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Anaesthesia management of patients with airway susceptibilities: what have we learnt from animal models?

Habre, Walid; Petak, Ferenc

European Journal of Anaesthesiology: September 2013 - Volume 30 - Issue 9 - p 519–528
doi: 10.1097/EJA.0b013e328361d404

Anaesthesia management of patients with airway susceptibility remains a challenge in daily clinical practice due to the increased risk of perioperative bronchospasm. Therefore, understanding the mechanisms participating in the interaction between anaesthetic drugs and the lungs is essential in providing the optimal care for patients with chronic lung diseases. Experimental studies performed on various animal models mimicking airway susceptibility have played a key role in understanding the pathogenesis of lung diseases and have characterised the different pathways involved in the altered airway and lung tissue responses to anaesthetic agents. This narrative review highlights the progress that has been achieved by investigations in animal models and discusses the potential translation of these experimental findings to the clinical setting. The application of animal models with normal and allergically sensitised airways demonstrated that volatile and intravenous anaesthetic agents, muscle relaxants, analgesics and local anaesthetics exert their pulmonary effects via different neurosensorial pathways and through activating various receptors in the lungs. Attention is drawn to the significant differences in the pulmonary effects of anaesthetic agents between lungs with normal and those with susceptible airways. Extrapolating clear-cut conclusions from animal research to clinical practices should be made with caution, particularly for muscle relaxants, opioids and local anaesthetics wherein complex pathophysiological mechanisms are responsible for the potential respiratory effects of these agents. Animal models are of great importance in evaluating the potential interaction between anaesthetic drugs and the lungs, in identifying the pathways involved and in targeting preventive or treatment strategies to the lung compartment primarily involved.

From the Paediatric Anaesthesia Unit, Geneva Children's Hospital, Geneva, Switzerland (WH) and the Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary (FP)

Correspondence to Dr Walid Habre, MD, PhD, Associate Professor, Head of Pediatric Anaesthesia Unit, Geneva Children's Hospital, University Hospital of Geneva, 6 rue Willy Donzé, 1205 Geneva, Switzerland Tel: +41 22 38 27 504; fax: +41 22 38 25 485; e-mail:

Published online 1 June 2013

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Airway inflammation is the main feature of many pulmonary diseases whether it is acute [such as upper respiratory tract infection (URI) or lower tract infection] or chronic (such as asthma, cystic fibrosis, nocturnal chronic cough, bronchopulmonary dysplasia, left ventricular failure, passive and active smoking). These conditions are associated with airway susceptibility that correlates highly with the occurrence of adverse perioperative respiratory events such as bronchospasm, laryngospasm, recurrent cough and oxygen desaturation.1–3 Anaesthesiologists are more and more frequently confronted with the management of high-risk patients in every day clinical practice. Therefore, it is crucial to be aware of those anaesthetic drugs with a potential to precipitate bronchoconstriction in patients with susceptible airways, to provide the best available preventive strategy and to establish guidelines to target the treatment towards the lung compartment primarily involved in the impairment of lung function.

In the anaesthetic management of patients with susceptible airways, three major triggering pathways may lead to the stimulation of the lung contractile apparatus. Airway instrumentation, such as laryngoscopy, tracheal intubation or insertion of a laryngeal mask airway may all stimulate the parasympathetic autonomous nervous system with consequent liberation of acetylcholine, which then stimulates the M3 muscarinic receptors in the airway smooth muscle, resulting in bronchoconstriction.4,5 Additionally, numerous drugs administered during anaesthesia, such as antibiotics, colloids and muscle relaxants have the potential to induce histamine release with subsequent activation of the histamine receptors and development of bronchospasm.6,7 Finally, immunoglobulin E (IgE)-antigen-mediated anaphylactic reaction in the presence of allergies to latex, muscle relaxants or to other various compounds initiates a life-threatening systemic response associated with severe bronchospasm (Fig. 1).



There has been considerable progress made towards the understanding of the pathogenesis of lung diseases from animal models.8 Despite the fact these models reproduce the key features of airway susceptibility with the consequent enhancement of airway responsiveness, chronic inflammation, airway and pulmonary vascular remodelling or eosinophilia, their adaptation to study drugs or interventions encountered in anaesthesia management has been considered only recently. This narrative review highlights the progress that has been made with the help of animal models that mimic airway susceptibility, towards providing a better understanding of the effect of anaesthetic drugs on the respiratory system. In order to address all relevant findings, the review was based on an extensive and systematic literature search in PubMed by using mesh terms related to the specific agent group; bronchial hyperreactivity (and/or airway hyperresponsiveness); and ‘experimental’ investigations irrespective of the language, journal, or publication type.

