Midazolam reverses histamine-induced bronchoconstriction in dogs

Purpose

Midazolam has been used clinically as a sedative and as an anaesthetic induction agent. However, the bronchodilating effects of midazolam have not been comprehensively evaluated. We sought to determine relaxant effects of midazolam on the airway.

Methods

After our Animal Care Committee approved the study, eight mongrel dogs were anaesthetized with 30 mg · kg^?1 pentobarbitoneiv, and were paralysed with 200 μg · kg^?1 · hr^?1 pancuronium. The trachea was intubated with an endotracheal tube (ID 7 mm) that had a second lumen for insertion of a superfine fibreoptic bronchoscope (OD 2.2 mm) to measure the bronchial cross-sectional area (BCA) continuously. The tip of the bronchoscope was placed at the level of the second or third bronchial bifurcation of the nght bronchus. A videopnnter printed the BCA which was then measured with a NIH Image program. Bronchoconstnction was produced with histamine (H) 10 μg · kg^?1 followed by 500 μg · kg^?1 · hr^?1. Thirty minutes later, 0 [saline], 0.01, 0.1 and 1.0 mg · kg^?1 midazolam and 25 μg · kg^?1 flumazenil were given. The BCA was assessed before (basal area) and 30 min after the start of H infusion, and was also measured five minutes after each midazolam and flumazeniliv. At the same time, arterial blood was sampled for plasma catecholamine measurement.

Results

Histamine infusion decreased BCA to 49.7 ± 17.3% of basal BCA More than 0.1 mg · kg^?1 midazolam increased BCA up to 71.7 ± 15.3% of the basal (1.0 mg · kg^?1) (P < 0.01). Plasma adrenaline concentration was decreased from 6.9 ± 3.8 to 3.7 ± 1.9 ng · ml^?1 by 1.0 mg · kg^?1 midazolam (P < 0.05). Flumazenil did not antagonize the relaxant effect of midazolam but reversed the inhibitory effect of midazolam on histamine-induced adrenaline release.

Conclusion

Midazolam has a spasmolytic effect on constricted airways but this bronchodilatation was not reversed by flumazenil.     

I.v. lidocaine worsens histamine-induced bronchoconstriction in dogs

We have assessed the effect of lidocaine (lignocaine) on histamine- induced bronchoconstriction by direct visualization with a superfine fibreoptic bronchoscope. Seven mongrel dogs were anaesthetized with pentobarbital (pentobarbitone) 30 mg kg-1 followed by 2 mg kg-1 h-1 and pancuronium 200 micrograms kg-1 h-1. The trachea was intubated with a tracheal tube containing a second lumen for insertion of a 2.2-mm fibreoptic bronchoscope. This allowed estimation of the bronchial cross- sectional area (BCA) of the third bronchial bifurcation of the right lung. We used NIH image, a public domain image processing and analysis program. Bronchoconstriction was produced with a bolus dose of histamine 10 micrograms kg-1 i.v. followed by continuous infusion of 500 micrograms kg-1 h-1. After 30 min the following i.v. doses of lidocaine were given: lidocaine 0 (saline), 0.01, 0.1, 1.0 and 10 mg kg- 1 at 10-min intervals. BCA was assessed 90 s after each dose. Arterial blood sampling was performed for measurement of plasma catecholamines. Lidocaine 1.0 and 10 mg kg-1 significantly reduced histamine-decreased BCA from 69.7 (SEM 4.1)% to 59.8 (7.3)% and 34.3 (6.8)%, respectively. Plasma concentrations of catecholamines decreased significantly after lidocaine 10 mg kg-1 i.v. In addition, there was a significant correlation between percentage decreases in plasma concentrations of epinephrine (adrenaline) and norepinephrine (noradrenaline) and reduction in %BCA (epinephrine-BCA, P < 0.01, r = 0.674; norepinephrine- BCA, P < 0.01, r = 0.510). This study suggests that i.v. lidocaine may exacerbate histamine-induced bronchoconstriction by a sympatholytic effect. This may have therapeutic implications for patients with acute asthma or anaphylactic shock who may become dependent on circulating catecholamines.      

