• View in gallery

    Values of R1 (A), R5:R10 ratio (B), X1 (C), and clinical scores (D) for 6 asthmatic horses that either were administered salbutamol (800 μg) by inhalation via an aerosol chamber and mask or underwent a mock manipulation with the same equipment in a crossover design experiment with a 48-hour washout period (experiment 1a). Lung function data were obtained by use of an IOS before (0 minutes [T0]) and 30 minutes (T30) after administration of salbutamol and at similar time points during the mock inhalation procedure. Baseline R1 and X1 values for 1 horse during the mock procedure were excluded from analysis because of a technical problem and replaced by the mean of the baseline values obtained for this horse during the other experiments. Clinical variables were assessed at the times of IOS measurement. For clinical scores, nasal flaring was scored as 1 to 4 as follows: 1 = no flaring, 2 = slight, occasional flaring of nostrils, 3 = moderate flaring of nostrils, and 4 = severe continuous flaring of nostrils. The abdominal component of breathing was scored from 1 to 4 as follows: 1 = no abdominal component, 2 = slight abdominal movement, 3 = moderate abdominal movement, and 4 = severe, marked abdominal movement. Nasal and abdominal scores from 1 to 4 were summed to obtain a combined clinical score ranging from 2 to 8. *Mean values at the 2 time points differ significantly (P < 0.05).

  • View in gallery

    Values of R1 (A), R5:R10 ratio (B), X1 (C), and clinical scores (D) for 6 asthmatic horses that were administered either an infusion of MgSO4 solution at a rate of 2.2 mg/kg/min for 20 minutes or an equivalent volume of saline (0.9% NaCl) solution adjusted to the same osmolarity in a crossover design experiment with a 48-hour washout period (experiment 1b). Salbutamol administration (experiment 1a) took place later in the same day that horses received the saline solution treatment. Lung function data were obtained by use of an IOS before (0 minutes [T0]) commencement of the infusion (hatched rectangles) of MgSO4 or saline solution, at the end of the infusion (20 minutes [T20]), and 10 minutes after the end of the infusion (30 minutes [T30]). Clinical variables were assessed at the times of IOS measurement. For each data set, the horizontal bar represents the mean. *Mean values at the 2 time points differ significantly (P < 0.05). For a given variable, the baseline (0-minute) value when horses received the MgSO4 infusion was significantly (P < 0.05) different from that when the horses received the saline infusion. See Figure 1 for remainder of key.

  • View in gallery

    Values of R1 (A), R5:R10 ratio (B), X1 (C), and clinical scores (D) for 6 asthmatic horses that were administered 800 μg of salbutamol via inhalation followed by either MgSO4 solution at a rate of 2.2 mg/kg/min for 20 minutes or no additional treatment in a crossover design with a 24-hour washout period (experiment 2). Infusion of MgSO4 solution started 10 minutes after salbutamol administration. Lung function data were obtained by use of an IOS before the administration of salbutamol (0 minutes [T0]), before commencement of the infusion of MgSO4 (hatched rectangles) or at 10 minutes after salbutamol administration (T10), at the end of the infusion or at 30 minutes after salbutamol administration (T30), and 10 minutes after the end of the infusion or at 40 minutes after salbutamol administration (T40). Clinical variables were assessed at the times of IOS measurement. One clinical score was missing for 1 horse at the 40-minute time point in experiment 2 (salbutamol inhalation alone). *Mean values marked by ends of a bar are significantly (P < 0.05) different. See Figure 1 for remainder of key.

  • View in gallery

    Respiratory rate (A) and tidal volume (B) for the 6 horses in experiment 2 before the administration of salbutamol (0 minutes [T0]) and at the end of the MgSO4 infusion or at 30 minutes after salbutamol administration (T30). *Mean values at the 2 time points differ significantly (P < 0.05). See Figure 3 for remainder of key.

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Effects of magnesium sulfate infusion on clinical signs and lung function of horses with severe asthma

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  • 1 Department of Clinical Sciences, Cell and Molecular Biology Respiratory Laboratory, Faculty of Veterinary Medicine, Université de Montréal, St-Hyacinthe, QC J2S 2M2, Canada.
  • | 2 Department of Clinical Sciences, Cell and Molecular Biology Respiratory Laboratory, Faculty of Veterinary Medicine, Université de Montréal, St-Hyacinthe, QC J2S 2M2, Canada.
  • | 3 Department of Clinical Sciences, Cell and Molecular Biology Respiratory Laboratory, Faculty of Veterinary Medicine, Université de Montréal, St-Hyacinthe, QC J2S 2M2, Canada.
  • | 4 Department of Clinical Sciences, Cell and Molecular Biology Respiratory Laboratory, Faculty of Veterinary Medicine, Université de Montréal, St-Hyacinthe, QC J2S 2M2, Canada.

