Sedation for flexible bronchoscopy: current and emerging evidence

Anti-cholinergic drugs

Anti-cholinergic drugs, such as atropine and glycopyrrolate, have been used due to their sympathetic effects which can prevent vasovagal reactions (bradycardia), and reduce coughing and airway secretions which may improve procedure tolerance and visualisation of the airways. In the past they were used as standard practice by many bronchoscopists but in clinical trials these drugs have failed to demonstrate benefits in bronchoscopy. Cowl et al. [23] and Malik et al. [24] compared intramuscular atropine and glycopyrrolate to placebo. Cowl et al. [23] found no significant benefit in the use of anti-cholinergics in reducing secretions, cough and complication rates or in increasing patient comfort. Despite demonstrating a reduction in airway secretions Malik et al. [24] found no benefits on patient comfort, oxygen desaturation or the time it took to complete the procedure and there were greater haemodynamic fluctuations and rise in blood pressure and pulse rate with the use of atropine.

Clonidine

Clonidine, a centrally acting α₂-adrenergic agonist, has been used due to the sympatholytic effects on the cardiovascular system that may reduce the incidence of arrhythmias and myocardial infarction during bronchoscopy, which is often associated with tachycardia and hypertension [25]. In a small randomised controlled trial, Matot and Kramer [26] showed that oral clonidine attenuated the haemodynamic response to flexible bronchoscopy but with higher doses (4–4.5 μg·kg⁻¹) it resulted in hypotension. In a trial of intravenous clonidine, de Padua et al. [27] demonstrated the beneficial effect of clonidine on blood pressure and heart rate with a reduction in frequency in arrhythmias but didn't demonstrate an improvement in patient comfort. Clonidine is probably not used more frequently due the prolonged sedative effects of oral administration, the rebound hypertension seen occasionally on withdrawal of the drug and the lack of larger randomised controlled trials [28].

Labetalol

Labetalol is an α₁- and β₁/β₂-antagonist used for its ability to reduce peripheral vascular resistance and arterial blood pressure without causing a reflex tachycardia. Fox et al. [29] performed a randomised controlled trial of intravenous labetalol versus placebo in addition to midazolam–alfentanil sedation and found no beneficial effect of adding labetalol as patients appropriately sedated with midazolam–alfentanil had adequate attenuation of their sympathetic stress responses.

Dextromethorphan

Dextromethorphan is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist with anti-tussive properties that has been used in bronchoscopy with midazolam sedation by Schwarz et al. [30]. Dextromethorphan (dose of 90 mg) led to a reduction in cough with less topical lignocaine and midazolam being required, whilst achieving better analgesia and patient comfort.

Fenoterol

Fenoterol is an inhaled short-acting β₂-agonist. It was used pre-procedure in addition to intramuscular atropine and hydroxyzine by Vesco et al. [31] in a small, randomised controlled trial. Fenoterol, in addition to atropine was found to have significant anti-tussive effects leading to less topical lignocaine being used.

Codeine phosphate

Codeine phosphate is an opiate with analgesic and anti-tussive properties and has been assessed by Tsunezuka et al. [32] in bronchoscopy as an adjunct to sedation with midazolam. The authors found that the addition of codeine phosphate 0.4 mg·kg⁻¹ given orally 60 min before the procedure led to a reduction in the dosage of topical anaesthetic and the degree of oxygen desaturation compared to placebo. Codeine is converted by cytochrome P450 2D6 (CYP2D6) to morphine but genetic polymorphisms exist that alter the conversion of the drug, leading to decreased effect in slow metabolisers and an increased effect and complications in ultra-rapid metabolisers [33]. The use of this drug has been replaced in bronchoscopy by newer short-acting opiates.

Benzodiazepines

Lorazepam and temazepam have been found to improve patient comfort and willingness to undergo a future procedure and this was thought to be related to its amnesic effect as patients were less likely to recall the procedure [34, 35]. These drugs have now been replaced by midazolam with more favourable properties and used in intra-procedural sedation.

With the present methods of sedation, pre-medication does not appear to be necessary to improve procedure tolerance and patient satisfaction. The administration of pre-medication may, in this case, lead to the potential of over-sedation and adverse effects. However, more trials of the use of clonidine and labetalol or other sympatholytic agents are needed to evaluate the effect on the reduction of arrhythmias and myocardial infarction.

