Cardiovascular side effects of aminophylline in meconium-induced acute lung injury.

As inflammation plays an important role in the pathogenesis of neonatal meconium aspiration syndrome (MAS), anti-inflammatory agents including inhibitors of phosphodiesterases (PDE) are increasingly used in the treatment. To evaluate side effects of PDE inhibitors, this study analyzed changes in blood pressure, heart rate (HR) and heart rate variability (HRV) during and after intravenous aminophylline in the animal model of MAS. Oxygen-ventilated rabbits were given meconium intratracheally (25 mg/ml, 4 ml/kg) or saline. Thirty minutes later, the animals were treated by intravenous aminophylline (Syntophyllin, 2 mg/kg) or saline (sham-treated controls). A second dose of the treatment was given 2 h later. During (5 min) and immediately after (5 min) the treatment, and during 5 h after the treatment, mean blood pressure in the femoral artery (MAP), HR and HRV were evaluated. In meconium-instilled animals, increases in MABP, HR, and HRV were observed already 5 min after aminophylline administration, while in saline-instilled animals aminophylline increased HR and caused inconsistant changes in HRV parameters compared to sham-treated animals. Within 5 h after the treatment administration, MAP, HR, and HRV parameters gradually returned to the initial values. Concluding, intravenous aminophylline may lead to acute cardiovascular changes. Thus, if aminophylline is used for treatment of MAS, its possible cardiovascular effects should be considered, particularly in patients with cardiovascular instability.

Dexamethasone treatment improved lung functions in meconium-instilled rabbits, but influenced cardiovascular variables.

BACKGROUND: In this study, the effects of single and repetitive dexamethasone administration on lung functions in meconium-instilled rabbits were compared. In addition, short-term adverse effects of dexamethasone on blood pressure, heart rate, and heart rate variability were evaluated. METHODS: Artificially ventilated adult rabbits intratracheally received 4 ml/kg of meconium suspension (25 mg/ ml). When respiratory failure developed, animals received single-dose of dexamethasone (0.5 mg/kg i.v.) 0.5 h after meconium instillation (Dex1), two doses of dexamethasone (each 0.5 mg/kg i.v.) 0.5 and 2.5 h after meconium instillation (Dex2) or were left without treatment (Mec). Animals were oxygen-ventilated for 5 h after the first dose of treatment. RESULTS: Dexamethasone treatment significantly improved gas exchange and reduced right-to-left pulmonary shunts, central venous pressure, and lung edema, whereas trend to more pronounced improvement in some parameters was observed after two doses of dexamethasone. There were no significant between-group differences in blood pressure, however, decreased heart rate and increased heart rate variability were observed particularly after repetitive dexamethasone administration. CONCLUSION: Intravenous dexamethasone, especially when given in two doses, improved lung functions, but influenced cardiovascular variables in meconium-instilled rabbits (Tab. 2, Fig. 3, Ref. 34). Full Text (Free, PDF) www.bmj.sk.

Comparison of the effects of low-dose vs. high-dose aminophylline on lung function in experimental meconium aspiration syndrome.

Due to missing information on appropriate dosing of aminophylline in meconium aspiration syndrome (MAS), this study compared effects of high-dose and low-dose aminophylline on lung function of animals with MAS. Meconium-instilled rabbits were treated by low-dose (LD, 1.0 mg/kg), or high-dose (HD, 2.0 mg/kg) aminophylline at 0.5 and 2.5 h after meconium instillation, or were left untreated. Within 5 h of oxygen ventilation, HD-aminophylline improved gas exchange, reduced pulmonary shunts and ventilatory pressures, and decreased edema formation and lung neutrophils. LD-aminophylline enhanced lung function to a lower extent than HD-aminophylline, and failed to reduce lung edema and the number of lung neutrophils. Both treatments decreased lung peroxidation, with a stronger effect of HD-aminophylline on lipid oxidation and of LD-aminophylline on protein oxidation. Tracheal reactivity to histamine decreased after HD-aminophylline, while lung tissue reactivity was more reduced after LD-aminophylline. Although LD-aminophylline showed some anti-inflammatory potential, HD-aminophylline improved most of the parameters more effectively.

Combination of budesonide and aminophylline diminished acute lung injury in animal model of meconium aspiration syndrome.