Abstract

OBJECTIVE To evaluate whether MgSO4 solution administered IV would improve the clinical signs and lung function of horses with severe asthma and potentiate the effects of salbutamol inhalation in those horses.

ANIMALS 6 adult horses with severe asthma.

PROCEDURES Asthmatic horses were used in 3 crossover design experiments (6 treatments/horse). Clinical scores for nasal flaring and the abdominal component associated with breathing and lung function were determined before and after administration of salbutamol (800 μg, by inhalation), MgSO4 solution (2.2 mg/kg/min, IV, over 20 minutes), and combined MgSO4-salbutamol treatment. The data were collected during experimental procedures to assess salbutamol inhalation versus mock inhalation, MgSO4 infusion versus infusion of saline (NaCl) solution (adjusted to the same osmolarity as the MgSO4 solution), and the combined MgSO4-salbutamol treatment versus salbutamol inhalation alone.

RESULTS Infusion of MgSO4 significantly improved clinical scores when administered alone or in combination with salbutamol inhalation. With the combination treatment, lung function improved, albeit not significantly. Tidal volume also increased following combined MgSO4-salbutamol treatment. Salbutamol alone significantly improved lung function, whereas saline solution administration and a mock inhalation procedure had no effect on the studied variables.

CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that MgSO4 infusion alone or in combination with salbutamol inhalation improved the clinical signs of severely asthmatic horses. The effects of MgSO4 were not associated with significant lung function improvement, which suggested that the changes observed were attributable to alterations in the horses' breathing patterns. Infusion of MgSO4 solution at the studied dose offers little advantage over currently used medications for the treatment of severe equine asthma.

Abstract

OBJECTIVE To evaluate whether MgSO4 solution administered IV would improve the clinical signs and lung function of horses with severe asthma and potentiate the effects of salbutamol inhalation in those horses.

ANIMALS 6 adult horses with severe asthma.

PROCEDURES Asthmatic horses were used in 3 crossover design experiments (6 treatments/horse). Clinical scores for nasal flaring and the abdominal component associated with breathing and lung function were determined before and after administration of salbutamol (800 μg, by inhalation), MgSO4 solution (2.2 mg/kg/min, IV, over 20 minutes), and combined MgSO4-salbutamol treatment. The data were collected during experimental procedures to assess salbutamol inhalation versus mock inhalation, MgSO4 infusion versus infusion of saline (NaCl) solution (adjusted to the same osmolarity as the MgSO4 solution), and the combined MgSO4-salbutamol treatment versus salbutamol inhalation alone.

RESULTS Infusion of MgSO4 significantly improved clinical scores when administered alone or in combination with salbutamol inhalation. With the combination treatment, lung function improved, albeit not significantly. Tidal volume also increased following combined MgSO4-salbutamol treatment. Salbutamol alone significantly improved lung function, whereas saline solution administration and a mock inhalation procedure had no effect on the studied variables.

CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that MgSO4 infusion alone or in combination with salbutamol inhalation improved the clinical signs of severely asthmatic horses. The effects of MgSO4 were not associated with significant lung function improvement, which suggested that the changes observed were attributable to alterations in the horses' breathing patterns. Infusion of MgSO4 solution at the studied dose offers little advantage over currently used medications for the treatment of severe equine asthma.

Severe equine asthma, also known as heaves or recurrent airway obstruction, is a chronic respiratory disease affecting approximately 15% of adult horses in the Northern Hemisphere.1 Exacerbations of asthma are induced by airborne antigens mostly present in hay and are characterized by episodes of airway inflammation and obstruction. The clinical signs are primarily attributed to bronchoconstriction, mucus accumulation, and airway remodeling. Bronchoconstriction is thought to account for 60% to 70% of acute airway obstruction during clinical exacerbation of asthma.2 Interventions are directed at controlling antigen exposure, decreasing inflammation, and counteracting bronchoconstriction. Corticosteroid administration and antigen avoidance result in improved lung function, but only after days and weeks of intervention, respectively.3,4 Intravenously administered bronchodilators, such as atropine or N-butylscopolammonium bromide,5 can rapidly induce bronchodilatation, but adverse effects (ie, colic or tachycardia) limit their administration to horses undergoing severe exacerbation. Inhalation of bronchodilators is associated with fewer adverse effects, but devices used to administer the medications are not always available to practitioners. Also, some horses cannot tolerate this form of drug administration; therefore, the clinical response to inhaled bronchodilators varies.6

