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ORIGINAL ARTICLE

Target-controlled versus fractionated propofol sedation in flexible bronchoscopy: A randomized noninferiority trial

DANIEL FRANZEN, DANIEL J. BRATTON, CHRISTIAN F. CLARENBACH, LUTZ FREITAG AND MALCOLM KOHLER

1Department of Pulmonology, University Hospital Zurich, Zurich, Switzerland

ABSTRACT

Background and objective: Fractionated propofol administration (FPA) in flexible bronchoscopy (FB) may lead to oversedation and an increased risk of adverse events, because a stable plasma concentration of propofol is not maintainable. The purpose of this randomized noninferiority trial was to evaluate whether target-controlled infusion (TCI) of propofol is non- inferior to FPA in terms of safety in FB. Methods: Coprimary outcomes were the mean lowest arterial oxygen saturation (SpO2) during FB and the number of propofol dose adjustments in relation to procedure duration. Secondary outcomes were the number of occasions with SpO2 < 90% and/or oxygen desaturations of >4% from baseline, number of occasions with systolic blood pressure < 90 mm Hg, cough frequency, cumulative propofol dose, recovery time, maximum transcutaneous CO2, mean SpO2 and O2 delivery during FB. Results: Seventy-seven patients were included. TCI was noninferior to FPA in terms of mean (standard deviation) lowest SpO2 during the procedure (88.3% (5.4%) vs 86.9% (7.3%)) and required fewer dose adjustments (0.04/min vs 0.28/min, P< 0.001) but a higher cumulative propofol dose (264 vs 194mg, P= 0.003). All other secondary outcomes were comparable between the groups. Conclusion: We suggest that TCI of propofol is a favourable sedation technique for FB with equal safety issues and fewer dose adjustments compared with FPA.

Clinical trial registration: NCT02246023 at ClinicalTrials.gov

Key words: flexible bronchoscopy, propofol, sedation.

Abbreviations: ASA, American Society of Anesthesiology; BAL, bronchoalveolar lavage; BMI, body mass index; CI, confidence interval; CV, collateral ventilation; EBUS, endobronchial ultrasound; FB, flexible bronchoscopy; FPA, fractionated propofol administration; GFR, glomerular filtration rate; NAAP, nonanaesthesiologist adminis- tration of propofol; SBP, systolic blood pressure; SD, standard deviation; SpO2, oxygen saturation; TBNA, transbronchial needle aspiration; TCI, target-controlled infusion; tcpCO2, transcutaneous carbon dioxide pressure value.

INTRODUCTION

Nonanaesthesiologist administration of propofol (NAAP) has been shown to be a feasible and safe sedation method for flexible bronchoscopy (FB).1,2 In daily clinical practice, propofol sedation is given manually in repeated doses (fractionated) by a specially trained nurse in attendance of the bronchoscopist. However, fractionated propofol administration (FPA) may lead to oversedation and an increased risk of side effects (i.e. oxygen desaturation or arterial hypotension), as a stable plasma concentration of propofol is not maintainable with this technique. For the purpose of sedation during FB, continuous infusion of propofol has recently been shown to be as safe as FPA,3 but the continuous technique may be preferable to minimize haemodynamic and respiratory side effects.4 Propofol infusion devices can be manually controlled or applied as target-controlled infusion (TCI). In the latter, the physician sets a target blood or effect site (i.e. brain) concentration, and the computerized infusion device makes the necessary changes to the infusion rate according to age, gender and biometric parameters of the patient. The system has been developed as a standardized infusion system for the administration of propofol by TCI for the purpose of general anaesthesia in surgery.5 Similarly, TCI of propofol could be used for FB, and a target effect site concentration of 2.5 μg/mL of brain tissue has been proposed for this purpose.6 Because there is no randomized study comparing propofol TCI with FPA concerning patient safety and sedation quality during bronchoscopy, we aimed to prove noninferiority, assessed by oxygenation, ventilation and blood pressure, and sedation quality assessed by the number of dose adjustments and cough frequency.

Correspondence: Daniel Franzen, Department of Pulmonology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland. E-mail: [email protected]

Received 26 January 2016; invited to revise 17 March 2016; revised 24 March 2016; accepted 22 April 2016 (Associate Editor: Lonny Yarmus).