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Animal models of airway susceptibility

In order to trigger enhanced lung responsiveness as a key feature of airway susceptibility, exposure to an allergen is commonly applied in experimental models to sensitise the airways. Allergens like ovalbumin,9–26 which is a chicken-egg extract containing a complex mixture of proteins or aqueous extract of ascaris suum antigen,27–32 induce a T-cell-mediated immunologic response initiating mechanisms leading to sustained airway inflammation. The pro-inflammatory mediators subsequently released are responsible for different reactions occurring in cascade with the activation and migration of neutrophils and eosinophils that will sustain the inflammatory condition and will be responsible for the epithelial shedding, the vasodilation and plasma leakage, the mucus hypersecretion and the activation of the sensory nerves and the cholinergic system.33–35 After sensitisation, the repeated exposure to the allergen leads to an IgE-mediated allergic reaction with mast cell degranulation and release of various endogenous bronchoactive mediators (histamine, serotonin, tryptase, etc.); cholinergic stimulation manifested as acetylcholine release; and activation of the nonadrenergic noncholinergic (NANC) system via neurosensorial nerve terminals resulting in the release of neuropeptides. All these pathways are responsible for the observed bronchoconstriction and the enhancement of lung responsiveness.33,34 Although these models allow investigation of altered airway responsiveness 7,10,36–40 and anaphylactic lung reactions,36,37 the individual roles of IgE-mediated allergic lung response and the nonallergic ballast proteins present in natural allergen extracts cannot be distinguished.41 In addition, there is concern about the relevance of such sensitisations to human airway disease involving bronchial hyperreactivity.8 Interestingly, other forms of allergic sensitisation by exposing the animals to more relevant environmental allergens (ozone, grass pollen, house dust mite, aspergillus, airborne pollutants, diesel exhaust particles, passive or active smoking, etc.) are essentially missing from experimental anaesthesia research. Therefore, there is an unmet need for the development of an allergic animal model based on highly purified natural and recombinant allergen molecules in order to mimic the most commonly encountered environmental stimuli causing allergic reactions with adverse pulmonary consequences.

Over the past decade, there have also been considerable advances in the understanding of cardiopulmonary interactions as additional potential mechanism leading to airway susceptibility related to adverse changes in the pulmonary vasculature.42,43 A wide variety of animal models have been established to investigate the pulmonary consequences of lung congestion induced by left ventricular dysfunction following coronary ischaemia,42,44,45 increasing pulmonary blood flow and pressure by creating an aortocaval shunt,46–49 and by enhancing the pulmonary vascular resistance by chronic hypoxia.50 These experimental studies have revealed the main mechanisms contributing to the lung function impairment and enhanced lung responsiveness when they are of pulmonary vascular origin. The major causes appear to be related to the close mechanical interdependence between the pulmonary vasculature and the bronchoalveolar network via a loss of lung volume due to the dilated vessels,51,52 a compromised airway lumen,53–55 stiffening of the alveolar wall subsequent to pulmonary capillary congestion52 or development of interstitial oedema that may uncouple the terminal airways from the surrounding lung tissue.56 Apart from these mechanical mechanisms, the elevated pulmonary vascular pressure or flow may also modulate the autonomous nervous system via stimulation of the NANC and cholinergic pathways contributing further to the development of compromised airway lumen and adversely affecting lung tissue mechanics.57,58 Finally, the complex cardiopulmonary interactions may be disturbed by an endogenous release of mediators participating in the regulation of the pulmonary circulation,59 which may further compromise the lung function and enhance its responsiveness to exogenous stimuli.60–62

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Inhalational agents

Apart from the neural, humoral mechanisms participating in the regulation of the lung ventilation, it has been well established that the resident gas in the pulmonary system plays an important role in the regulation of bronchial smooth muscle tone and consequently influences the contractile response of the lungs to exogenous stimuli.

