In vitro morphine does not reduce cilia beat frequency, a key factor determining bronchial mucus transport velocity (BTV) . However, both in vivo and in vitro animal studies indicate that some opioids may affect BTV [2–4]. As the relatively new opioid remifentanil shows an affinity for opioid receptors which differs from that of morphine, we hypothesised that it might influence BTV differently. The aim of this prospective randomised trial was to investigate BTV among patients having total intravenous anaesthesia with either propofol and morphine, or propofol and remifentanil.
In vitro morphine does not reduce cilia beat frequency, a key factor determining bronchial mucus transport velocity. There are no reports about the effect of remifentanil on bronchial mucus transport. We compared the bronchial mucus transport velocity in patients having total intravenous anaesthesia with either propofol and morphine, or propofol and remifentanil. Twenty patients scheduled for elective surgery were randomly allocated to the two groups. Fifteen minutes after insertion of the laryngeal mask airway, bronchial mucus transport velocity was assessed by fibreoptic observation of the movement of methylene blue dye applied to the right main bronchus. Compared with morphine, bronchial mucus transport velocity was significantly reduced in patients receiving remifentanil (morphine mean (SD) 9.2 (5.8) vs remifentanil 4.2 (3.0) mm.min−1, p = 0.028). Anaesthesia with remifentanil may lead to significantly impaired bronchociliary clearance in comparison to morphine. This could have clinical implications, in particular in patients at risk.
After approval by the regional ethics committee and having given written informed consent, 20 patients (ASA physical status 1–2) undergoing minor elective orthopaedic or plastic surgery were randomly assigned by sealed envelope allocation to receive anaesthesia with either propofol and morphine (group MORPH) or propofol and remifentanil (group REMI). Patients with a history of respiratory tract pathology, expected difficult airway, atopy, smoking or those using drugs known to influence the BTV (β-adrenoceptor antagonists, cortisone, atropine, theophylline, and catecholamines) were excluded from the study. Induction of anaesthesia was standardised. After insertion of a peripheral intravenous cannula, morphine was given as a bolus of 0.15 mg.kg−1 (group MORPH) or a remifentanil infusion was commenced at 0.2 μg.kg−1.min−1 (group REMI). Two minutes later, a propofol target controlled infusion (IVAC TCITM, Alaris Medical Systems, Basingstoke, UK), was commenced with an initial target of 6 μg.ml−1 and cis-atracurium 0.2 mg.kg−1 was administered for neuromuscular block. Two minutes after the administration of cis-atracurium, a disposable laryngeal mask airway (SoftSeal™, Portex Ltd, Hythe, UK) was inserted. The lungs of the patients were ventilated using a pressure-controlled mode with a maximum pressure of 20 cm H2O and no positive end-expiratory pressure (PEEP). A circle anaesthetic breathing system (Aestiva™, Datex Ohmeda Inc., Madison, WI) with an antimicrobial filter for air humidification (Thermovent Hepa™, Portex Inc., Keene, NH) was used. Fresh gas flow was 2 l.min−1 with an inspired oxygen fraction (Fio2) of 0.5 in an oxygen-air mix. Ventilation rate and maximum airway pressure were adjusted to maintain a normal end-tidal CO2 (4.4–5.7 kPa). In the MORPH group, anaesthesia was maintained with propofol targeting a plasma concentration of 3–8 μg.ml−1. In the REMI group, patients also received propofol at a target concentration of 3–8 μg.ml−1 and remifentanil 0.2 μg.kg−1 min−1. In both groups the target controlled infusion of the propofol was adjusted to clinical need, within the given limits.