Effect of phenylephrine on histamine-induced bronchoconstriction in dogs

Purpose Although an α-adrenoceptor has been suggested to be involved in the mechanism of asthma, the effect of α₁-agonist on the airway is still unclear. In this study we evaluated the effect of phenylephrine on the airway with a direct visualization method using a superfine fiberoptic bronchoscope (SFB). Methods Seven mongrel dogs were anesthetized with pentobarbital (30 mg·kg⁻¹ IV) and paralyzed by pancuronium (0.2mg·kg⁻¹·h⁻¹). The trachea was intubated with an endotracheal tube (ID 7 mm) that has a second lumen for insertion of a SFB (OD 2.2 mm) to monitor the bronchial cross-sectional area (BCA) continuously. The tip of a SFB was placed at the level between the second and third bronchial bifurcation. To assess hemodynamics, the direct arterial blood pressure (ABP) and pulmonary arterial pressure (PAP) were monitored via a femoral arterial catheter and Swan-Granz catheter. Bronchoconstriction was elicited by histamine (10 μg·kg⁻¹+ 500 μg·kg⁻¹·h⁻¹_. At 30 min after the histamine was started, saline or phenylephrine (1, 10, and 100μg·kg⁻¹) was given intravenously. The BCA and hemodynamic variables were assessed before (basal) and 30 min after the histamine was started and 5 min after saline and each phenylephrine dose. Results Histamine reduced BCA by 40.3±6.3%. Phenylephrine at 10 and 100 μg·kg⁻¹ significantly increased the ABP and PAP; and it significantly decreased the BCA, by 6.5±6.9% and 14.2±7.9%, respectively. Plasma epinephrine and norepinephrine were also significantly reduced following phenylephrine 100 μg·kg⁻¹ IV. Conclusion The dose of phenylephrine that produced vasopressive actions worsened the histamine-induced bronchoconstriction slightly but significantly. Therefore, phenylephrine should be used with caution in asthmatic patients.     

Histamine induced bronchoconstriction and end tidal inspiratory activity in man.

BACKGROUND: End tidal inspiratory activity (ETIA) in diaphragm and parasternal intercostal muscles can be evoked in man and in animals by administration of histamine. Exacerbations of asthma and administration of histamine are often accompanied by hyperinflation. The aims of the study were to determine (1) the magnitude of ETIA in response to histamine in man, (2) the relative contributions of chemical and mechanical stimulation of airway receptors to ETIA, and (3) the importance of ETIA to hyperinflation. METHODS: The effects of inhalation of histamine on the electrical activities of the diaphragm and parasternal intercostal muscles measured with surface electrodes were studied in 21 subjects. The experiments were repeated after inhalation of 600 micrograms of salbutamol to prevent histamine induced bronchoconstriction and concomitant mechanical stimulation of airway receptors. Subjects were connected to a closed breathing circuit to measure the changes in functional residual capacity (FRC) for the different experiments. RESULTS: The mean values of histamine induced ETIA were 60.6% and 46.9% of peak inspiratory activities during control conditions for the diaphragm and intercostal muscles, respectively. After salbutamol histamine induced ETIA was reduced to about one quarter of pre-salbutamol values. FRC increased by 427 ml as a result of inhalation of histamine, but after salbutamol this increase was only 53 ml. The data for ETIA and FRC were interpreted as indicating that the contributions of airflow limitation and ETIA to histamine induced hyperinflation are comparable. CONCLUSIONS: Histamine is a forceful stimulus for inducing ETIA. Both chemical and mechanical stimulation of airway receptors contribute to evoke ETIA, of which the contribution of mechanical stimulation is the more important one. ETIA contributes substantially to histamine induced hyperinflation.     

Peak expiratory flow at altitude.

The mini Wright peak flow meter is a useful, portable instrument for field studies but being sensitive to air density will under-read at altitude. True peak expiratory flow will increase at altitude, however, because of the decreased air density, given that dynamic resistance is unchanged. The effect of simulated altitude on peak expiratory flow (PEF) was determined in six subjects with both the mini Wright meter and a volumetric spirometer (which is unaffected by air density). With increasing altitude PEF as measured by the spirometer increased linearly with decreasing pressure, so that at a barometric pressure of 380 mm Hg* (half an atmosphere, corresponding to an altitude of 5455 m) there was a 20% increase over sea level values. The mini Wright flow meter gave readings 6% below sea level values for this altitude--that is, under-reading by 26%. Measurements of PEF made at altitude with the mini Wright meter should be corrected by adding 6.6% per 100 mm Hg drop in barometric pressure.     

Tidal expiratory flow patterns in airflow obstruction.

