 2 ng ml−1 for older volunteers; an i.v. morphine bolus injection of 0.1 mg kg−1 for young volunteers and 0.07 mg kg−1 for older volunteers. Using a random number generator, order of treatment was randomly assigned in blocks of two, to remifentanil or morphine first, in a 1 : 1 ratio stratified by age (younger, older). The volunteers, as well as the assessor of the data, were blind as to who received which study drug. Remifentanil and morphine were administered from unmarked syringes by study personnel, who did not participate in data analysis.

Measurement technique

A solid-state combined manometric and impedance catheter with a 4.2 mm outer diameter, incorporating 36 circumferential pressure sensors (spaced at 1 cm intervals) and 18 impedance segments (each 2 cm long) was used to acquire pressure and impedance data (Sierra Scientific Instruments, Inc., Los Angeles, California, USA). After a brief physical examination, the volunteers underwent trans-nasal placement of the catheter, which was positioned with sensors straddling the entire pharyngoesophageal segment. Before, and immediately after the investigation, the catheter was calibrated outside the body using the calibration options provided by the software. Boluses consisting of 10 ml of 0.9% saline (normal saline, used instead of water to enhance bolus conductivity) were administrated orally via a syringe at more than 20 s intervals and volunteers were asked to swallow on command. Ten normal saline swallows were performed on three occasions: before any treatment to obtain a baseline (T0), 15 min after start of treatment (T1) and 30 min after start of treatment (T2). In parallel with swallowing, volunteers were asked to assess any swallowing difficulty based on a four-point scale (no difficulty, mild difficulty, moderate difficulty or severe difficulty).

Pressure-flow analysis

AIM pressure-flow analysis integrates the pressure signals and flow signals (from impedance) to derive individual ‘pressure-flow variables’ (Fig. 1). During a swallow these measures quantify timing of bolus flow relative to pharyngeal propulsion, any mechanical resistance to flow during propulsion, and the overall pharyngeal contractility, thus providing objective numerical values indicative of the different physiological processes governing safe pharyngeal swallowing. The raw manometric and impedance data for each swallow were exported from the recording system as a .txt file and analysed using AIM analysis, a purpose-designed matrix laboratory-based (MathWorks, Natick, Massachusetts, USA) analysis program (AIMplot software copyright, Taher Omari, Adelaide, Australia). To operate AIM analysis the assessor defines the following four space-time landmarks from a standard pressure iso-contour plot of the pharyngeal swallow (Fig. 1a): the time of onset of pharyngeal swallow, defined by the onset of upper oesophageal sphincter (UOS) relaxation that is often but not always associated with a proximal excursion of the UOS high pressure zone; the position of the UOS proximal margin immediately after pharyngeal swallow; the position of the velopharynx, defined as the pressure zone immediately above the propagated pharyngeal stripping wave; and the position of the UOS distal margin preswallow. Guided by definitions of these landmarks, the AIM analysis software automatically derives and exports the pharyngeal pressure-flow variables, and two global indices for the level of swallow dysfunction on the basis of the established method of Omari,8–11 summarised in brief in Fig. 1. UOS relaxation variables were derived by the method of Ghosh.12 A summary description of all variables calculated has been provided in Table 1.