SUMMARY AT A GLANCE

In this randomized noninferiority trial, we evaluated whether target-controlled infusion (TCI) of propofol is noninferior to fractionated administration in terms of safety in flexible bronchoscopy. TCI of propofol is a favourable and safe sedation technique for flexible bronchoscopy.

METHODS

Study subjects In this randomized, single-blinded, noninferiority trial, we aimed to compare propofol TCI with FPA in FB, where FPA served as control group. Four hundred twenty-six patients underwent FB in NAAP sedation between January 20 and 15 September 2015. Of these, 186 were eligible for the study (Fig. 1). Exclusion criteria are listed in Table S1 in Supplementary Information. Patients were randomized in a 1:1 ratio using sequen- tially numbered sealed opaque envelopes to sedation performed with either TCI of propofol (intervention arm) or FPA applying NAAP (control arm). Blinding of the patient to the assigned procedure was achieved by hiding the device from the patients’ view. The investigators were not blinded to the allocated seda- tion technique. The study was approved by the local ethics committee

(2014-0121/SNCTP000000706) and is registered at ClinicalTrials.gov (identifier number: NCT02246023).

Written informed consent was obtained from all patients before inclusion.

Study design The purpose of study was planned and powered for noninferiority to evaluate whether TCI of propofol is noninferior to FPA in terms of safety in patients undergoing FB. Coprimary outcomes were the mean lowest arterial oxygen saturation (SpO2) during FB as the noninferiority outcome measure and the number of propofol dose adjustments or repeat doses, in relation to procedure duration as the superiority outcome measure. Secondary outcomes were the number of occasions with SpO2 < 90% and/or oxygen desaturations of >4% from baseline during FB, number of occasions with systolic blood pressure< 90mmHg during FB, cough frequency, cumulative propofol dose, procedure and recovery time, maximum transcutaneous carbon dioxide pressure value (tcpCO2), mean SpO2 during the procedure, and otherwise complications that

Figure 1 Study flow chart.

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make additional treatment necessary. Recovery time was defined as time between termination of bron- choscopy and first verbal contact or eye opening, whereas procedure time was defined as time between insertions until removal of the bronchoscope. Cough frequency and unscheduled awakening during the examination were measured manually by a study- independent clinical nurse, where a cough-free interval of at least 3s between two coughs was considered to differentiate between two coughing episodes. Transcutaneous SpO2 and tcpCO2 was measured continuously using a TOSCA 500 instrument (Radiometer, Basel, Switzerland), which has been validated repeatedly for SpO2/tcpCO2 monitoring in various circumstances.7–11

Sample size Assuming a mean lowest arterial SpO2 of 94.8% with a standard deviation of 2.7% in the arm treated with FPA,12 a total of 78 patients (39 in each treatment arm) were required to demonstrate that propofol TCI is associated with a reduction in mean lowest saturation of no more than 2% (noninferiority margin) compared with FPA, with 90% power and a one-sided significance level of 0.025.

Procedure-related details and sedation Bronchoscopy procedures were performed transna- sally or transorally, with the patients in the recumbent position, by supervised fellows (who had in the past performed at least 50 bronchoscopies) or consultants assisted by experienced nurses who also adjusted the infusion pumps and recorded all events. Electro- cardiographic and transcutaneous pulse oxymetric monitoring were recorded continuously during the procedure. In addition, automated noninvasive blood pressure measurements were performed every 3min. Supplemental oxygen was given at a rate of 4L/min via a nasal cannula to all patients. In the case of desaturation to <90%, oxygen delivery was increased to 6–10 L/min. Patients were routinely given 5mg of hydrocodone and 0.2mg of glyco- pyrrolate intravenously immediately prior to FB. Nasal anaesthesia was achieved by 2% lidocaine gel. Bronchoscopists were advised to instil 10mL of aliquots of 1% lidocaine over the vocal cords, on the trachea, and on both right and left main bronchi. Instilled lidocaine doses were recorded for each patient. All doses of supplemental local anaesthesia required, as judged by the bronchoscopist, were recorded for each patient. In both treatment arms, additional medication (i.e. analgesics) or doses other than those mentioned earlier were not allowed during FB. For TCI propofol delivery, the Perfusor Space