Tidal expiratory flow pattern was analysed in 99 subjects with a view to assessing it as a quantitative measurement of airflow obstruction. Fifteen normal volunteers, nine patients with dyspnoea referred for investigation in whom airway resistance was within normal limits, 24 patients with restrictive lung disorders, and 51 patients with airway obstruction were studied. The expiratory flow pattern against time had a quadrilateral configuration in airway obstruction, which differed from the more sinusoidal form that is seen in subjects without airflow obstruction. The rapid rise to tidal peak flow was analysed in two ways, percentage of volume expired at tidal peak flow (delta V/V) and percentage of expiratory time to tidal peak flow (delta t/t). Both these indices correlated significantly with conventional measurements of airway obstruction. The pattern of expiratory flow in airflow obstruction during quiet breathing resembles that of a forced expiratory maneuver at similar lung volumes. In some cases this may be caused by dynamic compression occurring during tidal breathing. In others, the pattern may result from the static recoil of the lung being permitted to drive flow freely in expiration, rather than being braked by postinspiratory contraction of inspiratory musculature.     

Modulation of histamine-induced bronchoconstriction with inhaled, oral, and intravenous clemastine in normal and asthmatic subjects.

Although histamine plays an important role in the pathophysiology of asthma through stimulation of H1 receptors, H1 antagonists are of only limited use in this disease when given orally. In order to investigate the pharmacological response to a specific H1 antagonist administered by different routes, we measured the effect of inhaled clemastine on airway responsiveness to histamine aerosol and compared the results with those after oral and intravenous administration in normal and asthmatic subjects. Inhalation of 0.6 mg clemastine provided significant protection without side effects and was comparable to intravenous administration of 1.0 mg in both groups. In normal subjects 2.0 mg clemastine orally was significantly less effective than the two other routes of administration whereas in asthmatics an enhanced reaction to histamine was observed.     

Factors influencing peak expiratory flow in teenage boys.

BACKGROUND: Peak expiratory flow (PEF) is a useful measure of pulmonary health status and is frequently utilised in asthma management. Reduction in PEF is usually indicative of onset of asthma symptoms. However, use can be made of PEF values only if normal values are known. The definition of normal range is always difficult and may vary between regions and be affected by a variety of factors. OBJECTIVE: To establish PEF values for teenage boys in a Cape Town suburb and examine factors that possibly influence this measurement. SETTING: A high school for boys in the southern suburbs of Cape Town. METHODS: Measurements of PEF were taken for 124 boys. Subjects were approximately 16 years old and apparently healthy at the time of survey. Further details were provided by means of a questionnaire. RESULTS: PEF ranged from 350 to 760 l/min, with a mean (+/- standard deviation (SD)) of 539 +/- 68 l/min. Factors expected to influence PEF included height and mass, whereas unexpected factors included sport intensity and academic grade. A trend to reduced peak flow was already evident in boys who smoked and boys from homes where a parent smoked. Regression analysis suggested peak flow differences in our population compared with the standard reference. CONCLUSION: Interpretation of results obtained from peak-flow instruments should take into account additional knowledge concerning the individual. Further surveys of the South African population and of different groups should be done to establish local standards and factors influencing PEF.     

Forced expiratory volume and expiratory flow rate in Black miners and in a control group.

The peak expiratory flow rate and the forced expiratory volume and 1 second were measured in 772 Black miners who did not have pneumoconiosis, tuberculosis or chronic bronchitis. The same tests were done in 164 non-mining workers. It was found that exposure to dust associated with the miners' work had no effect on the results of these tests.     

Intrasubject variability of maximal expiratory flow volume curve.

Analysis of airflow in the terminal portion of the maximal expiratory flow volume curve has been suggested as a useful test for the early diagnosis of chronic airways obstruction. Whether such an analysis can identify early disease, and whether any subsequent action can prevent the progress of chronic airways obstruction, is unknown and will require prospective studies. As a precursor of such a study we have tried to establish the intrasubject variability of those tests of forced expiration which may be used for screening. We therefore measured expiratory flow volume curves of five healthy males and five healthy females aged 20-30 years as this is an age-group in which early detection of airways obstruction may be of value. Flow volume curves were obtained on the same day of the week for six weeks, and on three separate days during this period we carried out three flow volume curves every hour from 9 am to 6 pm. The data were subjected to analysis of variance to determine the variability of each measurement. Data were collected from forced expired volume in one second (FEV1) forced vital capacity (FVC), maximum expiratory flow rates at 50% and 75% of expired vital capacity, and forced expiratory time (FET). The results showed no consistent pattern of diurnal variation over the working day. The variation in any subject for FEV1 and FVC over the study period was considerably less than variations detected in the maximal expiratory flow rates at 50% and 75% of the expired vital capacity and FET. Our results suggest that the intrasubject variation found in flow rates of the terminal portion of the maximal expiratory flow volume curve and forced expiratory time may limit the usefulness of these tests in detecting early airways obstruction. FEV1 and FVC are more reproducible tests and are therefore particularly suited for cross-sectional screening. The more sensitive maximal expiratory flow volume curve may, however, be more useful for long-term studies in individuals when the onset of disease is sought, or for short-term challenge studies requiring the most sensitive index of change in airway characteristics.     