As a consequence, it is of interest to investigate treatment alternatives that could be used as a rescue medication during severe asthma exacerbations in horses. Magnesium sulfate solution has bronchodilator effects and is used as a second-line treatment in combination with corticosteroids and bronchodilators to treat humans hospitalized because of acute asthma attacks.7 Administration of MgSO4 solution has been shown to decrease the number of hospitalizations and need for assisted ventilation in adults and children with asthma.7,8 In 1987, Okayama et al9 determined that MgSO4 infusion administered alone had bronchodilator effects in humans with asthma and improved their lung function in a manner comparable to that achieved by treatment with albuterol (salbutamol). However, results of other studies10,11 indicated that MgSO4 infusion had a lesser effect than other bronchodilators. A possible potentiation effect of MgSO4 and inhaled bronchodilators on smooth muscle relaxation has been described,12 but it is not clear whether true potentiation was observed or if an additive effect was more likely.13 Reported adverse effects of MgSO4 infusion in humans are usually minor and transient and include hypotension, nausea, vomiting, flushing, headaches, and a burning sensation at the catheter site.7

Magnesium sulfate solution is readily available to equine practitioners, relatively easy to administer, and inexpensive, and it can be given to horses orally as a laxative or IV as an anti-arrhythmic agent with few adverse effects. Only 1 recent reporta has described some bronchodilator effects of MgSO4 infusion in horses, to our knowledge. The purpose of the study reported here was to evaluate whether MgSO4 solution administered IV would improve the clinical signs and lung function of horses with severe asthma and potentiate the effects of inhaled salbutamol in those horses. We hypothesized that treatment with MgSO4 solution would have bronchodilator effects and potentiate the effects of inhaled salbutamol in severely asthmatic horses.

Materials and Methods

Animals and housing

Six adult horses (4 mares and 2 geldings) with severe asthma belonging to the research herd of the Cell and Molecular Biology Respiratory Laboratory, Université de Montréal were used in the study. The group included 4 Quarter Horses, 1 Standardbred, and 1 crossbreed. The horses' ages ranged from 10 to 24 years (median, 16 years), and weights ranged from 425 to 620 kg (median, 547 kg). Each horse had a documented history of developing reversible airway obstruction and pulmonary neutrophilia when exposed to hay. Horses were housed indoors in individual stalls with daily turnouts starting 5 weeks prior to and for the duration of the study. They were fed hay, and were bedded on wood shavings throughout the study period. The horses were otherwise considered healthy on the basis of history and results of a CBC and clinical examination; they had not received corticosteroids or bronchodilators for > 3 months prior to the study. All horses were regularly dewormed and vaccinated. All animal manipulations were performed in accordance with the guidelines of the Canadian Council for Animal Care, and the protocol was approved by Animal Care and Use Committee of the Université de Montréal (approval number: Rech1791).

Study design

In the first experiment (experiment 1a), the goals were to evaluate bronchospasm reversibility achieved by administration of a short-acting β2-adrenoceptor agonist (salbutamol) and to compare this response with that achieved by administration of an infusion of MgSO4 solution (experiment 1b). In the second experiment (experiment 2), the capacity of MgSO4 infusion to potentiate the effects of salbutamol was investigated.

Salbutamol inhalation versus mock procedure (experiment 1a)—In a crossover design experiment with a 48-hour washout period, the horses either were administered salbutamolb (800 μg) by inhalation via an aerosol chamber and maskc or underwent a mock manipulation with the same equipment but without drug administration. The order of treatments was randomly assigned to each horse by use of a manual draw. The investigator (LT) recording the data was unaware of the treatment given to each horse.

Infusion of MgSO4 solution versus infusion of saline solution (experiment 1b)—In a crossover design with a 48-hour washout period, the horses were given either MgSO4 solution (40% magnesium sulfate heptahydrated diluted in saline [0.9% NaCl] solution for a total volume of 250 mL administered via an IV catheter placed in the left jugular vein, over a 20-minute period) at a rate of 2.2 mg/kg/min or an equivalent volume of saline solution adjusted to the same osmolarity. The dose was extrapolated from the bronchodilator dose used in humans7 and from the antiarrhythmic dose used for the treatment of ventricular tachycardia in horses.14 The order of treatments was randomly assigned to each horse by use of a manual draw. Fluid bags were coded and the investigator recording the data (LT) was unaware of the treatment given to each horse. Salbutamol administration (experiment 1a) took place later in the same day that horses received the saline solution treatment.

Infusion of MgSO4 solution and inhalation of salbutamol versus salbutamol inhalation alone (experiment 2)—Twenty-four hours after the end of experiment 1, all horses received 800 μg of salbutamolb and were then randomly assigned by use of a manual draw to receive either MgSO4 solution (40% magnesium sulfate heptahydrated diluted in saline solution for a total volume of 250 mL administered via an IV catheter placed in the right jugular vein, over a 20-minute period) at a rate of 2.2 mg/kg/min or no additional treatment in a crossover design with a 24-hour washout period. Infusion of MgSO4 solution started 10 minutes after salbutamol administration. The investigator (LT) recording the data was unaware of the treatment given to each horse by use of mock IV catheters covered by neck bandages.