Despite the worldwide spread of total intravenous anaesthesia, inhalational anaesthetic agents remain the most common means of hypnosis both for induction and maintenance of anaesthesia. Early experimental studies focused primarily on the most popular agent at that time, halothane, and highlighted the beneficial relaxation potential of this inhalation agent on the airways, demonstrating its ability to diminish airway tone63 and protect from bronchial hyperresponsiveness.28 As a result, halothane became the gold standard for all other modern volatile anaesthetics. Since this early work, the adaptation of the allergically sensitised models to anaesthesia research revealed differences among the currently used volatile agents in their protective or reversal profiles against constrictor stimuli, and in the strength of their relaxation ability depending on the mechanism responsible for the development of bronchoconstriction (i.e. cholinergic or allergic origin).

In relation to the protective effects of inhalational volatile agents, there is a consensus in the literature that all agents exert obvious blunting against airway constriction mediated by the muscarinic receptor stimulation.12,16,64,65 However, if the ability of the volatile anaesthetics was assessed against an anaphylactic lung constrictor response, the few available studies have revealed conflicting results. Some authors reported that halothane and enflurane were equally effective in preventing allergen-induced elevation in total lung resistance,28 whereas in another study halothane appeared to be more potent than isoflurane in preventing antigen-induced contraction of isolated tracheal rings obtained from ovalbumin-sensitised guinea pigs.13 A very recent study performed on ovalbumin-sensitised rabbit pups showed the importance of timing in these investigations by demonstrating the lack of potential of isoflurane, sevoflurane and desflurane to inhibit the most severe acute phase of the bronchospasm developed in response to allergen following anaphylaxis in both the central airway and peripheral lung compartments.66 Nevertheless, the benefit of the inhalational volatile agents can be anticipated even from this recent study, as these drugs, particularly sevoflurane, clearly demonstrated a potential to promote a faster recovery from bronchospasm.

The advantage of experimental studies in allowing more room for manipulation was utilised to characterise the underlying mechanisms responsible for this relaxation effect.16,67 Apart from the neural-mediated effects of volatile agents from the inhibition of vagal activity,68,69 there are direct inhibitory effects on the voltage-dependent calcium channel activity, particularly the T-type,70,71 and inhibiting chloride currents through the calcium activated chloride channels.72,73 Although this mode of action has been reported to be fairly uniform for the vast majority of the volatile inhalation agents (halothane, isoflurane and sevoflurane), desflurane was demonstrated to exert a different profile with a potential to interact with the autonomous nervous system, particularly via activation of the NANC pathway.74,75 This atypical neural activity of desflurane may be responsible for its outlier irritation potential and subsequent airway narrowing, especially following its administration in sensitised airways.74,75 Consequently, the results of experimental studies with this volatile agent39,74,75 are reflected in the clinical findings demonstrating somewhat higher incidence of intraoperative airway irritation and subsequent airway narrowing from desflurane in children with airway susceptibility76 and in adults with normal77–79 and sensitised airways.80 It is noteworthy, however, that desflurane appears to exhibit beneficial properties with similar relaxation potential to other volatiles if the triggering mechanism leading to the bronchospasm is cholinergic in origin.12,81–84 Nevertheless, desflurane may enhance airway tone if the NANC pathway is involved in the stimuli, such as following an anaphylactic response.74,75 This seemingly opposing potential of desflurane, depending on the mode of activation of the airway smooth muscle contraction, may explain the controversy in the assessment of its bronchial activity.

Due to the marked neuroprotective potential of xenon, there has been increasing interest in this gas as an inhalation hypnotic, particularly in patients with compromised cardiovascular function and haemodynamic instability.85,86 In addition, elderly patients may benefit from such a drug as it has been recently shown to be associated with a faster recovery and potentially better early postoperative cognitive function.87 However, early experimental studies have pointed out mild but systematic increases in airway resistance following xenon inhalation.88,89 Recently, this potential adverse airway effect has been challenged. When the markedly different physical properties of this gas were taken into account it was shown that the increased airway pressure observed under xenon anaesthesia is solely attributed to its higher density and viscosity.90 Therefore, a neutral airway effect is expected for xenon in patients with normal airways; however, the potential modulation of bronchial tone in the presence of airway susceptibility has yet to be addressed. There are even fewer reports of the possible bronchial effects of another widely used anaesthetic gas, nitrous oxide, with the only available experimental studies indicating no significant effect on the airway tone in healthy mammals.88,89