Peak expiratory flow in the detection of retrosternal goitre

In 24 patients where the lower border of a cervical goitre was poorly defined, the value of simple lung function tests in the prediction of the presence of a retrosternal goitre was assessed. At operation there were nine patients with retrosternal extension (Group I) and 15 without (Group II). The preoperative PEF ratio (observed to predicted) was significantly different between the two groups (P = 0.004) with a positive predictive value of 90% for a retrosternal goitre. This difference was abolished after thyroidectomy. There was a significant improvement in PEF in patients with retrosternal goitres after thyroidectomy (P less than 0.001). It is concluded that the preoperative measurement of PEF is a simple method of detecting the retrosternal extension of a cervical goitre.     

Quantitative versus qualitative analysis of peak expiratory flow in occupational asthma.

BACKGROUND: Peak expiratory flow rates (PEF) are often used to confirm the diagnosis of occupational asthma. The records are usually analysed qualitatively, and this may lead to interobserver disagreement. In this study the diagnostic value of a qualitative assessment of change in PEF was compared with objective measures of change in PEF and the results of a specific inhalation challenge test with plicatic acid. METHODS: Twenty five patients with possible red cedar asthma recorded PEF six times a day for three weeks at work and for two weeks away from work and underwent a challenge test with plicatic acid at the end of the recording period. Patients were considered to have cedar asthma if the FEV1 after inhalation of plicatic acid was 15% or more below that on the control day. PEF was plotted against time and assessed qualitatively by three physicians. The graph was considered positive for cedar asthma if two of the three physicians agreed that PEF was lower at work than away from work. The 95% confidence interval for variation in PEF between periods at work and away from work was also obtained from 15 asthmatic patients without occupational asthma. Differences in PEF between periods at work and away from work were considered positive for occupational asthma in the patients exposed to cedar when they were outside the 95% confidence interval for variations in PEF in the 15 patients whose asthma was nonoccupational. RESULTS: Of the 25 men studied, 15 had a positive response to plicatic acid. The qualitative PEF analysis had a sensitivity of 87% and a specificity of 90% in confirming red cedar asthma as diagnosed by the specific challenge test. Among the objective methods tested, only the difference in mean PEF between the maximum PEF at weekends and the minimum PEF on working days had a sensitivity (93%) greater than that of the qualitative method and a similar specificity. CONCLUSIONS: The qualitative assessment of PEF is a good diagnostic test for cedar asthma. Only one objective method of PEF analysis proved to be slightly more sensitive than the qualitative method and similar in specificity.     

Circadian rhythm of peak expiratory flow in asthmatic and normal children.

A study was undertaken to examine the circadian rhythm of peak flow rate in asthmatic and normal children in the community by means of cosinor analysis. An initial study of 12 matched pairs of asthmatic and normal children was used to determine the mean amplitude of peak expiratory flow (PEF) variability in the two groups (7.8% and 4.4%) and the number of subjects required to show a significant difference. On the basis of this study 37 community based children with asthma diagnosed by questionnaire and 40 control subjects measured PEF four times daily for 14 days. Cosinor analysis of the data produced a significant fit in 20 asthmatic and 18 control children. A small but significant difference in amplitude was observed between the asthmatic (6.2%) and the control (4.2%) children. There was no significant phase difference between the rhythms in the two groups. Cosinor analysis explained 14% of PEF variance. It did not provide a reproducible estimate of phase between week 1 and week 2; the acrophase changed by more than one hour in 26 of 37 asthmatic children. The cosinor model may be inappropriate for the investigation of low amplitude circadian rhythms, especially when measurements are made infrequently.     