Fig. 1
Fig. 1:
The pressure-flow analysis method used for calculation of pharyngeal swallow variables (a–c, refer to reference 8 for more detail) and flow interval (d–f, refer to reference 9 for more detail). PZn, pressure at nadir impedance; PeakP, peak pressure; TZn-PeakP, time from nadir impedance to peak pressure; UOS, upper oesophageal sphincter. (a) Plot of pressure generated by the pharyngo-oesophageal segment during a 10 ml bolus swallow: time (x-axis), distance along the pharyngo-oesophageal segment (y-axis), pressure (mmHg) is shown by colour (scale at right side of Fig. 1a). The plot shows the proximal 15 cm of the total 36 cm pressure array. The UOS high pressure zone is an easily recognisable region of tonic pressure (labelled ‘UOS’) located at the junction between the pharynx (labelled Phar) and oesophagus (labelled Oesoph). Onset of swallowing (labelled ‘sw’) is associated with relaxation of the UOS high pressure zone (labelled ‘relax’ – change in colour from red to dark blue). The boxes outlined in black in Fig. 1a show the regions of interest (labelled Region of interest (ROI) 1 and ROI 2) used to calculate swallow variables. The position of the ROI boxes is based upon analyst-defined landmarks (the four landmarks are shown as black dots •) these identify the time of onset of pharyngeal swallow (labelled x), the position of the velopharynx (labelled y1), the position of the UOS proximal margin immediately after the pharyngeal swallow (labelled y2), and the position of the UOS distal margin preswallow (labelled y3). Note: the temporal boundaries of the ROI 2 are fixed relative to swallow onset (x). The upper margin of ROI 2 is 50% of the pharyngeal length (midpoint between y1 and y2). (b) The expanded section contained in the box ROI 1, using the same pressure scale. The two lines on this plot show the position of pharyngeal nadir impedance (Nad Imp, purple line) and maximum pharyngeal pressure (PeakP, black line) over time. Data mapped to these lines were used to determine the ‘pressure at nadir impedance’ (PZn, average pressure along the purple line), ‘peak contractile pressure’ (PeakP, average pressure along the black line), and time from nadir impedance to peak pressure (TZn-PeakP, average time interval between the purple and black lines). (c) The pressure and timing information extracted from Fig. 1b (ROI 1 in Fig. 1a). (d) The impedance values during the same 10 ml bolus swallow, with the regions of interest (ROI 1, ROI 2) in the same spatiotemporal location as in the pressure topography plot, Fig. 1a. Time (x-axis), distance along the pharyngo-oesophageal segment (y-axis), impedance (ohms) is shown by colour (scale at right side of Fig. 1d). Following the onset of swallowing, bolus passaged is identified by a fall (darker purple colour) and then recovery of the impedance. (e) Impedance over time data, extracted from ROI 2 (Fig. 1d). An impedance ‘cumulative time’ plot. Using the data from Fig. 1e. This plot is constructed by re-ordering the impedance data samples from lowest to highest are presented as impedance vs. the cumulative time. Each impedance datum point represents 0.025 s. This plot can be mathematically described using a third-order polynomial equation (the typical equation for a curve with one inflexion). The cumulative time at the inflexion point of the best-fit curve was used to determine the ‘flow interval.’ The flow interval defines the time during which the bolus is flowing through the pharynx.9–11
Table 1
Table 1:
Description of pressure flow and upper oesophageal sphincter relaxation variables

Pharyngeal pressure-flow variables

Pressure flow-variables were peak pressure (PeakP), pressure at nadir impedance (PZn), time from nadir impedance to peak pressure (TZn-PeakP) and bolus flow interval (flow interval). All four pharyngeal pressure-flow variables were then combined to derive a swallow risk index (SRI), providing a global assessment of swallowing and defining a level of swallowing dysfunction that may predispose to aspiration risk. The formula for calculating the SRI is shown in Table 1.

Upper oesophageal sphincter relaxation variables

UOS relaxation characteristics were measured using the established method of Ghosh et al.12 that objectively calculates UOS relaxation interval (UOS-RI), the UOS nadir relaxation pressure (UOS-NadP), the UOS median intrabolus pressure (UOS-IBP), and the UOS resistance (calculated as UOES-IBP/UOS-RI).

Post-swallow residue

Post-swallow residue was determined using the integrated ratio of nadir impedance to impedance (iZn : Z) that relates post-swallow impedance to the impedance during bolus passage and is elevated with large clinically significant post-swallow residues.10

Protocol

The volunteers were studied on two different occasions, usually with about a 1-week interval. i.v. access was obtained before the study commenced. Throughout the procedure, the volunteers were monitored by electrocardiography, pulse oximetry, respiratory rate, automatic non-invasive blood pressure measurement and end-tidal carbon dioxide. After correct positioning, the manometric catheter was taped to the nose and continuous manometric and impedance recordings were started, whereas the volunteers lay supine with a 30° elevation of the upper body. After a 5-min stabilisation period, the volunteers performed the first of the three series of 10 swallows of 10 ml boluses of normal saline and thereafter, either a remifentanil infusion was started or an i.v. morphine injection was given. The volunteers then completed the second and third series of 10 ml swallows of normal saline as described above. Then the catheter was removed and the study session was finished. During the study sessions, the volunteers were provided with supplemental oxygen if their oxygen saturation decreased to less than 92%, and they were instructed to breathe more frequently if their respiratory frequency decreased to less than 6 breaths min−1.