infusion pump was used (B. Braun Melsungen AG, Melsungen, Germany). Bronchoscopy was started after reaching the initial targeted effect site concentration (Ce) of 2.5μg/mL using the Schnider pharmacokinetic model described elsewhere, which is based on certain biometric values as total weight, lean body mass and height.6,13–16 Thereafter, Ce could be adjusted depending

on the clinical effect by increments of 0.2 μg/mL, in order to maintain the required level of sedation. The adequate level of sedation for starting the bron- choscopy was considered after loss of reaction to verbal and tactile stimuli, corresponding to a target sedation level between 3 and 4 (moderate to deep sedation) according to the American Society of Anesthesiology (ASA).17 Signs of pain or discomfort, agitation, extensive cough and inadequate motor or verbal response to manipulation were considered indicators of insufficient sedation, leading to Ce increment of 0.2 μg/mL. For patients assigned to FPA, the loading doses of

propofol were titrated in order to achieve the adequate sedation level (onset of ptosis). Patients received an initial bolus of 30–40mg of propofol, followed by a carefully titrated dose of 10–20mg of propofol based on the clinical response. Between each bolus, a pause lasting more than 20s had to be observed. Additional intravenous boluses of propofol were given if the patient showed signs of discomfort during the examination in order to maintain the required level of sedation. The adequate level of sedation for starting the bronchoscopy was identical to the TCI group (ASA 3–4). In case of the aforementioned indicators of insufficient sedation, an additional dose of propofol (10–20mg) was administered. If adverse events happened and patients desaturated, chin-lift and jaw- thrust manoeuvers or nasopharyngeal airway insertion were performed by a bronchoscopy nurse. In case of an ongoing hypoxaemia despite the aforementioned measures, anaesthesiology support was called with placement of a laryngeal mask or endotracheal tube. Both procedures were defined as serious adverse events.

Statistical analysis The coprimary noninferiority outcome was assessed by calculating the absolute difference in mean lowest SpO2 between treatment arms using a multiple linear regression model adjusting for treatment allocation, smoking status (current/former vs never), body mass index (BMI), collar size, age and maximum O2 delivery. TCI was considered to be noninferior to FPA in terms of safety if the lower bound of the 95% confidence interval (CI) for the treatment difference was greater than �2%. Continuous outcomes were analysed using multiple linear regression, and binary outcomes were analysed using binomial regression with a log link function to obtain the risk ratio between treatment arms. Count data (e.g. number of dose adjustments) were compared between treatment arms using inci- dence rate ratios estimated using negative binomial regression, offsetting the model for the length of the FB procedure. Each outcome was analysed under the intention-to-treat principle including all randomized patients with complete data, except for the non- inferiority outcome, which was also analysed in a per- protocol sample excluding patients who received a maximum of more than 10L/min of oxygen or an intervention via a nasopharyngeal airway insertion during the procedure. All superiority outcomes were performed at the two-sided 5% significance level.

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RESULTS

In total, 77 patients could be included in the study (Fig. 1). As a result of randomization, baseline characteristics of patients including intervention type were similar between treatment groups (Table 1). The majority of patients were in ASA class I or II and had a Mallampati classification (distance from the tongue base to the roof of the mouth) of 1 or 2. The main indication for bronchoscopy was suspected malig- nancy. Therefore, the leading bronchoscopic pro- cedures were endobronchial ultrasound (EBUS) with the convex and/or radial probe. Due to the frequent use of the convex EBUS probe in this study, bronchoscopes were mainly introduced via the oral rather than the nasal route.

Primary outcomes In the intention-to-treat analysis, the mean (standard deviation) lowest SpO2 was 86.9% (7.3%) in the FPA group compared with 88.3% (5.4%) in the TCI group (Fig. 2). After adjusting for possible risk factors of oxygen desaturations including age, BMI, neck circumference and cigarette smoking, and the given maximum O2 delivery, the absolute mean difference in lowest SpO2 between arms was 1.2% (95% CI: �1.7%, 4.2%; Table 2). Sixteen patients were excluded from the per-protocol analysis, which estimated a similar difference of 1.6% (95% CI: �1.6%, 4.9%; Fig. 2 and Table 2). Notably, there was no life-threatening oxy- gen desaturation.