Peak expiratory flow in rural residents of Tamil Nadu, India.

BACKGROUND: In a country such as India that covers several latitudes, climatic zones, ethnic groups, and dietary habits lung function within the normal population would be expected to vary. Several studies have looked at normal values of peak expiratory flow (PEF) in different regions of urban India but none has looked at rural South India. A study of PEF has now been carried out in a rural population of Tamil Nadu. METHODS: All subjects were of Dravidian stock and lived at sea level with rice as their staple food. Ten five year age groups from 10 to 59 years with 100 males and 100 females in each were studied. Peak flow was measured by mini-Wright peak flow meter, and height was also measured. Regression equations for predicting normal PEF were calculated. RESULTS: Peak flow ranged from 150 to 680 l/min in males and from 150 to 500 l/min in females. Maximum values of PEF were attained at the age of 32.5 years in men and 35.6 years in women. There was a significant linear correlation between height and PEF and a curvilinear relation between age and PEF in both sexes. CONCLUSION: Regression equations are now available for PEF values in normal subjects from rural South India. PEF was related to age and height and values were greatest in the fourth decade.     

Factors determining maximum inspiratory flow and maximum expiratory flow of the lung

The factors determining maximum expiratory flow and maximum inspiratory flow of the lung are reviewed with particular reference to a model which compares the lung on forced expiration to a Starling resistor. The theoretical significance of the slope of the expiratory maximum flow-volume curve is discussed. A method of comparing maximum expiratory flow with maximum inspiratory flow at similar lung volumes is suggested; this may be applied either to a maximum flow-volume curve or to a forced expiratory and inspiratory spirogram.     

The effects of positive expiratory pressure on peritoneovenous shunt flow.

Cirrhotic patients with peritoneovenous shunts may require mechanical ventilation. Despite the importance of flow to shunt patency and the relevance of intrathoracic pressure to that flow, the relationship between shunt flow and positive airway pressure has not been documented. To study the effects of positive expiratory pressure (PEEP) on shunt flow, models of ascites (n = 8) were created in adult male mongrel dogs. Each animal was anesthetized, intubated, and mechanically ventilated. Peritoneovenous shunts with in-line electromagnetic flow meters were surgically placed. Shunt flow, central venous pressure (CVP), and intraabdominal pressure (IAP) were monitored. Initial intraabdominal pressures were adjusted by infusion of warmed saline and positive expiratory airway pressures were added in increments. Changes in pressures (IAP, CVP) and shunt flow were tabulated and analyzed with linear and polynomial regression. Intraabdominal and central venous pressures increased linearly with PEEP at different rates such that IAP-CVP varied inversely with PEEP. Shunt flow varied inversely as a polynomial function of PEEP. Analyses of these relationships allowed creation of a nomogram which can be interpolated to indicate required intraabdominal pressure needed to maintain shunt flow throughout the clinically useful range of positive airway pressure.     

Validity of peak expiratory flow measurement in assessing reversibility of airflow obstruction.

BACKGROUND: Assessing the reversibility of airflow obstruction by peak expiratory (PEF) measurements would be practicable in general practice, but its usefulness has not been investigated. METHODS: PEF measurements were performed (miniWright peak flow meter) in 73 general practice patients (aged 40 to 84) with a history of asthma or chronic obstructive lung disease before and after 400 micrograms inhaled sulbutamol. The change in PEF was compared with the change in forced expiratory volume in one second (FEV1). Reversible airflow obstruction was analysed in two ways according to previous criteria. When defined as a 9% or greater increase in FEV1 expressed as a percentage of predicted values reversibility was observed in 42% of patients. Relative operating characteristic analysis showed that an absolute improvement in PEF of 60 l/min or more gave optimal discrimination between patients with reversible and irreversible airflow obstruction (the sensitivity and specificity of an increase of 60 l/min in detecting a 9% or more increase in FEV1 as a percentage of predicted values were 68% and 93% respectively, with a positive predictive value of 87%). When defined as an increase of 190 ml or more in FEV1, reversible airflow obstruction was observed in 53% of patients. Again an absolute improvement in PEF of 60 l/min or more gave optimal discrimination between patients with reversible and irreversible airflow obstruction (sensitivity 56%, specificity 94%, and positive predictive value 92%). CONCLUSION: Absolute changes in PEF can be used as a simple technique to diagnose reversible airflow obstruction in patients from general practice.