Lung function measurement

By use of an IOS, lung function measurement was performed on standing, unsedated horses as described by Van Erck et al.15 Each horse was trained to stand quietly in a stock and wear a mask, while keeping its head in a standardized position with the help of a handler. A loudspeaker generating multifrequency impulses was connected to the mask for 30 seconds. The response of the respiratory system was superimposed on the horse's spontaneous breathing and measured by use of a pneumotachograph and a pressure transducer. Data were processed with integrated data-acquisition and analysis softwaree,f; fast Fourier transform algorithms were used to compute resistance and reactance of the respiratory system at frequencies from 0.5 to 10 Hz (ie, 0.5, 0.7, 1, 2, 3, 5, 7, and 10 Hz). Resistance describes the resistive properties of the respiratory system, which are directly dependent on the airway diameter, and reactance describes the elastic and inertive properties of the airways.16,17 Ratios of resistances at different frequencies express the frequency dependence that changes between physiologic conditions and bronchospasm.18 The R5:R10 ratio was chosen for assessment because it can be used to identify bronchodilation in severely asthmatic horses.19 The system was calibrated before experiments 1 and 2. Recordings were obtained in duplicate and data with the best coherence were kept for analysis.

In experiment 1a, lung function was recorded before (0 minutes) and 30 minutes after administration of salbutamol and at similar time points during the mock inhalation procedure. In experiment 1b, lung function was recorded before commencement of the infusion of MgSO4 or saline solution (0 minutes), at the end of the infusion (20 minutes), and 10 minutes after the end of the infusion (30 minutes). In experiment 2, lung function was recorded before the administration of salbutamol (0 minutes), before the infusion of MgSO4 or saline solution (10 minutes), at the end of the infusion (30 minutes), and 10 minutes after the end of the infusion (40 minutes). In experiments 1b and 2, tidal volume was also recorded at the 0- and 30-minute time points.

Monitoring

For each experiment, each horse's heart rate, respiratory rate, attitude (quiet vs excited), sweating (present vs absent), and clinical scores were obtained at the time of IOS measurement by the same investigator (LT), who was unaware of each horse's treatment. For clinical scores, nasal flaring was scored as previously described20 from 1 to 4 as follows: 1 = no flaring, 2 = slight, occasional flaring of nostrils, 3 = moderate flaring of nostrils, and 4 = severe continuous flaring of nostrils. The abdominal component of breathing was scored from 1 to 4 as follows: 1 = no abdominal component, 2 = slight abdominal movement, 3 = moderate abdominal movement, and 4 = severe, marked abdominal movement. Nasal and abdominal scores were added to obtain a combined clinical score ranging from 2 to 8.

Statistic analysis

Values of R1, X1, R5:R10 ratio, heart and respiratory rates, tidal volume, and clinical scores were compared with a linear mixed model adapted to the repeated measures design with 2 crossover factors, namely time period (0- and 30-minute time points for experiment 1a; 0-, 20-, and 30-minute time points for experiment 1b; and 0-, 10-, 30-, and 40-minute time points for experiment 2) and treatment (mock or salbutamol inhalation for experiment 1a, saline or MgSO4 infusion for experiment 1b, and salbutamol inhalation alone or salbutamol inhalation and MgSO4 infusion for experiment 2). In the linear mixed model, horse identification, horse identification nested within time, and horse identification nested within treatment were treated as random factors and time, treatment, and the interaction between time and treatment were treated as fixed factors. The compound symmetry covariance structure was used for each random factor. A priori contrasts were used to compare pairs of means. Statistical analysis was performed with commercial software,g and the level of significance was set at a value of P ≤ 0.05. Unless mentioned otherwise, data are reported as mean ± SD. Adverse effects were recorded as being present or absent (sweating and change in attitude) and were too few to be analyzed statistically.

Results

Adverse reactions

One horse developed mild to moderate sweating at the end of the MgSO4 infusion in experiments 1b and 2. One horse undergoing the mock procedure in experiment 1a had an episode of excitement that prevented the duplicate lung function measurement recording at the 30-minute time point. No other adverse effects were observed in any horse during any part of the study.

Data distribution and crossover effect

On the basis of visual inspection of data and the robustness of the linear mixed model used, data were considered to be normally distributed. There was no significant crossover effect, except in experiment 1b wherein clinical scores were lower when horses received the MgSO4 infusion on the second day of treatment. Baseline (0-minute) resistance, reactance, and tidal volume values for 1 horse during the mock procedure in experiment 1a were excluded from analysis because of a technical problem. For this horse, the 0-minute values were calculated as the mean of the baseline values obtained for this horse during other parts of the experiments. One clinical score was missing for 1 horse at the 40-minute time point in experiment 2 (salbutamol inhalation alone).