Fifteen minutes after insertion of the laryngeal mask airway, and with the patient in the supine position, a swivel connector (Bodai PEEP Safe™, Sontek Medical Inc., Hingham, MA) was inserted between the laryngeal mask airway and the circle system. BTV was assessed using a modification of the method described by Keller and Brimacombe  and Sackner et al. (Fig. 1). A fibrescope (Videoscope type PI60™, Olympus Optical Co. GmbH, Hamburg, Germany) was passed through the swivel connector and the right main bronchus was visualised. A 16-gauge epidural catheter (Portex Ltd) with the tip cut off to achieve one single, end-standing hole, was inserted into the working channel of the scope. The catheter was inserted until it was seen through the lens of the scope and was almost touching the mucus membrane of the right main bronchus. A drop of 1% methylene blue dye (approximately 0.02 ml) was inserted into the epidural catheter and flushed through with an air filled 1-ml syringe, to place it onto the posterior surface of the bronchial mucosa, approximately 2.5 cm below the carina. The time required to apply the dye was approximately 1 min. After placement of the dye, the lens of the bronchoscope was positioned neutrally and moved up to the proximal margin of the drop. The scope was marked where it entered the swivel connector and removed from the laryngeal mask airway. The distance between the connector and the mark was considered the baseline value. At 2, 4 and 6 min after the application of the dye, the position of the proximal margin of the dye was determined again by the method described (Fig. 1). The mean of the three assessments was calculated and divided by two to give the BTV in mm.min−1. In our experience, the method of BTV assessment has a certain probability of error due to either overestimating or underestimating the position of the dye. Hence, three assessments every 2 min were preferred to only one assessment after 6 min, to minimise that source of error. Nasal core body temperature, doses of morphine, remifentanil and propofol, end-tidal CO2, Fio2, maximum airway pressure and PEEP, ventilation rate and tidal volumes were all recorded at the times of BTV assessment. One investigator (SH) performed all assessments.
The investigator was not blinded to the treatment, but during each assessment he was blinded to the previous (baseline) marks on the scope by utilising the scope's video screen, rather than looking at the scope itself.
Sample size calculation/statistical analysis
For sample size estimation we used the data (mean, standard deviation) of a previous investigation  using the same method and calculated that a minimum number of eight patients per group was required to detect a difference of at least 3.5 mm.min−1 (a value demonstrated by Konrad et al.  to be clinically significant) with a power of 80%. To account for the possible loss of patients as experienced in a previous study using the same method , we included 10 patients per group. Statistical analysis was performed using two-factor analysis of variance (anova), Spearman's correlation coefficient and Chi-squared test. The Kolmogorov-Smirnov test was used for testing the data for normal distribution and the homogeneity of variance test (Levene statistic) was used to test for the equality of group variances. Alpha error was 0.05 and beta error 0.2. Unless otherwise stated, data are presented as mean (SD). In addition, the ranges of BTV are reported for both groups.
Twenty subjects (aged 19–65 years) were included in the trial. The data of one patient of the REMI group had to be excluded because on bronchoscopic examination we found excessive secretions, necessitating suction. The groups showed no significant differences regarding type of surgery, age, body weight, height, body temperature, Fio2, end-tidal CO2, peak airway pressures, tidal volume and minute volume (Table 1). The target controlled infusion target of propofol was significantly higher in the MORPH group, compared to the REMI group (mean (SD) 6.4 (1.9) vs 4.4 (0.8) μg.ml−1), but no correlation between the dose of propofol and the BTV was found in either group.
|MORPH (n = 9)||REMI (n = 10)|
|Age; years||34.4 (15.4)||44.9 (18.6)|
|Height; cm||175.0 (11.8)||172.0 (11.8)|
|Body weight; kg||75.1 (13.9)||78.9 (8.6)|
|Body temperature; °C||35.8 (0.7)||35.8 (0.6)|
|End-tidal CO2; kPa||4.6 (0.4)||4.7 (0.6)|
|Fio2||0.55 (0.05)||0.57 (0.17)|
|Peak airway pressure; cm H2O||15.2 (2.9)||16.1 (2.2)|
|Ventilation rate; × min−1||10.4 (1.3)||10.4 (1.3)|
|Tidal volume; ml.kg−1||7.1 (0.9)||6.4 (1.2)|
|Minute volume; litres||5.5 (1.1)||5.1 (0.8)|
Compared to MORPH, REMI resulted in a significantly lower BTV: Mean (SD, range) MORPH 9.2 (5.8, 2.2–20) mm.min−1vs REMI 4.2 (3.0, 0.2–10.3) mm.min−1; p = 0.028 (Fig. 2).