The mean procedure duration was similar between treatment arms with 26.1min in the FPA group compared with 26.5min in the TCI group. The mean number of dose adjustments or repeat doses in the FPA arm was 0.28/min compared with 0.04/min in the TCI arm, leading to an incidence rate ratio of 0.17 (95% CI: 0.12, 0.23; P< 0.001) after adjusting for smoking, BMI, neck circumference, age and maximum O2 delivery (Table 3).

Secondary outcomes All but one of the secondary outcome measures were comparable between the groups (Tables 4 and 5). Cumulative propofol dose was significantly higher in the TCI compared with the FPA group (264 vs 194mg; P=0.003). However, the mean recovery time after FB was not influenced by the mode of sedation (Figure S1 in Supplementary Information and Table 5). There were no serious adverse events that made additional treatment necessary or deaths in either treatment arms.

Table 1 Baseline characteristics

Characteristics FPA

(n = 38) TCI

(n = 39)

Age (years) 64.0 (11.6) 65.6 (11.3) Gender, male 24 (63) 23 (59) BMI (kg/m2) 24.5 (3.7) 25.0 (4.5) Smoker 25 (66) 32 (82) Collar size (cm) 39.0 (4.3) 39.5 (4.1) Mallampati classification 1 13 (34) 11 (28) 2 16 (42) 15 (38) 3 8 (21) 13 (33) 4 1 (3) 0 (0)

GFR (mL/min) 83.4 (15.2) 90.0 (16.7) ASA classification I 8 (21) 3 (8) II 19 (50) 24 (62) III 10 (26) 12 (31) IV 1 (3) 0 (0)

Comorbidities Chronic lung disease 11 (29) 9 (23) Chronic heart disease 10 (26) 7 (18) Arterial hypertension 13 (34) 12 (31) History of malignancy 8 (21) 8 (21)

Indication for FB Suspected malignancy 27 (71) 29 (74) Cancer staging 5 (13) 1 (3) Interstitial lung disease 2 (5) 2 (5) Infection 1 (3) 1 (3) Suspected sarcoidosis 4 (10) 3 (8)

Bronchoscopic procedures EBUS-TBNA 25 (66) 24 (62) Radial EBUS mini probe 8 (21) 17 (44) BAL 6 (16) 10 (26) Measurement of CV Chartis (Pulmonx International Sarl, Neuchatel, Switzerland)

1 (3) 1 (3)

FB by oral route 31 (82) 26 (67)

Values are presented as mean (standard deviation) or n (%) as appropriate.

ASA, American Society of Anaesthesiology; BAL, bronchoalveolar lavage; BMI, body mass index; CV, collateral ventilation; EBUS, endobronchial ultrasound; FB, flexible bronchoscopy; FPA, fractionated propofol administration; GFR, glomerular filtration rate; TBNA, trans- bronchial needle aspiration; TCI, target-controlled infusion.

Figure 2 Results of the intention-to-treat and per-protocol analyses on lowest oxygen saturation (SpO2). Forest plot of the treatment differences on mean lowest SpO2 showing noninferiority of propofol target-controlled infusion compared with fractionated propofol administration for flexible bronchoscopy in nonanaesthesiologist administration of propofol sedation in the intention-to-treat (P = 0.42) and per-protocol (P = 0.31) analyses. Filled circles indicate the position of the point estimates for between-group differences, and vertical lines indicate the 95% confidence interval.

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Basic measures to maintain an appropriate oxygena- tion of the patient, as increase of oxygen delivery (53% vs 56%, P =0.8), chin-lift and jaw-thrust manoeuver (49% vs 53%, P=0.7) or insertion of a nasopharyngeal

airway (18% in both groups, P=0.9), did not differ between the groups. No serious adverse events (i.e. need for advanced airway support) occurred in any of the study groups.