The primary outcome was the pressure-flow and UOS relaxation variables. The secondary outcome was the subjective swallowing difficulties.

Statistical analysis

Individual patients had the average for each parameter calculated from each series of 10 saline swallows and these averages were then used for the statistical calculations. Pressure-flow variables are presented with boxplots indicating medians, 25th and 75th percentiles, and minimum and maximum values. Normality assumptions were evaluated with Shapiro–Wilk test and, because of non-normality, all statistical evaluation were performed after logarithmic (base 10) transformation. Nonparametric methods were used for sensitivity analysis in circumstances of non-normality after log (base 10) transformation (Shapiro–Wilk test). These results are indicated in tables.

The remifentanil effect on the variables was determined by a one-way Analysis of variance (ANOVA) with time (T0, T1 and T2) as within factor variables, and mean ratios of treatment effect, post vs. pre-treatment (mean T1, T2 vs. T0) with 95% confidence intervals (CI) and P values are presented. A mean ratio of 1 indicates no difference and a mean ratio of 1.4 indicates 40% higher mean level post-treatment compared with pre-treatment. Secondly we tested, with an interaction test in a two-way ANOVA, if age (young <30 years and old >65 years) had different effects from the treatment and, if so, treatment effects were presented stratified by age. The same analysis strategy was used for evaluation of the morphine effect.

Remifentanil and morphine effects were compared by two-way ANOVA to evaluate if the parameter investigated responded differently to these drugs. The response variable was the difference from baseline (T0) for each parameter with two within subject factors, time (T1 and T2) and agent (remifentanil and morphine). The mean ratio of response variable (mean T1 T2) between remifentanil and morphine effects with 95% CI and P values are presented.

Vital parameters were evaluated with two-way repeated measure ANOVA. The response variable was the difference from baseline for each vital parameter and within factors were agent and time and their interaction.

The Wilcoxon paired signed-rank test was used to determine statistically significant differences in swallowing experiences by comparing each agent at baseline (T0) with T1 and T2.

A two-tailed significance level of 5% was used. All statistical analyses were performed using Statistical Package for the Social Sciences version 19 (IBM Corp., Armonk, New York, USA).

Power analysis

The number of study subjects was estimated from the pressure-flow variable PeakP with reference to Omari et al.8 Assuming a similar magnitude of effect for the primary hypothesis in the present study then using paired t-test with 5% two-sided significance level a sample size of 11 would have an 80% power to detect a mean difference of 39 mmHg with a SD of 40 mmHg. The present study was planned to include 12 young and 12 older study subjects to allow for potential dropouts.

Results

Between September 2013 and April 2014, 20 volunteers provided informed consent and participated in the study. Recordings from one young volunteer were unusable because of a technical malfunction, and one older volunteer failed to tolerate the procedure and withdrew before the protocol was completed. Paired data were, therefore, available from 18 study participants (Fig. 2). Study participants comprised 11 young and seven old, five women and 13 men. The mean age of the young group was 23 years (range, 18–28 years), and that of the old group was 73 years (range, 65–79 years). Mean BMI was 22 ± 4 kg m−2 for young volunteers and 27 ± 2 kg m−2 for old volunteers. No unintended effects were associated with the study.

Fig. 2
Fig. 2:
Flow chart.

Vital parameters are presented in Table 2. Heart rate decreased significantly over time in both groups but no significant differences were found in the vital parameters between remifentanil and morphine treatment.

Table 2
Table 2:
Vital parameters, n = 18

The effects of each treatment on the different swallow function variables are presented as effect mean ratios (Table 3) and comparisons of the two treatments are presented in Table 4. Distributions of two pressure-flow variables, TZn-PeakP and SRI, are shown in Fig. 3a and b, respectively. Six of the 10 variables showed a significant age effect, with the old volunteers having higher mean values.