Benzodiazepines

Benzodiazepines have a long history of safety and efficacy in bronchoscopy and are widely used for sedation. These drugs enhance the effect of the gamma-aminobutryic acid (GABA) and have sedative, hypnotic, anxiolytic, anti-convulsant and muscle relaxing properties [18]. In higher doses they may have amnesic-dissociative properties, which have been reported to be a reason why patients are less reluctant to have another bronchoscopy in the future if needed [34]. Another advantage is the ability to safely and effectively reverse their action with the antagonist, flumazenil, which must be available in every unit if these drugs are going to be used for sedation [37]. Benzodiazepines are metabolised in the liver via the cytochrome P450 (CYP) 3A4 and 3A5 system and excreted mainly in the urine. Due to natural variability in this system among various populations, the elimination half-life of these drugs may be prolonged in 5–8% of the population [38]. Midazolam has a large volume of distribution similar to diazepam but a short elimination half-life (2 h) and faster onset of action [18].

Benzodiazepines have relatively small cardiovascular depressant effects and only result in slight decreases in arterial blood pressure and increases in heart rate with some decrease in vagal tone resulting in heart rate variability seen with midazolam [18]. The ventilatory drive is depressed and although apnoea is not usually seen with low doses used for moderate sedation this may occur with higher doses, in those with comorbidities and when used in combination with other respiratory depressants.

Flumazenil, an imidazobenzodiazepine derivative, is a competitive antagonist of benzodiazepines at the GABA receptor and is used for reversal of benzodiazepine effects. It has a shorter half-life than the benzodiazepines used in bronchoscopy so its effect may cease before that of the benzodiazepine and lead to re-depression of the respiratory drive unless supplemental doses are given. It is essential that the patient is appropriately monitored until the effect of the benzodiazepine has completely ceased without supplemental doses of the antagonist. For reversal of benzodiazepine sedation, the dose of flumazenil is 0.2 mg, repeated every 60 s up to 1 mg; if a continuous infusion is required the dose is 0.1–0.4 mg·h⁻¹ [39].

Lorazepam [34] and diazepam [4] have been used in bronchoscopy but midazolam is the most frequently used benzodiazepine due to its properties having advantageous effects over others, especially the rapid onset of action, rapid time to peak effect and short duration of action [18]. The doses used for sedation of midazolam, lorazepam and diazepam are 0.01–0.1 mg·kg⁻¹, 0.03–0.05 mg·kg⁻¹ and 0.04–0.2 mg·kg⁻¹, respectively [18]. In a recent randomised controlled trial, Rolo et al. [7] showed that patients sedated with midazolam had less cough and dyspnoea and had increased patient-reported comfort and willingness to have a repeat procedure compared with placebo. This has been previously shown by others, such as Cases Viedma et al. [40] who also showed that the use of midazolam, reduced operator difficulties in performing the procedure and procedure time. Midazolam has been used safely and effectively in combination with opiates [8].

Opioids

Opioids are now frequently used in bronchoscopy in combination with benzodiazepines for their analgesic, anti-tussive and sedative properties. These properties complement those of the benzodiazepines, offering advantages in improving conditions for the bronchoscopist, improving patient tolerance of the procedure and attenuating sympathetic responses associated with intubation. At the same time it leads to a reduction in the amount of other pharmacological sedatives (e.g. benzodiazepines and propofol).

Opioids bind to mu (μ), kappa (κ), delta (δ) and sigma (σ) receptors that are found in the brain, spinal cord, peripheral sensory neurons and gastrointestinal tract [18]. The opioids used in bronchoscopy are agonists mainly of the μ receptor, responsible for supraspinal analgesia, respiratory depression and muscle rigidity [18]. They are mainly metabolised by the liver and excreted in by the kidneys. Due to renal elimination, opioids (especially morphine) can accumulate (metabolites) in patients with renal failure leading to prolonged sedation and ventilatory depression. In high doses opioids lead to bradycardia and associated hypotension but do not depress cardiac contractility. The effects on the respiratory system are more noteworthy, particularly reduction of the respiratory rate resulting in ventilatory depression. Due to the effects of opioids on the respiratory centres in the brainstem the apnoeic threshold is increased and the hypoxic drive is reduced.

Naloxone is the competitive opioid antagonist at the μ, κ and δ receptors. The intravenous dose for reversal of opioid respiratory depression and over sedation is usually 100–200 μg (1.5–3 μg·kg⁻¹) with supplemental doses of 100 μg every 2 min until reversal occurs to the desired level of respiration and consciousness [41]. With a short mean half-life of 64 min, over sedation may recur and an infusion or repeated dosing every 1–2 h [42] may be required.