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Intravenous anaesthetics

Since the development of pharmacokinetic models for intravenous anaesthetic agents, total intravenous anaesthesia has gained increasing popularity in clinical practice. The adverse bronchial effects of thiobarbiturates and oxybarbiturates are exerted via stimulation of the cholinergic pathway,91 demonstrated consistently in experimental studies91–94 and confirmed later under clinical conditions.95,96 They contributed to their gradual replacement by propofol for intravenous anaesthesia. This change in the intravenous anaesthesia regimen was further promoted by accumulating evidence for the beneficial profile of propofol on the airways, where the experimental evidence from animal models also played a key role.22–24,97,98 The animal models also revealed the mechanisms of the airway smooth muscle tone reduction by propofol and pointed to the importance of reduced vagal tone24,97,98 and blunting of the serotonin24 or ATP-induced contraction.22 Additionally, clinical studies performed on the basis of the experimental results confirmed the lack of the adverse effect of propofol on the airway tone even in the presence of airway susceptibility.76,99,100 Despite these consistent results with propofol, it is worth noting that the ability of this intravenous drug to induce bronchodilation is less than that exerted by volatile anaesthetics.93

The use of ketamine as the intravenous drug of choice in the presence of airway constriction relies on considerable experimental evidence demonstrating its potent spasmolytic activity on airway smooth muscle even in the presence of sensitised airways.27,101,102 Although the mechanisms responsible for this relaxation potential of ketamine have been addressed in experimental research, the major pathways have not been fully elucidated. Nevertheless, the direct relaxing action on the airway smooth muscle exerted by ketamine appears to be independent of the release of relaxing mediators from the epithelium101 and N-methyl-D-aspartic acid (NMDA) receptors,103 and may be mediated by altered calcium ion influx.104 In addition to these direct mechanisms, experimental studies have proposed the coexistence of indirect pathways via a ketamine-induced release of endogenous catecholamines with bronchodilation action.105

There is increased interest in the use of α2 adrenergic receptor agonists in anaesthesia and intensive care. Drugs such as clonidine, or the more selective agent dexmedetomidine, have a large range of beneficial clinical effects and are used routinely in anaesthesia as adjuvants for their sedative, analgesic and anaesthesia-sparing effects.106 Therefore, characterisation of their bronchoactive properties is of relevance for safe use in patients with airway susceptibility. Early experimental studies have highlighted the potential of clonidine to decrease airway tone by inhibiting the sensory neurotransmission in normal airways.107–109 These beneficial features were recently confirmed in an ovalbumin-sensitised guinea pig model demonstrating that both clonidine and dexmedetomidine protect from bronchial hyperreactivity and promote relaxation of the airway smooth muscle via possible suppression of the intracellular calcium signal transduction, particularly in the sensitised model.15 However, there are some remaining questions about their exact relaxation mechanism, with some authors reporting possible relaxation mediated by the prejunctional alpha-2 receptors on the cholinergic nerves with subsequent inhibition of acetylcholine release.110 Another unclear aspect is related to the differences in response of clonidine, which appears to exert a beneficial profile only when it was inhaled.111 In addition, the apparent pharmacological differences between species may explain the lack of concordance between findings in animal models and humans.107 Therefore, there is a need for further experimental studies on various species before advocating the safe use of these drugs in patients with bronchial hyperreactivity.

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Muscle relaxants

Muscle relaxants are the drugs most involved in perioperative respiratory morbidity with the frequent development of bronchospasm.6,112–122 Animal models have played a key role in identifying the major components of the complex mechanisms involved. These models revealed the coexistence of three major pathophysiological pathways responsible for lung constriction subsequent to administration of muscle relaxants, with substantial differences between the particular agents. Direct histamine release by the degranulation of the mast cells is considered to be the primary cause for bronchospasm. Mivacurium has been demonstrated to be the most potent histamine-releasing agent followed by suxamethonium, rocuronium and vecuronium.6,7 Atracurium has a lower histamine-releasing potential,10 although the dose (<0.5 mg kg−1) and the speed of administration play a key role in this regard.123 Since it has been well established both in animals and humans that pancuronium does not induce histamine release,124,125 this agent remains the drug of choice as far as histamine-releasing potential is concerned. However, its use in clinical practice is decreasing because of the increasing need for short-acting drugs.