Table 2 Mean lowest oxygen saturation—noninferiority outcome with noninferiority margin Δ = �2%

Treatment n Mean (SD) (%) Unadjusted treatment

effect (95% CI) Adjusted† treatment

effect (95% CI)

Intention to treat FPA 38 86.9 (7.3) 1.4% (�1.5, 4.3) 1.2% (�1.7, 4.2) TCI 39 88.3 (5.4)

Per protocol‡

FPA 30 87.4 (7.6) 1.6% (�1.7, 4.9) 1.6% (�1.6, 4.9) TCI 31 89.0 (4.9)

CI, confidence interval; FPA, fractionated propofol administration (control group); TCI, target-controlled infusion of propofol (intervention arm); SD, standard deviation.

†Adjusted for smoking, body mass index, neck circumference, age and O2 delivery. ‡Sixteen patients excluded from the per-protocol analysis (two received more than a maximum of 10 L/min of oxygen, and 14 received an

intervention via a Wendel tube).

Table 3 Number of dose adjustments—superiority outcome

Treatment n Mean number of dose

adjustments (SD) Mean length of

procedure (SD) (min) Adjusted incidence rate ratio† (95% CI), P-value

FPA 38 7.4 (4.6) 26.1 (13.2) 0.17 (0.12, 0.23), P < 0.001 TCI 39 1.2 (1.3) 26.5 (11.6)

CI, confidence interval; FPA, fractionated propofol administration; SD, standard deviation; TCI, target-controlled infusion. †Adjusted for smoking, body mass index, neck circumference, age and O2 delivery.

Table 4 Count variables (number of occasions with oxygen saturation < 90% and/or oxygen desaturations of >4% from baseline during flexible bronchoscopy, number of occasions with systolic blood pressure < 90 during flexible bronchoscopy, cough frequency)

Outcome

Mean number of events/min (SD) Incidence rate ratio (95% CI) P-valueFPA (n = 38) TCI (n = 39)

Oxygen desaturations 0.17 (0.14) 0.13 (0.10) 0.84 (0.59, 1.20) 0.35 SBP < 90 0.01 (0.03) 0.02 (0.05) 1.86 (0.62, 5.61) 0.27 Cough 0.84 (0.66) 0.74 (0.70) 0.88 (0.62, 1.26) 0.50

CI, confidence interval; FPA, fractionated propofol administration; SBP, systolic blood pressure; SD, standard deviation; TCI, target-controlled infusion.

Table 5 Continuous outcomes (cumulative propofol dose, recovery time, maximum transcutaneous carbon dioxide pressure value, mean oxygen saturation, maximum O2 delivery)

Outcome

Mean (SD) Absolute mean

difference (95% CI) P-valueFPA (n = 38) TCI (n = 39)

Cumulative propofol dose (mg) 193.7 (95.0) 264.1 (105.8) 70.4 (24.7, 116.1) 0.003 Recovery time (min) 5.0 (2.5) 4.6 (2.0) �0.3 (�1.4, 0.7) 0.52 Max. tcpCO2 (kPa) 6.1 (1.0) 6.3 (1.4) 0.2 (�0.4, 0.7) 0.51 Mean SpO2 (%) 96.1 (2.1) 96.6 (1.1) 0.6 (�0.2, 1.3) 0.16 Maximum O2 delivery (L/min) 7.3 (2.2) 6.9 (2.4) �0.4 (�1.4, 0.7) 0.46

CI, confidence interval; FPA, fractionated propofol administration; SpO2, oxygen saturation; SD, standard deviation; TCI, target-controlled infusion; tcpCO2, transcutaneous carbon dioxide pressure value.