Experiment 1a

In experiment 1a, data were obtained after all horses received salbutamol (800 μg) by inhalation or underwent a mock manipulation (no drug administration). Compared with findings at 0 minutes, there were significant decreases in R1 (P = 0.03) and in the R5:R10 ratio (P = 0.02) at 30 minutes after salbutamol administration (Figure 1) that were not reflected by changes in X1 or clinical scores. The difference in R1 at the 30-minute time point between salbutamol treatment and mock inhalation procedure was not significant (P = 0.06); similarly, differences in time-treatment interaction for R1 and the R5:R10 ratio were not significant (P = 0.05 and 0.07, respectively). There were no changes in lung function or clinical score between 0 and 30 minutes when horses underwent the mock inhalation procedure; furthermore, no change in heart rate or respiratory rate between 0 and 30 minutes (Table 1) was observed.

Figure 1—
Figure 1—

Values of R1 (A), R5:R10 ratio (B), X1 (C), and clinical scores (D) for 6 asthmatic horses that either were administered salbutamol (800 μg) by inhalation via an aerosol chamber and mask or underwent a mock manipulation with the same equipment in a crossover design experiment with a 48-hour washout period (experiment 1a). Lung function data were obtained by use of an IOS before (0 minutes [T0]) and 30 minutes (T30) after administration of salbutamol and at similar time points during the mock inhalation procedure. Baseline R1 and X1 values for 1 horse during the mock procedure were excluded from analysis because of a technical problem and replaced by the mean of the baseline values obtained for this horse during the other experiments. Clinical variables were assessed at the times of IOS measurement. For clinical scores, nasal flaring was scored as 1 to 4 as follows: 1 = no flaring, 2 = slight, occasional flaring of nostrils, 3 = moderate flaring of nostrils, and 4 = severe continuous flaring of nostrils. The abdominal component of breathing was scored from 1 to 4 as follows: 1 = no abdominal component, 2 = slight abdominal movement, 3 = moderate abdominal movement, and 4 = severe, marked abdominal movement. Nasal and abdominal scores from 1 to 4 were summed to obtain a combined clinical score ranging from 2 to 8. *Mean values at the 2 time points differ significantly (P < 0.05).

Citation: American Journal of Veterinary Research 79, 6; 10.2460/ajvr.79.6.664

Experiment 1b

In experiment 1b, data were obtained after all horses received each of 2 treatments: infusion of MgSO4 solution or infusion of an equivalent volume of saline solution. When horses received the saline infusion, mean values of R1, R5:R10 ratio, and X1 at 0, 20, and 30 minutes and clinical score at 0 and 30 minutes did not differ significantly (Figure 2). Following MgSO4 infusion, there was a significant (P = 0.03) decrease in clinical score at 30 minutes, compared with findings at 0 minutes, but this was not reflected by corresponding improvement in IOS variables. Regardless of whether horses received the infusion of MgSO4 or saline solution, no changes in heart rate, respiratory rate, or tidal volume were observed at 30 minutes, compared with findings at 0 minutes (Table 1). However, when horses received the infusion of MgSO4 or saline solution, there were differences in R1 (P = 0.03) and X1 (P = 0.02) at baseline (0 minutes), which made comparisons between the treatments difficult.

Figure 2—
Figure 2—

Values of R1 (A), R5:R10 ratio (B), X1 (C), and clinical scores (D) for 6 asthmatic horses that were administered either an infusion of MgSO4 solution at a rate of 2.2 mg/kg/min for 20 minutes or an equivalent volume of saline (0.9% NaCl) solution adjusted to the same osmolarity in a crossover design experiment with a 48-hour washout period (experiment 1b). Salbutamol administration (experiment 1a) took place later in the same day that horses received the saline solution treatment. Lung function data were obtained by use of an IOS before (0 minutes [T0]) commencement of the infusion (hatched rectangles) of MgSO4 or saline solution, at the end of the infusion (20 minutes [T20]), and 10 minutes after the end of the infusion (30 minutes [T30]). Clinical variables were assessed at the times of IOS measurement. For each data set, the horizontal bar represents the mean. *Mean values at the 2 time points differ significantly (P < 0.05). For a given variable, the baseline (0-minute) value when horses received the MgSO4 infusion was significantly (P < 0.05) different from that when the horses received the saline infusion. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 79, 6; 10.2460/ajvr.79.6.664

Table 1—

Mean ± SD heart rate, respiratory rate, and tidal volume for 6 asthmatic horses studied to evaluate bronchospasm reversibility achieved by inhalation of administration of salbutamol and administration of an infusion of MgSO4 solution.