Fentanyl is 100 times as potent as morphine and has a more rapid onset of action and elimination half-life making it more suitable for use in bronchoscopy [43]. The recommended dose of fentanyl in moderate sedation is 50–200 μg followed by supplemental doses of 50 μg but, at the upper limit of this range, ventilatory depression is more likely, especially when co-administered with other sedatives; therefore, an initial dose of 25–50 μg is recommended with supplemental doses of 25 μg as required until the desired effect is achieved or a total dose of 200 μg has been reached. Continuous infusion at a rate of 0.05–0.08 μg·kg⁻¹·min⁻¹ may also be used [42]. It is important to realise that in most circumstances doses of 200 μg are not required and that the dose needs to be reduced when used in combinations with other sedatives. Papagiannis and Smith [44] reported their observation of consecutive patients receiving either fentanyl (dose range 50–100 μg) or midazolam (dose range 5–15 mg) in addition to pre-medication with oral lorazepam and atropine for flexible bronchoscopy. They did not report any significant differences between the two except for the reduction in cough in those receiving fentanyl.

Alfentanil is less potent than fentanyl, but it has an almost immediate onset of action and shorter elimination half-life [45]. An initial dose of 250–500 μg is given followed by 250 μg supplemental doses as required [45]. Houghton et al. [46] conducted a randomised controlled trial of alfentanil versus midazolam for flexible bronchoscopy. They did not demonstrate large differences in outcomes between the two groups. Those receiving alfentanil had less cough but patients reported more discomfort. In the randomised controlled trial by Hwang et al. [47] the combination of propofol and alfentanil preserved haemodynamic stability throughout the procedure but mean oxygen saturation dropped below 90% (87.3±7.3%) after the initial bolus, immediately before the procedure, but this was transient with oxygen saturation levels returning to baseline after starting the procedure with no patients requiring assisted ventilation. When used in combination with midazolam, Fox et al. [29] found that these patients had adequate sedation and attenuation of sympathetic responses. Dreher et al. [48] compared consecutive patients with stable pre-existing respiratory failure undergoing flexible bronchoscopy receiving midazolam alone or midazolam-alfentanil combination. They did not find any differences in oxygen desaturation or hypoventilation but those in the combination group reported less discomfort. Greig et al. [49] compared midazolam alone, alfentanil alone and midazolam–alfentanil combination for flexible bronchoscopy. Alfentanil provided adequate sedation and with its anti-tussive properties significantly attenuated coughing. The combination of midazolam–alfentanil though did not provide better sedation or improve patient tolerance and was associated with a greater risk of oxygen desaturation. The only advantage of alfentanil over fentanyl when used for moderate sedation is its quicker onset of action and shorter sedation time [50] although in bronchoscopy there have been no trials directly comparing these two short-acting opioids.

Propofol

Propofol (2,6-diisopropylphenol) is a short-acting anaesthetic agent with a rapid onset of action that has been used in bronchoscopy for moderate sedation. It is rapidly metabolised, mainly by conjugation in the liver, with a short initial distribution half-life (2–8 min) and initial two-phase elimination half-life of 30–60 min allowing rapid recovery [18, 51]. It works by binding to the β-subunit of the GABA-A receptor increasing the chloride conductance and results in hyperpolarisation of the post-synaptic membrane [18]. The major effects on organ systems are on the cardiovascular, respiratory and central nervous system and it is used for its hypnotic, anti-emetic and anti-pruritic effects but it does not have any analgesic properties. It causes a decrease in systemic vascular resistance and cardiac contractility resulting in a drop in the arterial blood pressure. Propofol can attenuate upper airway reflexes and can cause profound respiratory depression leading to apnoea at induction doses and in doses used for conscious sedation it can inhibit the hypoxic ventilatory drive. Propofol may cause pain on injection but this may be reduced by using the vein in the antecubital fossa, pre-treatment with opioids or pre-treatment with lignocaine together with venous occlusion if a hand vein is used [52].

Propofol is manufactured in a lipid-based oil emulsion that contains soybean oil, egg lecithin, and glycerol [51]. It is not necessarily contra-indicated in patients with egg allergy because most egg allergies are due to ovalbumin in the egg white and egg lecithin is extracted from highly purified egg yolk [53]. There is an increased risk of bacterial infection of propofol vials as it contains no anti-bacterial preservatives [51].