The use of animal models that allow manipulation of antihistaminic receptors revealed that a complete blockade of this pathway does not completely eliminate lung constriction following administration of muscle relaxants.6,10 These experimental findings provide evidence for the involvement of pathways other than the release of histamine in the pathogenesis of adverse respiratory changes, which ultimately limits the usefulness of the prophylactic administration of antihistaminic drugs in clinical practice

Apart from the histamine release, a further mechanism contributing to the adverse respiratory events is related to the allergic IgE-mediated anaphylactic pathway. In this respect, suxamethonium and rocuronium were proved to be the most frequently incriminated drugs (in more than 90% of the adult cases),112,120 and vecuronium caused the largest number of anaphylactic reaction in children.126

Due to the structural analogy between muscle relaxants and acetylcholine, a direct bronchoconstrictive potential of these drugs can be anticipated due to allosteric interactions with muscarinic receptors. Indeed, animal experiments have proved the presence of such interactions. The most striking example is rapacuronium blockade of M2 and M3 muscarinic receptors.127,128 These experimental findings were essential to understand the mechanisms responsible for the life-threatening bronchospasm seen with this agent and contributed greatly to its withdrawal from routine clinical practice.129 Further studies involving animals with normal airways demonstrated that all muscle relaxants can stimulate muscarinic receptors directly, but they differ in their potential to do so, and in their selectivity to act on the receptor subtypes M1, M2 or M3.120,121,130,131 These findings were also confirmed in allergically sensitised animals in which the different receptor subtypes were selectively blocked.10 The lack of difference in the airway responses when M1, M2 or M3 receptor subtypes were antagonised demonstrates similar affinities of suxamethonium to act on all three subtypes. Conversely, in-vivo and in-vitro experiments on animals with normal airways revealed the highest affinity was that of atracurium on M2 receptors,120,131 whereas the further activation of M1 receptors can be anticipated in the presence of an allergic inflammation.10 Furthermore, interactions with M3 receptors were proved in guinea pigs with normal lungs,130 and in ovalbumin-sensitised rabbits.10

All these previous findings obtained from animal studies together explain the caution needed when establishing clinical standards for the use of the muscle relaxants, especially in the presence of atopy or bronchial hyperreactivity in which there is an increased risk for adverse respiratory events. Considering the continuous efforts for further development of novel muscle relaxants with ideal pharmacodynamic properties, it is crucial to undertake preclinical evaluation of the potential adverse respiratory symptoms involving experiments in normal animals and in those modelling airway susceptibility, before launching new agents for clinical use.

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Opioids are routinely used in anaesthesia and among the analgesics, these agents are known to have the least interaction with airway tone. This feature was first demonstrated in experimental studies involving animals with normal airways, which demonstrated modulation of the cholinergic neurotransmission by opioids with subsequent decrease in airway tone.30,132–134 The inhibition of cholinergic neural activity was further confirmed with fentanyl in ovalbumin-sensitised rats,21 promoting the use of fentanyl in clinical practice in patients with bronchial hyperreactivity. Nevertheless, morphine failed to inhibit the bronchoconstriction following electrical field stimulation in ascaris-sensitised tracheal ring preparations.30

It is now established that opioid receptors are present on the afferent nerves of the neurosensorial NANC system in the lungs.135,136 Experimental studies have contributed greatly to the characterisation of the ability of opioids to inhibit the release of neuropeptides from the neurosensorial nerves and to inhibit the bronchoconstriction mediated by the activation of the NANC pathway.137,138

Apart from this beneficial airway profile evoked by neural pathways, the potentiation of airway smooth muscle contraction via release of histamine or other bronchoconstrictive mediators was also reported following administration of morphine.139–141 Thus, utilisation of animal models revealed that morphine has a dual action on bronchial tone with opposing effects from the inhibition of the cholinergic activity leading to relaxation of the airway smooth muscle, and a potential enhancement of bronchoconstriction via a release of mediators. Whether the constrictive or relaxation profile dominates after morphine administration is the subject of further investigation, but it seems that it depends on the particular experimental and clinical condition, with the likelihood of lung function deterioration in the presence of airway susceptibility.