 Experiment 1aExperiment 1b
 Mock inhalation procedureSalbutamol inhalationInfusion of saline solutionInfusion of MgSO4 solution
VariableT0T30T0T30T0T30T0T30
Heart rate (beats/min)37.3 ± 9.336.7 ± 4.738.0 ± 9.040.7 ± 12.546.0 ± 14.5   
Respiratory rate (thoracic movements/min)24.7 ± 3.924.7 ± 6.926.0 ± 3.328.0 ± 6.227.3 ± 3.3   
Tidal volume (L)4.2 ± 15.2 ± 1.64.5 ± 0.84.9 ± 1.54.7 ± 0.8   

In experiment 1a, horses either were administered salbutamol (800 mg) by inhalation via an aerosol chamber and mask or underwent a mock manipulation with the same equipment in a crossover design experiment with a 48-hour washout period. In experiment 1b, the horses were administered either an infusion of MgSO4 solution at a rate of 2.2 mg/kg/min for 20 minutes or an equivalent volume of saline (0.9% NaCl) solution adjusted to the same osmolarity in a crossover design experiment with a 48-hour washout period. Salbutamol administration (experiment 1a) took place later in the same day that horses received the saline solution treatment. Lung function data were obtained by use of an IOS. In experiment 1a, assessments were made before (0 minutes [T0]) and 30 minutes (T30) after administration of salbutamol and at similar time points during the mock procedure. In experiment 1b, assessments were made before (0 minutes [T0]) commencement of the infusion of MgSO4 or saline solution, at the end of the infusion (20 minutes [data not shown]), and 10 minutes after the end of the infusion (30 minutes [T30]). Baseline tidal volume values for 1 horse during the mock procedure were excluded from analysis because of a technical problem and replaced by the mean of the baseline values obtained for this horse during the other experiment.

Experiment 2

In experiment 2, data were obtained after all horses received salbutamol inhalation and then an infusion of MgSO4 solution or no additional treatment. When horses received salbutamol alone at 0 minutes, there was a significant decrease in R1 at 30 minutes (P = 0.04), an increase in X1 at 10 and 30 minutes (P = 0.03 and P = 0.03 respectively), and a decrease in clinical score at 10 minutes (P = 0.007; Figure 3). The mean ± SD heart rate at 30 minutes (47.3 ± 12.7 beats/min) was significantly (P = 0.01) greater than that at 0 minutes (36.7 ± 9.6 beats/min). Between 0 and 30 minutes, no changes in respiratory rate or tidal volume were observed (Figure 4).

Figure 3—
Figure 3—

Values of R1 (A), R5:R10 ratio (B), X1 (C), and clinical scores (D) for 6 asthmatic horses that were administered 800 μg of salbutamol via inhalation followed by either MgSO4 solution at a rate of 2.2 mg/kg/min for 20 minutes or no additional treatment in a crossover design with a 24-hour washout period (experiment 2). Infusion of MgSO4 solution started 10 minutes after salbutamol administration. Lung function data were obtained by use of an IOS before the administration of salbutamol (0 minutes [T0]), before commencement of the infusion of MgSO4 (hatched rectangles) or at 10 minutes after salbutamol administration (T10), at the end of the infusion or at 30 minutes after salbutamol administration (T30), and 10 minutes after the end of the infusion or at 40 minutes after salbutamol administration (T40). Clinical variables were assessed at the times of IOS measurement. One clinical score was missing for 1 horse at the 40-minute time point in experiment 2 (salbutamol inhalation alone). *Mean values marked by ends of a bar are significantly (P < 0.05) different. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 79, 6; 10.2460/ajvr.79.6.664

Figure 4—
Figure 4—

Respiratory rate (A) and tidal volume (B) for the 6 horses in experiment 2 before the administration of salbutamol (0 minutes [T0]) and at the end of the MgSO4 infusion or at 30 minutes after salbutamol administration (T30). *Mean values at the 2 time points differ significantly (P < 0.05). See Figure 3 for remainder of key.

Citation: American Journal of Veterinary Research 79, 6; 10.2460/ajvr.79.6.664

When salbutamol and MgSO4 solution were administered, the horses' clinical scores were significantly decreased at 30 and 40 minutes (P = 0.04 and P = 0.01 respectively), compared with findings at 0 minutes. Although the R5:R10 ratio at 30 and 40 minutes was less than that at 0 minutes, the differences were not significant (P = 0.06 and P = 0.08, respectively). Heart rate at 0 minutes (39.3 ± 13.2 beats/min) and 30 minutes (42.0 ± 9.0 beats/min) did not differ significantly. Between 0 and 30 minutes, no changes in respiratory rate were observed (Figure 4), but tidal volume was significantly (P = 0.04) increased at 30 minutes, compared with the finding at 0 minutes.

