Background information
Equine asthma treatment has traditionally always relied heavily on corticosteroids for effective treatment. However, there are a few limitations with corticosteroids – namely systemic usage has restrictions around competition and the increased risk of laminitis in natives and overweight horses and ponies, and inhaled corticosteroids are expensive and increasingly unavailable. Having alternative or corticosteroid-sparing treatment options could prove very useful for equine veterinarians and their patients. Nebulised lidocaine appears to be a promising novel therapeutic for equine asthma, but studies are lacking to determine its safety, pharmacokinetic behaviour, and efficacy in horses.
What is equine asthma?
Equine asthma is characterised by airway inflammation, hyperresponsiveness, and increased mucus production, which results in chronic coughing. This inflammation is usually in response to inhaled airborne particles such as dust, spores, pollens etc. Equine asthma can have a debilitating effect on performance in sport and racehorses and can sometimes take a long time to resolve with the risk of repeated episodes seasonally. Clinical signs of equine asthma include coughing, nasal discharge, increased respiratory rate, increased respiratory effort, wheezing and poor performance. Typically, equine asthma is associated with increased stabling in poorly ventilated barns with dusty bedding and hay. This is more likely to affect horses in the winter or on long periods of box rest due to injury, however, summer-pasture-associated equine asthma affects horses in the summer due to seasonal pollens.
What do we know so far regarding nebulised lidocaine in horses?
Lidocaine is a local anaesthetic and class 1b anti-arrhythmic that is FDA-approved for use in local anaesthesia and treatment of ventricular arrhythmia. It is also an Association of Racing Commissioners International (ARCI) Class 2 foreign substance. Lidocaine has been used for its corticosteroid-sparing effects in human respiratory medicine and has also been shown to have promise in cats for reducing airway resistance and peripheral blood eosinophilia.
In a recent clinical trial with asthmatic horses in the laboratory of the authors of this study, bronchoalveolar lavage (BAL) neutrophilia and tracheal mucus score (TMS) decreased following 14 days of twice-daily lidocaine nebulization (1.0 mg/kg), thus showing support of its anti-inflammatory effect in horses with equine asthma.
What do we not know about nebulised lidocaine in horses?
Intravenous lidocaine has been used extensively in horses; however safe nebulised doses are relatively unknown. The extent to which nebulised lidocaine is deposited in the lung fluid and systemically absorbed in horses is also completely unknown. Other questions around safety with respect to swallowing function and bronchomotor tone remain unanswered currently. This study aimed to describe the effect of nebulised lidocaine on upper airway sensitivity, lung mechanics, and lower respiratory cellular response in healthy horses, as well as delivery of lidocaine to lower airways and its subsequent absorption, clearance, and duration of detectability.
Study Design
This was a prospective, descriptive study with a total population of 6 healthy horses completing each of the 4 experiments described below over 1 year. For all nebulisation procedures, the portable equine Flexineb® nebuliser was used with a 4% preservative-free lidocaine solution at a 1ml/kg dose.
Upper airway sensitivity
- Airway endoscopy was performed with an atraumatic probe. The larynx was gently probed prior to and after lidocaine nebulisation in a sequence of 5 specific areas. The sensitivity to the probes and briskness of swallowing was recorded, blind reviewed and scored.
- Endoscopy of the trachea was also used to grade mucus (0-5) and the number of coughs was recorded.
Lung function and cellular inflammation in BALF of healthy horses
- Horses were assessed over 2 days, the first without lidocaine nebulisation, and the second within minutes of lidocaine nebulisation.
- The horses had an oesophageal balloon placement in the mid-thoracic region, and this recorded transpulmonary pressure, pulmonary pressure, volume and flow, pulmonary resistance and dynamic compliance.
- Histamine bronchoprovocation (HBP) was also performed before and after nebulisation of lidocaine to determine how sensitive the lower airways were to an asthma-triggering inhalant (histamine).
- A BAL was performed at the end of each day for cytology.