Table 3
Table 3:
Effects of remifentanil and morphine on pressure-flow and upper oesophageal sphincter relaxation variables in 18 volunteers
Table 4
Table 4:
Remifentanil compared with morphine effects on pressure-flow and upper oesophageal sphincter relaxation variables in 18 volunteers
Fig. 3
Fig. 3:
Boxplots showing two pressure flow variables over time in young and old volunteers randomly assigned to receive remifentanil or morphine. (a) Time (milliseconds) from nadir impedance to peak pharyngeal pressure. (b) Swallow risk index. The median is identified by a thick line inside the box. The length of the box is defined by the 25th and 75th centiles and represents the interquartile range (IQR). The whiskers are minimum and maximum values if no outliers are present. Values represented by o are outliers, and are defined as lying outside more than 1.5 times the IQR. Values represented by ‘*’ are extreme values, and are defined as lying outside more than three times the IQR.

Pharyngeal pressure flow variables

Following remifentanil, the PeakP decreased significantly (P = 0.034), and the TZn-PeakP shortened significantly (P = 0.003) (Fig. 3a). Consistent with drug induced impairment of global swallowing function, the SRI increased significantly (P = 0.002) (Fig. 3b). The nadir impedance to post-swallow impedance-ratio (iZn/Z) was found to be low in these healthy study participants, and decreased following exposure to remifentanil (P < 0.001) hence post-swallow residues did not increase even though overall swallowing function was impaired.

With morphine, the PeakP decreased significantly (P = 0.013) and the PZn increased significantly (P = 0.046). The SRI increased significantly (P = 0.022) and the iZn/Z decreased significantly (P = 0.007).

Upper oesophageal sphincter relaxation variables

With remifentanil, measures of flow resistance (UOS-Nad-P, UOS-IBP, UOS resistance) were increased. Furthermore, young volunteers showed significant increases in UOS-Nad-P and UOS-IBP, whereas no significant effect was seen with the old volunteer.

In the same manner as remifentanil, morphine significantly increased measures of flow resistance. However, no significant interaction with age was found.

Remifentanil vs. morphine

TZn-PeakP decreased significantly with remifentanil, whereas no significant differences were found with morphine (Table 3), difference in mean effects (remifentanil vs. morphine) of 12% (P = 0.013) (Table 4). UOS resistance increased significantly with both treatments but the increase was 37% greater with remifentanil (P = 0.024), and iZn/Z decreased significantly with both treatments but the decrease was 15% greater with remifentanil (P = 0.041).

Subjective swallowing difficulties

Two study participants reported swallowing difficulties at baseline (T0): a man aged 26 years subsequently assigned to remifentanil; a man aged 27 years subsequently assigned to morphine. No study participant reported swallowing difficulties after morphine, whereas two study participants (two men, aged 22 and 65 years) reported swallowing difficulties during remifentanil infusion. This difference was not statistically significant (P = 0.41).

Discussion

In this study, we evaluated the effects of remifentanil and morphine on pharyngeal function during swallowing. Remifentanil changed several pressure flow swallow variables in a manner consistent with greater swallow dysfunction. The main effects seen were decreased pharyngeal propulsion and vigour and increased bolus flow resistance by the UOS. The net effect of these changes was an increase in the SRI, a marker of the overall level of swallowing function.13 Based on the SRI, the study participants had normal swallowing (SRI < 1513). This was consistent with the fact none of the study participants experienced significant symptoms during the experiment.

Oropharyngeal swallowing is a complex, stereotypical sequence of inhibition and activation of different pairs of muscles driven by several motor neuron pools located in various cranial motor nuclei in the brainstem and upper part of the cervical spinal cord.14 In turn, these motor neuron pools are influenced by both central and peripheral inputs. Consequently, several sites of action of opioid drugs, altering peripheral and central neural circuitry or muscle tone/rigidity15 may explain these findings. Based on the level of statistical confidence and the numbers of individual measures that were affected, the effects of remifentanil were greater than morphine at the experimental doses evaluated. This objective finding is consistent with our clinical experience of patients undergoing anaesthesia, and our previously published study, showing that remifentanil induces significant swallowing difficulties.16

An important mechanistic observation emerging from our study was that we detected significant differences between the treatments in relation to one metric in particular, that is, TZn-PeakP, which was selectively shortened during remifentanil exposure. TZn-PeakP measures the latency from maximum bolus distension of the pharyngeal lumen to the time when the pharyngeal constrictors contract maximally. As the timing of distension depends upon a combination of lingual and pharyngeal propulsion, we interpret the change in distension-contraction latency as reflecting a mismatch and/or weakening of these forces. This change may be because of the central and/or peripheral effects of the drug on sensory-motor mechanisms governing the pharyngeal swallow. Many dysphagia patients demonstrate weak lingual bolus propulsion, poor oral bolus containment and/or delayed pharyngeal trigger. It has been recently shown that TZn-PeakP is shorter in relation to these particular modes of swallow defect.17 As a corollary to these objective findings, our previous study16 showed that study participants who reported swallowing problems following remifentanil exposure reported an impaired ability to initiate a swallow. The selective effects of remifentanil in this regard suggest that it may have a greater effect on lingual bolus propulsion and/or pharyngeal swallow trigger, than morphine.