The choice of NSAIDs as first-line therapy for pain has been promoted by the evidence in the literature about their efficacy. However, there is concern when these agents are prescribed for patients with bronchial hyperreactivity.142–144 The results of animal experiments have allowed the characterisation of the intimate pathophysiological mechanisms responsible for the potential adverse airway effects of NSAIDs, particularly aspirin. These agents inhibit cyclo-oxygenase with subsequent activation of lypo-oxygenase pathway, which may lead to release of cysteinyl leukotrienes.145,146 The consequence of such an increase in cysteinyl leukotriene is more severe in patients with nasal polyposis, asthma and increases endogeneous leukotriene levels.147 NSAIDs should be avoided in patients with such clinical symptoms, in whom aspirin-exacerbated respiratory disease is more frequently reported.

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Local anaesthetics

While the use of regional anaesthesia as part of routine anaesthesia management is gaining popularity, the potential interaction of local anaesthetics with the respiratory system has been extensively investigated in experimental and clinical research. The large number of publications may be related to the confusion in the results obtained with local anaesthetics. Some authors reported a beneficial airway profile of lidocaine25,26,32,148,149 and ropivacaine,148 whereas others have demonstrated its neutral effect on the pulmonary system,31 or even the development of bronchospasm,150,151 and an enhancement of agonist-induced bronchoconstriction.151,152 Although the reason for this discrepancy needs to be elucidated, the results of experimental studies suggest that lidocaine inhibits reflex bronchoconstriction in normal airways,32,151 whereas it has little effect or even a detrimental effect on the lung function in the presence of chronic airway inflammation.26,31,32 Although the pulmonary effects of lidocaine would be expected to be affected by its route of delivery, we were unable to discover a systematic difference in the pulmonary effects of this drug when it was delivered by the intravenous route or inhaled. These experimental findings reinforce the need for prudence when lidocaine is administered to patients with susceptible airways. Indeed, in line with this finding from animal models, enhancement of airway tone in clinical settings was observed in asthmatic patients,150,152,153 and lack of the beneficial profile was reported in children with airway susceptibility.3,154

The potential pulmonary effects of local anaesthetics can be addressed via their administration for neuroaxial blockade. Scarce experimental findings have highlighted the potential of spinal anaesthesia or high thoracic epidural analgesia to enhance the pulmonary responsiveness to exogenous stimuli, most probably by the inhibition of catecholamine release from the adrenal glands.155,156 However, clinical studies have promoted the use of neuroaxial blockade in patients with bronchial hyperreactivity in order to avoid general anaesthesia with tracheal intubation. In particular blockade of sympathetic fibres with high thoracic epidural analgesia was not associated with significant alteration in airway function.157

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We have provided an overview of the considerable progress made in anaesthesia research by systematically evaluating experimental results obtained in animal models of various lung diseases involving airway susceptibility. Recent developments of animal models with airway inflammation mimicking chronic lung diseases involving airway hyper-reactivity (such as asthma, chronic obstructive airways disease, chronic bronchitis, etc.) have contributed greatly to a better understanding of the adverse and beneficial respiratory consequences of the wide range of agents used routinely in anaesthesia (Fig. 1). The experimental results obtained in animals with normal and sensitised airways for volatile inhalational and intravenous anaesthetic agents were consistent with clinical observations. In this research area, the extrapolation of experimental findings to clinical settings seems sound and it can be concluded with confidence that halothane, isoflurane, sevoflurane, propofol and ketamine can be used safely even in patients with bronchial hyperreactivity. Conversely, such clear-cut conclusions for clinical practice cannot be made from animal research in relation to muscle relaxants, morphine and lidocaine, in which complex pathophysiological mechanisms are responsible for the potential respiratory morbidities. For these agents, translation to clinical practice should be made carefully due to the substantial wide variability between species in the different receptor distribution or drug affinities. Therefore, it is mandatory to evaluate the potential modulation of airway tone by any novel anaesthetic agent in clinically relevant concentrations and to keep in mind that the effect of a given drug on the respiratory system may be fundamentally affected by the presence of a lung disease involving airway susceptibility.

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Assistance with the study: none declared.

Financial support and sponsorship: this work was supported by the Department of Anaesthesiology, Pharmacology and Intensive Care of the University Hospitals of Geneva and by the Hungarian Basic Research Grant OTKA K81179. FP is supported by a Bolyai Janos Research Fellowship from the Hungarian Academy of Sciences and the TAMOP 4.2.2.A-11/1/KONV-2012-0052.

Conflicts of interest: WH has received a research grant from Maquet Solna, Sweden.

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