Discussion

In the present study, the IOS detected bronchodilator effects of inhaled salbutamol in horses during both experiments 1a (salbutamol inhalation vs mock procedure) and 2 (infusion of MgSO4 solution and inhalation of salbutamol vs salbutamol inhalation alone), but infusion of MgSO4 solution (alone or in combination with inhaled salbutamol) failed to significantly improve lung function as measured by the IOS. Conversely, infusion of MgSO4 solution improved the clinical scores in both experiments 1b (infusion of MgSO4 solution vs infusion of saline solution) and 2, which was associated with an increase in tidal volume in experiment 2. These results suggested that the clinical score changes following MgSO4 infusion may be attributable to mechanisms other than bronchodilation. For example, MgSO4 solution could improve ventilation-perfusion mismatch or decrease pulmonary vascular resistance and hypoxemia (through its effects on blood pressure and prostaglandin I221,22). These changes could modify their breathing pattern, leading to improved clinical scores without affecting the measured resistance and reactance. Pulmonary vascular resistance was not measured in the horses of the present study, but it has been noted that hypoxemia in horses is improved by MgSO4 infusion.a Magnesium sulfate also has some effects on skeletal muscle tone,23 and a decrease in abdominal, intercostal, or diaphragmatic muscle tone could be in part responsible for the clinical score improvement observed in the horses of the present study. Magnesium sulfate also has analgesic and mild sedative or calming effects in human patients,9,24,25 and magnesium aspartate has sedative effects in horses26; such effects could have also altered the scores. Regardless of the underlying explanation, an improvement in clinical score alone should not be sufficient to support the use of a new medication, especially as it may not reflect a bronchodilator effect or how the patient perceives its own breathing limitation. Interestingly, when the Borg dyspnea scale (a subjective assessment by the patient) was used by people with asthma, IV administration of MgSO4 solution did not ease breathing comfort.27–29 Finally, in the present study, clinical score improvement was often small (from 1 to 3 grades), and some horses remained with a clinical score of 5 or greater, suggesting that marked respiratory limitation persisted despite treatment.20

For the present study, the IOS was chosen over the conventional esophageal balloon technique because of its recording rapidity and potentially increased sensitivity.30,31 However, in both experiments (1b and 2), MgSO4 infusion improved clinical scores without concurrent improvement of measured lung mechanics, which raises some questions. As mentioned, this could have been a result of a change in other physiologic variables without bronchodilatory effects, but it could also have been a result of a lower than expected sensitivity of the lung function measurement method. In human medicine, results of impulse oscillometry are correlated with clinical signs of asthma32 and have good correlation with spirometry findings33; an IOS can detect effects of inhaled bronchodilators, such as salbutamol. An IOS has been validated to detect changes in lung mechanics in mildly and severely asthmatic horses.15,30,31 The IOS is sufficiently sensitive to detect the bronchodilator effects of ipratropium bromide given by inhalation30 or buscopan given IV19 and can detect subclinical airway obstructions in severely asthmatic horses that are in clinical disease remission.30 The IOS data also correlate with airway remodeling.19 Despite the apparent low sensitivity for detection of changes in lung function in the present study, the IOS used was nevertheless able to detect the bronchodilator effects of salbutamol in experiments 1a and 2. It should be noted that clinical scores were recorded for the study horses when the mask required for IOS recording was not in place; the mask is designed to offer little resistance to air movement, but could still increase resistance or change the breathing pattern. Finally, tidal volume was recorded and increased following MgSO4 infusion and salbutamol administration in experiment 2, without changes in lung mechanics. In severely asthmatic horses, results of previous studies20,34,35 are conflicting and tidal volume is not always correlated with lung resistance, which could explain a change in breathing pattern and clinical scores without improvement in airway resistance.

The lack of significant improvement in resistance and reactance following MgSO4 infusion in the present study could have been a result of administration of a subtherapeutic dose. The dose of MgSO4 used (2.2 mg/kg/min delivered over a 20-minute period [total dose, 44 mg/kg]) was extrapolated from the bronchodilator dose used in human medicine and is known to be effective for the treatment of ventricular tachycardia in horses. Although a dose-dependent effect of MgSO4 on bronchospasm in severely asthmatic horses has been reported,a this has not been consistently observed in people. Okayama et al9 found a dose-dependent effect of MgSO4 infusion in humans, whereas others concluded that the effect of 75 mg of MgSO4/kg (total dose) is not superior to the effect of 25 mg of MgSO4/kg.36 Nevertheless, increasing the dose of MgSO4 or prolonging infusion until effects are seen warrants future investigation. Of note, monitoring the serum magnesium concentration was not performed in the horses of the present study because serum concentration of magnesium (a mostly intracellular ion) poorly correlates to intracellular concentration10 and does not correlate to its bronchodilator effects.29