Generally, when compared with young volunteers, the older volunteers showed differences in pressure flow variables that suggested greater swallow dysfunction and these findings are consistent with a previous study evaluating older adults with AIM analysis.13 Furthermore, when stratified by age, following remifentanil infusion the pressures during UOS relaxation (UOS nadir pressure and UOS IBP) showed a divergent treatment effect: in young volunteers these UOS flow resistance variables increased with remifentanil whereas, in contrast, older volunteers were influenced less by the treatment – possibly because UOS flow resistance values were already two-fold greater at baseline in the older age group. One explanation may be that old volunteers already exhibit values near the limit for a specific variable with no capacity to increase more. Another explanation may be that the lower doses of opioid given to older study participants were insufficient to induce an effect on these variables. Other variables in this study did not show differing effects by treatments when stratified by age, although this could be because of low statistical power: we planned to recruit 12 old volunteers, as indicated by the power analysis, but we only managed to include seven.

Clinical implications

In a previous study, we have shown an increased incidence of aspiration of pharyngeal contents in healthy young volunteers receiving remifentanil4 and the current study suggests that remifentanil impairs pharyngeal swallowing. Changes in objective measures were consistent with impaired lingual bolus propulsion and/or pharyngeal swallow triggering and these may be possible underlying mechanisms exacerbating the aspiration risk. In this study, both young and old volunteers were included, and pharyngeal swallowing was shown to be affected even in the younger age group. Impairment of pharyngeal swallowing is a relevant clinical concern, especially in non-fasting patients, for example, women in labour, for whom remifentanil has come to be more commonly used for pain relief.18,19 Furthermore, the present study showed that even morphine affects pharyngeal swallowing with a trend toward greater dysfunction. Although the morphine induced effect is not as great as that of remifentanil, it could impair a patient's airway protection during the postoperative period when morphine is commonly used in significant doses.

Limitations

The doses of remifentanil and morphine were intended to represent clinically relevant dosages and were adjusted according to the age group because of safety concerns. No blood concentrations were measured nor did we aim for equipotency in the two drugs. Had we done so it would have been possible to correlate the level of pharmacological exposure to the physiological effects. However, because these two agents have totally different pharmacokinetic profiles along with different lipid solubilities and different potency of metabolites, even equipotent blood concentrations would not have been comparable. The concentration of remifentanil used in young volunteers was chosen so as to be the same as that in our previous study which showed aspiration induced by remifentanil,4 and the dose of morphine was chosen so it could be given as a single i.v. injection at a clinically relevant dose. Recording times after injection were chosen according to the known peak effect interval of morphine after i.v. injection (range, 15 to 30 min).20

Secondly, although investigating different target concentrations of remifentanil would have strengthened the study, because we also aimed to study the impact of morphine, adding further remifentanil doses would have rendered the study protocol unworkable.

Thirdly, no correction for multiple testing was done because of explorative nature of the study, although it should be noted that the primary outcome was measured across more than one variable.

Conclusion

Remifentanil and morphine produce measurable swallowing dysfunction at doses that are in clinical use. These effects may elevate the risk of aspiration in patients with reduced functional swallowing reserve, as are associated with aging and other pre-existing conditions. Further studies to quantify these effects in different patient populations are indicated.

Acknowledgements relating to this article

Assistance with the study: none.

Financial support and sponsorship: the Research Fund of the Örebro County Council.

Conflicts of interest: TO is the recipient of an Australian National Health and Medical Research Council Senior Research Fellowship (APP1079715). TO also holds an Australian Patent (2011301768) in relation to the analytical methods described. This patent is not commercialised.

Presentations: preliminary data for this study were presented as a poster at the Scandinavian Society of Anaesthesiology and Intensive Care Congress in Reykjavik, Iceland, 10–12 June 2015.

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