The mucociliary transport system, which protects the respiratory system from exogenous insults, is dependent on a concerted effort of mucus secretion by goblet cells and propulsion of the layer of mucus by the ciliated epithelium . Impairment of function of mucociliary clearance predisposes to retention of secretions and inability to maintain a patent airway, leading to lower respiratory tract infections. Konrad et al.  demonstrated a significantly reduced BTV in smokers (median BTV 2.5 mm.min−1) compared to non-smokers (median BTV 8.2 mm.min−1) and pulmonary complications were found more often among smokers. The correlation between a low BTV and the incidence of pulmonary complications has also been shown in ventilated intensive care unit (ICU) patients (median BTV without complications 4.7 mm.min−1vs 0 mm.min−1 with complications) . The BTV values found in our trial (group MORPH mean (SD) 9.2 (5.8) mm.min−1vs group REMI 4.2 (3.0) match with those published by Keller and Brimacombe . They reported a mean (SD) BTV in patients with an laryngeal mask airway of 13.6 (2.1) mm.min−1vs patients with a tracheal tube whose BTV was 6.9 (1.2) mm.min−1.
BTV can be altered by a number of chemical and physical factors from the external environment, e.g. drugs  (catecholamines, theophylline, cortisone, atropine, β-adrenoceptor antagonists), high oxygen concentration , volatile inhalational anaesthetics , dry anaesthetic gases , trauma due to suction procedures , and the presence of a cuffed tracheal tube [5, 15].
In this study we demonstrated a significant depressant effect of remifentanil on BTV when compared to morphine. The mechanisms by which opioids inhibit BTV remain uncertain. Studies have shown the presence of opioid binding sites in the respiratory system . Opioid inhibition of neurally mediated mucus secretion in human bronchi in vitro has been demonstrated by Rogers and Barnes . In contrast, Wang and co-workers  concluded from an in vivo study on dogs that the observed decrease in mucociliary clearance was more likely caused by an opioid induced reduction of ciliary beat frequency, rather than decreased mucus production or an increase in periciliary fluid. Selwyn et al.  did not find a significant change in ciliary beat frequency in vitro after exposure of human nasal cilia to morphine.
However, these contradictory results from in vitro trials might not be applicable to humans in vivo, as they do not account for the possible neural control of BTV .
A limitation of this study is that morphine and remifentanil were administered differently and equipotency at the time of BTV assessment was not established (for example by measuring plasma opioid levels). We decided to administer both opioids as they would most likely be used in a normal clinical setting. In addition, we cannot comment on the influence of propofol on BTV because no pre-induction BTV assessment was performed as a control measurement. The lack of any correlation between the dose of propofol and BTV in the current and a previous  study makes a significant influence of propofol unlikely. This is supported by the findings of Padda et al. , who did not find an effect of propofol on mucus secretion or clearance.
One potential limitation of the study method itself, although it did not affect our results, is the risk of losing track of the proximal border of the methylene dye. With an average tracheal length of 11.25 cm, and assuming the dye is placed 2.5 cm distally from the carina, the resulting distance to assess BTV is approximately 14 cm. As the fastest movement in our study was 20 mm.min−1 (or 12 cm within 6 min), we did not experience difficulties in our patients. To avoid this problem, we recommend placement of the methylene blue dye as far distally in the right main bronchus as practical.
An important question is whether our in vivo findings are clinically relevant. As we did not assess any clinical outcome variable, this study did not address this issue.
However, the mean difference between groups in this trial (5.0 mm.min−1) in relation to the findings of previous outcome orientated studies suggests our findings may have clinical relevance. Konrad et al.  reported a mean difference of 5.8 mm.min−1 for BTV in the right main bronchus when comparing smokers and non-smokers under general anaesthesia. A significantly higher rate of pulmonary complications was also reported in the group of smokers. However, a number of potentially confounding factors arising from tobacco inhalation, other than a change in BTV, make it difficult to interpret the data.
The same authors  reported a BTV difference of 3.5 mm.min−1 (left main bronchus) and 4.7 mm.min−1 (right main bronchus) between ventilated ICU patients, some of whom later developed pulmonary complications, such as retention of secretions or pneumonia.
In conclusion, compared to morphine, remifentanil significantly depresses BTV in patients without lung disease. It remains to be determined whether this might have clinical implications with respect to postoperative respiratory complications, in particular for patients with pre-existing risk factors for retention of secretions, atelectasis and pulmonary infection.
We would like to thank Mr Roy Wyatt and his team of technicians from the Department of Anaesthesia and Pain Medicine, Royal Perth Hospital, Australia, for their enthusiastic help with the clinical set up.