Propofol can be administered intravenously by bolus doses or as a continuous variable rate infusion but the latter is preferable to minimise undesirable cardiorespiratory effects. For induction of sedation a dose of 0.5–1 mg·kg⁻¹ over 1–5 min is usually required followed by maintenance concentrations of 1.5–4.5 mg·kg⁻¹·h⁻¹ (concentrations needed for the maintenance of anaesthesia in normal individuals range 4–12 mg·kg⁻¹·h⁻¹) [51]. When administered as a sole agent, a single intravenous bolus dose of 0.5–1.0 mg·kg⁻¹ given at a rate of 40 mg over 10 s until the desired level of sedation is achieved (1–2.5 mg·kg⁻¹ for induction of anaesthesia) with top up doses of 25–50 mg every few minutes as required [51].

Randomised controlled studies of the use of propofol in bronchoscopy are summarised in table 4. These studies have demonstrated that sedation with propofol compared to no sedation leads to less cough, pain, sensation of asphyxiation, total amnesia and improved tolerance of the procedure with no differences in oxygen saturations between the groups [5]. Compared to sedation with midazolam, propofol has similar efficacy and safety [21] but faster onset of action and a more rapid patient recovery for propofol leading to early discharge [20, 21, 54–56] and improved patient tolerance [20, 21, 54–56]. Propofol can be administered with other pharmacological agents including opiates. This results in a lower required dose of propofol, improves sedation, reduces cough and provides analgesia [47, 58, 60, 61]. Yoon et al. [57] compared propofol alone and the co-administration of propofol–alfentanil but did not find differences in patient or bronchoscopist satisfaction or in the degree of coughing, but those in the alfentanil group had significantly lower oxygen saturation levels. However, the lower levels of oxygen saturation reported in the alfentanil group are most likely not clinically significant. Carmi et al. [59] compared propofol to midazolam–alfentanil sedation whilst monitoring carbon dioxide tension and they found both to be equally safe but those in the midazolam–alfentanil group rather than the propofol group had higher carbon dioxide tension values and required more oxygen supplementation or airway support.

Due to the narrow therapeutic window between moderate sedation and anaesthesia with the use of propofol, and without the availability of an antagonist, it is generally recommended that it be used only by those formally trained in its use (e.g. anaesthetists) in an appropriate setting and with monitoring as used for deep sedation. Worldwide its use by non-anaesthetists remains controversial although in the literature it is extensively reported to have been used safely and effectively by non-anaesthetists either alone or in combination with other pharmacological sedatives [12, 56, 58, 62–67]. In the future, formal training and competency assessments in sedation practice for bronchoscopy may include the use of propofol given the evidence of benefit to patients.

Ketamine

Ketamine has been used in flexible bronchoscopy and endoscopy, especially for the paediatric population [68, 69]. Ketamine is a structural analogue of phencyclidine, a non-competitive NMDA receptor antagonist and partial agonist at opioid μ-receptors that has many central nervous system effects and dissociates the thalamus from the limbic cortex resulting in dissociative anaesthesia with the patient appearing conscious but unable to respond to sensory input [18]. It is biotransformed in the liver (mainly by CYP3A4) and excreted in the urine. It has a short-elimination half-life of 2 h [18]. In contrast to other pharmacological sedatives, ketamine results in an increased heart rate, cardiac output and arterial blood pressure due to stimulation of the sympathetic nervous system and inhibition of noradrenaline reuptake. When used alone it has minimal effect on ventilatory drive, generally preserving airway patency and respiratory function, but may cause apnoea when used in combination with other pharmacological sedatives and opioids. An advantage of ketamine is that it is a potent bronchodilator and analgesic, but it has the disadvantage of causing increased salivation and secretions, not attenuating upper airway reflexes and resulting in emergence delirium (e.g. confusion and hallucinations) in 10–20% of adults [70]. The latter may be reduced with the co-administration of midazolam or propofol [71, 72]. However, the co-administration of benzodiazepines with ketamine may result in a prolonged effect and attenuation of the cardiostimulatory effects of ketamine. Sympathetic antagonists such as β-blockers may unmask the myocardial depressant effects of ketamine. For moderate sedation, ketamine can be given intravenously as a bolus dose of 0.5 mg·kg⁻¹ and repeated every 5 min if required [36].

In the study of Hwang et al. [47], comparing the combination of propofol and alfentanil or propofol and ketamine via a patient controlled analgesia, ketamine was felt to be superior to alfentanil when combined with propofol. The sympathetic effects of ketamine maintained blood pressure values similar to pre-procedure levels and a higher percentage of patients in the propofol-ketamine group reported increased satisfaction with the procedure and demonstrated amnesia for the period of the bronchoscopy. The most commonly reported adverse effects by patients were delirium and hallucinations. As previously suggested [73], less propofol injection pain was seen in the propofol-ketamine group. A disadvantage to the use of ketamine is the longer duration of action compared to the other available sedatives currently used and the adverse effect of emergence delirium.