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DISCUSSION

In this randomized noninferiority trial, we compared propofol TCI with FPA for FB in NAAP sedation, with the latter serving as control group. TCI was noninferior to FPA in terms of mean lowest SpO2 during the procedure and was shown to require fewer dose adjustments but a higher cumulative propofol dose. Furthermore, the number of occasions with SpO2 < 90%, oxygen desaturations of >4% from baseline, hypotensive episodes, cough frequency, procedure and recovery time, maximum tcpCO2 and mean SpO2 during the procedure were not significantly different between the treatment arms. In a study published by Grendelmeier et al.,3 a

conventional continuous infusion device was used, where the infusion rate of propofol was changed manually according to a fixed protocol: the infusion rate was set at 0.3mg/kg/min after an initial bolus of 10 mg of propofol. Thereafter, the infusion rate was reduced to 0.2mg/kg/min after 3min and was further reduced to 0.1 and 0.05mg/kg/min after another 3 and 6min, respectively.3 In their study, continuous propofol infusion was shown to be as safe as FPA, although conclusions for their noninferiority endpoint were based on a P-value rather than a CI, and thus, the conclusions by the authors are questionable. Con- tinuous infusion was associated with a higher cumu- lative propofol dose and a longer procedure duration.3

Compared with the conventional infusion pump used in their study, TCI devices change the infusion rate automatically according to a programmed algorithm, which is based on pharmacokinetic–pharmacodynamic modelling studies.13,14,16 The main advantage of propofol administration using TCI is the achievement of a stable plasma (and effect site) concentration by satisfying the physiological circumstances of biodis- tribution and elimination of the drug. Thus, the risk of oversedation and, consequently, potentially life- threatening side effects may be reduced. Furthermore, safety concerns of NAAP and the burden for the staff can be minimized. According to our results, propofol TCI is at least noninferior compared with FPA in terms of patient safety. Although there was a significantly higher cumulative propofol dose in the TCI arm, procedure and recovery times were similar in both treatment arms. Thus, cumulative propofol dose does not seem to be a relevant argument against the use of TCI. For the purpose of general anaesthesia, a recently

published systematic review does not provide suffi- cient evidence to make firm recommendations about the use of TCI versus manually controlled infusion of propofol.18 However, fewer interventions were required by the anaesthesiologist, and the time course of propofol effects was shown to improve during the use of TCI compared with the manually controlled infusion, whereas no clinically significant differences were demonstrated in terms of quality of anaesthesia or adverse events.18 In nonintubated but noninvasively ventilated patients with acute respiratory failure who were treated in the intensive care unit, TCI with propofol for FB has been shown to be feasible and safe.19

Furthermore, subjects sedated with propofol TCI had fewer movements at insertion of the laryngoscope,

improved haemodynamic stability, fewer episodes of apnoea and less respiratory acidosis after endoscopy, and the recovery was also shorter compared with manual administration.20

Our study has some limitations. First, we have chosen an initial target effect site concentration of 2.5μL/mL of propofol as proposed by Lin et al.6 We do not know the treatment effect with other initial effect site concentrations. Ce was not reduced in phases during FB, in which excitatory stimuli were less intense (e.g. bronchoalveolar lavage compared with EBUS–transbronchial needle aspiration). This could be addressed in a future trial and may be associated with a reduced cumulative propofol dose. Moreover, we cannot determine if fixed dose premedication with midazolam and hydrocodone used in both treatment arms of this study has a relevant influence on the results. However, previous studies showed that patient discomfort and cough are reduced in patients given a premedication with midazolam and hydrocodone, and thus, this has become standard in many centres.21,22

Second, bronchoscopist and staff were not blinded for the sedation technique. Therefore, cough frequency could be confounded. Third, sedation quality was not assessed, neither by the bronchoscopist nor by the patient. We have rather chosen to focus on objectively measurable outcomes. Moreover, the value of self- referred sedation quality is highly questionable, because patients have anterograde amnesia after premedication with midazolam. Fourth, most of the patients were in ASA class I or II or had a Mallampati classification 1 or 2, which should be taken into consideration when interpreting the results of the study, especially when TCI is used.

In conclusion, we suggest that TCI of propofol is a favourable sedation technique for FB. Safety issues (oxygenation, ventilation and blood pressure), cough frequency and procedure times are comparable with FPA. Using TCI, fewer interventions are needed to induce and maintain sedation. However, the cumu- lative dose of propofol is higher with the use of TCI, which is maybe negligible, particularly when Ce is adapted to different stages of FB.

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Supplementary Information Additional Supplementary Information can be accessed via the html version of this article at the publisher’s website:

Figure S1 Kaplan-Meier plot of recovery times.

Table S1 Exclusion criteria.

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