Determine the extent of deposition of lidocaine in the lower airways
- Horses were nebulised and then immediately sedated for BAL. BALF lidocaine concentrations were determined using chromatography and mass spectrometry.
Establish systemic absorption and clearance of nebulized lidocaine
- Lidocaine was administered via the equine nebuliser and blood samples were obtained at 5-minute and 2-hour intervals post-nebulisation to measure the concentration of systemic lidocaine and its metabolites. Urine samples were also collected and analysed.
The horses were university-owned and deemed healthy by clinical exam and anamnesis, with no history of lower airway disease within the past 6 months. During the study, 3 horses were excluded due to behavioural problems, and one was euthanased for reasons not associated with the current study.
Study Validity
Strengths
- All horses used the same brand of equine nebuliser at the same dose and concentration.
- Due to the number of tests, they were spread out over a long period in order to minimise reactions and inflammation caused iatrogenically
- Very thorough investigation of all pharmacokinetics and clinical effects with multiple experiments.
Weakness/limitations
- Very small study population, which was made even smaller due to the exclusions, only 2 horses completed all experiments in the study.
- The population was not randomly chosen – they were university-owned.
- The horses had to be sedated with xylazine for urinary catheterisation, this allowed for potential ADH antagonist effects on urine concentration.
- Effects of serial lidocaine exposure on BAL cytology are unknown, therefore could affect this study’s cytology results.
Study findings
Upper Airway sensitivity
No structural upper airway abnormalities were noted prior to or after nebulisation. The number of probes needed to elicit a response in the larynx at the 5 different sites did not differ pre- or post-nebulization. 1 less horse (3/6 horses) coughed during tracheoscopy post-nebulisation. On average, the mucus score increased in horses post-nebulisation.
Lung function and cellular inflammation in BALF of healthy horses
Baseline respiratory rate, tidal volume, minute ventilation, RL and Cdyn were within normal ranges, and remained so after lidocaine nebulization, with no significant differences between the two-time points. Five of 6 horses completed HBP testing both before and after nebulization with lidocaine, including the maximum histamine dose of 16 mg/mL. Only 1 horse out of 6 had cytological evidence of airway inflammation consistent with equine asthma in BAL before and after nebulisation.
Determine the extent of deposition of lidocaine in the lower airways
Assuming accurate correction for dilution, lidocaine reached concentrations exceeding 9 μg/mL in the epithelial lining fluid of nebulised healthy horses. This indicates that the drug had a comparatively higher concentration at the site of action compared to maximum systemic levels.
Establish systemic absorption and clearance of nebulized lidocaine.
Lidocaine remained detectable in blood and urine for 24 and 48 hours post-nebulisation and MEGX (a metabolite) remained detectable in urine at 96 h. The authors sedated the horses with xylazine for safe urinary catheterisation so were unable to establish whether the a2-agonist decreased urine concentration and thus concentrations of lidocaine and MEGX.
Meanwhile, peak serum concentrations remained < 0.25 μg/mL, well below concentrations where toxic effects have been reported in horses (1.9–4.5 μg/mL).
Conclusions and clinical relevance
The authors of this study set out to find a safe dose for nebulised lidocaine in healthy horses as well as find out about the pharmacokinetic effects once nebulized. They found out that nebulisation of 1mg/kg 4% preservative-free lidocaine reached acceptable concentrations in the lower airways while having modest systemic absorption and no immediate adverse effect. It is worth noting that AHR (airway hyperreactivity) was appreciated in a subset of horses – however, with such a small sample size, it’s hard to determine the significance of this. Otherwise, no immediate inflammatory changes were seen.
This study is a vital step in getting closer to finding out if it will be an effective alternative therapy for equine asthma. However, before clinical recommendations can be made, additional data is needed to outline the safety, drug delivery, and immediate response to nebulized lidocaine in clinically affected equine asthmatics.
Check out our other articles on equine asthma here.