Fospropofol

Fospropofol, 2,6-diisopropylphenol methoxyphosphonic acid, is a water-soluble pro-drug of propofol and has a longer onset and duration of action compared to the propofol lipid emulsion but has a much shorter elimination half-life [74]. Blood levels of propofol after administration of fospropofol reach lower peak levels and are more sustained than after administration of intravenous propofol leading to predictable levels of moderate sedation [74]. The advantage of its use is that it does not cause pain on injection, does not have the high risk of bacterial contamination seen with propofol and leads to predictable levels of sedation, however, it has the disadvantage that if a patient is over sedated they will require ventilatory support for longer and is associated with the commonly reported adverse effects paraesthesiae and pruritus [75, 76].

Cohen and co-workers [76, 77] conducted two randomised controlled trials of fospropofol or midazolam following pre-medication with fentanyl for colonoscopy and found that a dose of 6.5 mg·kg⁻¹ provided appropriate sedation and high patient satisfaction. Silvestri et al. [6] conducted a phase III randomised controlled trial of fospropofol 2 mg·kg⁻¹ and 6.5 mg·kg⁻¹ (those >65 years of age or with ASA category 3 or 4 had the dose reduced by 25%) . With the higher dose they found better sedation, absence of procedure recall and patient satisfaction. Hypoxia was seen in 15.4% of patients receiving the higher dose. In a subgroup analysis hypoxia was found to be more common in patients >65 years of age compared to younger patients (13.1% versus 9.0%, respectively) [78].

Remifentanil

Remifentanil is μ-opioid receptor agonist with an analgesic potency similar to that of fentanyl that undergoes rapid metabolism by non-specific esterases in blood and has a short half-life of <10 min [79]. The benefits of this being that its effects do not last long after discontinuing its administration irrespective of the duration of the infusion and there is no accumulation of the drug and metabolic toxicity in patients with hepatic dysfunction. In children sedated with propofol and remifentanil full awakening was seen 5±1.3 min after stopping the remifentanil infusion [80].

Remifentanil has been used safely for flexible bronchoscopy in infants in combination with propofol [80, 81], but further studies are required to establish its role for flexible bronchoscopy compared with the other opiates. It is administered as an infusion at an initial rate of 0.1 μg·kg⁻¹·min⁻¹ and subsequently titrated in increments of 0.025 μg·kg⁻¹·min⁻¹ until the desired level of sedation is achieved but ideally shouldn't be >0.2 μg·kg⁻¹·min⁻¹ due to the increased risk of apnoea and chest wall rigidity [82].

Dexmedetomidine

Dexmedetomidine is a selective α₂-agonist with sedative and analgesic properties. It has the advantage of only causing mild respiratory depression at higher doses but does have sympathomimetic and vagolytic actions that may lead to bradycardia and hypotension [83]. These features are useful to attenuate the sympathetic response to intubation which it has been shown to do safely and effectively in flexible bronchoscopy for awake intubation [84] and in upper and lower gastrointestinal endoscopy [85–87], but it does require continuous cardiovascular monitoring to avoid unwanted complications. For upper gastrointestinal endoscopy dexmedetomidine resulted in a shorter recovery time and increased patient satisfaction when compared to midazolam [86]. Dexmedetomidine has been used successfully for bronchial thermoplasty [88] and recently for flexible bronchoscopy in a randomised controlled trial by Ryu et al. [89]. Dexmedetomidine was co-administered with propofol and compared with propofol–remifentanil combination. The advantage of the dexmedetomidine was that it resulted in a lower incidence of oxygen desaturation and reduced need for oral cavity suction (reduced salivation and airway secretions), but it did result in prolonged recovery times, increased cough and lower bronchoscopist satisfaction scores when compared to remifentanil. Dexmedetomidine does not have anti-tussive properties like the opioids so increased cough is expected and but further trials are required to determine the role of this drug in bronchoscopy.

Remimazolam

Remimazolam is a novel short-acting GABA receptor agonist that is rapidly metabolised by non-specific tissue esterases and its action can be reversed with flumazenil [90]. Studies in sheep have shown that remimazolam has a more rapid onset of action and a shorter duration of action compared with midazolam but was associated with more pronounced respiratory depression and hypotension, similar to propofol [91]. In this study the respiratory depression correlated well with the depth of sedation. In a phase I trial in humans, it has been also been shown to have a faster onset of action and shorter duration of action than midazolam, without the resulting in the requirement for oxygen supplementation or ventilation with doses of 0.075–0.20 mg·kg⁻¹.