In the present study, the effects of salbutamol administration on lung mechanics indicated that bronchospasm was reversible in the severely asthmatic study horses and validated the interpretation of results with MgSO4 infusion. In addition, these results indicated that a total dose of 800 μg of salbutamol given by nebulization would result only in a moderate bronchodilation in an asthma crisis.6 Bronchodilators can have cumulative effects,30 and repeated administration of salbutamol could perhaps have induced more marked changes in resistance and reactance but would have made comparison of experimental findings difficult. In asthmatic children, the combination of MgSO4 and salbutamol has greater effects than those of either drug alone,13 and although we did not observe a greater decrease in clinical score when MgSO4 infusion was combined with salbutamol inhalation, the improvement in clinical scores was somewhat delayed yet lasted longer. The loss of improvement in R1 and X1 when horses received the MgSO4-salbutamol combined treatment (experiment 2) could be interpreted as an antagonistic effect, but the nonsignificant pattern of decrease in the R5:R10 ratio following that treatment suggested otherwise, and such antagonism has not been reported in the veterinary medical literature, to our knowledge.

Recently, bronchodilator effects of IV administration of MgSO4 solution in horses with severe asthma (summer-pasture form) were reported.a Those results contrasted with results of the present report, but the populations studied and the methods of detection (conventional pulmonary mechanics vs IOS measurements) differed between the 2 studies. It is unclear why MgSO4 infusion appeared to have been less effective in the horses of present study; in addition to the possible lack of sensitivity of the IOS, one should consider the possibility that the horses with summer-pasture–associated asthma were more acutely affected or that their degree of bronchospasm was more pronounced (compared with the other causes of airflow limitation in asthma). In humans with asthma, the bronchodilator effects of MgSO4 infusion are more marked in severely affected patients27,29; few of the horses of the present study had a clinical score of 7 or 8 at baseline in any of the experiments.

Other possible confounding factors were the differences in baseline R1 and X1 when horses received saline solution IV versus when they received MgSO4 solution IV (experiment 1b). Despite random assignment of treatments and the lack of management modification during the study, the perceived ambient temperature and relative humidity (67% vs 77%) were higher during the second part of the crossover experiment, which could have contributed to worsening of the clinical signs.37 At the 0-minute time point when horses received the MgSO4 infusion, R1 was decreased and X1 was increased, compared with the values at that time point when horses received the saline solution infusion (Figure 2), which suggested decreased bronchospasm in the horses when they were treated with MgSO4 solution and consequently less likelihood of detecting improvement after MgSO4 infusion. However, no change in lung function variables could be attributed to MgSO4 solution administration in experiment 2, during which weather conditions were stable and there were no differences in baseline R1 and X1 between treatment groups.

Overall, infusion of MgSO4 solution alone or in combination with inhalation of salbutamol had a mild positive effect on clinical scores (reflecting the extent of nasal flaring and the abdominal component of breathing) in the severely asthmatic horses of the present study. This effect could have been attributable to an undetected bronchodilatory effect or a change in the breathing strategy, as indicated by the increased tidal volume following MgSO4 infusion.

Acknowledgments

Supported by the Fonds en santé équine de l'Université de Montréal, Zoetis, and the Fonds du Centenaire. Funding sources did not have any involvement in the study design, data analysis and interpretation, or writing and publication of the manuscript. The authors declare that there were no conflicts of interest.

Presented as a poster at the 35th Annual American College of Veterinary Internal Medicine Forum, National Harbor, Md, June 2017.

The authors thank Guy Beauchamp for assistance with statistical analysis.

ABBREVIATIONS

IOS

Impulse oscillometry system

R1

Resistance at 1 Hz

R5:R10

Resistance at 5 Hz to resistance at 10 Hz

X1

Reactance at 1 Hz

Footnotes

a.

Bowser J, Wenzel C, Wills R, et al. Intravenous magnesium sulfate as a rescue therapeutic for bronchoconstriction in horses (abstr), in Proceedings. 34th Annu Am Coll Vet Intern Med Forum 2016;703.

b.

Ventolin HFA, GlaxoSmithKline Inc, Mississauga, ON, Canada.

c.

AeroHippus Equine Aerosol Chamber, Trudel Medical International, London, ON, Canada.

d.

Gentes and Bolduc Pharmacy, St-Hyacinthe, QC, Canada.

e.

Equine MasterScreen IOS system, LabManager version 4.53, Jaeger, Würzburg, Germany.

f.

FAMOS, imc Meßsysteme, Berlin, Germany.

g.

SAS, version 9.1, SAS Institute Inc, Cary, NC.

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Contributor Notes

Dr. Tanquerel's present address is the Centre Hospitalier Vétérinaire Équin de Livet, Cour Samson, 14140 St-Michel-de-Livet, France.

Address correspondence to Dr. Leclere (mathilde.leclere@umontreal.ca).