Combination of low-dose budesonide and low-dose aminophylline may improve lung function in reduced adverse effects compared with high-dose monotherapy. Adult rabbits intratracheally received 4 ml/kg of saline or meconium (25 mg/ml). Meconium-injured rabbits were treated at 0.5 and 2.5 h after meconium instillation by intravenous aminophylline (1.0 mg/kg), by intratracheal budesonide (0.125 mg/kg) followed by intravenous aminophylline (1.0 mg/kg), or were untreated. Although aminophylline improved some respiratory parameters, budesonide+aminophylline more effectively reduced intrapulmonary shunts and improved gas exchange, without significant cardiovascular effects. Combined treatment reduced lung edema and number of lung neutrophils to a higher extent than aminophylline alone. Both treatments reduced lung peroxidation and in vitro airway reactivity to histamine, with a better effect after aminophylline alone. Combination of budesonide and aminophylline enhanced respiratory parameters more effectively, having fewer side effects than aminophylline alone. However, no additive effect of budesonide was observed on lung peroxidation and in vitro airway reactivity.

Single-dose versus two-dose dexamethasone effects on lung inflammation and airway reactivity in meconium-instilled rabbits.

Two doses of the corticosteroid dexamethasone may alleviate meconium-induced acute lung injury more effectively than a single dose. Meconium-instilled rabbits intravenously received dexamethasone (0.5 mg/kg) at one dose 0.5 hours after meconium instillation or at two doses 0.5 hours and 2.5 hours after meconium instillation or were left without treatment, and were oxygen-ventilated for additional 5 hours. At the end of experiment, lungs and trachea were excised. Two doses of dexamethasone effectively diminished meconium-induced lung edema, tracheal hyperreactivity to histamine, neutrophil count in bronchoalveolar lavage fluid, and decreased oxidative modifications of proteins and lipids in lung homogenate compared with the non-treated group. Single-dose dexamethasone also reduced lung edema, lung neutrophils, and tracheal hyperreactivity to histamine, but these effects were weaker than those after two-dose dexamethasone. We conclude that two-dose dexamethasone is superior to single-dose dexamethasone in prevention lung injury in meconium-instilled rabbits.

Intratracheally administered corticosteroids improve lung function in meconium-instilled rabbits.

Local administration of corticosteroids may diminish acute lung injury associated with meconium aspiration. Budesonide was given intratracheally in 2 doses of 0.25 mg/kg each by means of inpulsion effect of high-frequency jet ventilation 0.5 and 2.5 hours after meconium instillation to oxygen-ventilated adult rabbits. Within 5 hours after the first dose, budesonide significantly improved gas exchange and decreased right-to-left pulmonary shunts, central venous pressure, and ventilatory pressures. In addition, budesonide reduced the meconium-induced lung edema formation, airway hyperreactivity to histamine, count of neutrophils in bronchoalveolar lavage fluid associated with higher total white blood cell and neutrophil counts in the blood, and diminished oxidative modifications of proteins and lipids in lung tissue compared to non-treated meconium-instilled group. The intratracheally administered corticosteroid budesonide effectively improved pulmonary functions and alleviated changes associated with inflammation in meconium-instilled rabbits.

Aminophylline treatment in meconium-induced acute lung injury in a rabbit model.

Administration of methylxanthines may diminish meconium-induced acute lung injury. Meconium-instilled rabbits intravenously received aminophylline (2.0 mg/kg) at two doses 0.5 h and 2.5 h after meconium instillation or were left without treatment, and were oxygen-ventilated for additional 5 h. At the end of experiment, lungs and trachea were excised. Within 5 h after the first dose of treatment, aminophylline significantly improved gas exchange and decreased right-to-left pulmonary shunts, central venous pressure, and ventilatory pressures. Moreover, aminophylline reduced meconium-induced lung edema formation, airway hyperreactivity to histamine, count of neutrophils in bronchoalveolar lavage fluid associated with higher total white blood cells and neutrophils in the blood, and diminished oxidative modifications of proteins and lipids in lung tissue compared with the non-treated meconium-instilled group. In a rabbit model of the meconium aspiration syndrome, aminophylline treatment enhanced pulmonary functions and alleviated oxidative injury and changes in airway reactivity related to lung inflammation.

Cardiopulmonary and inflammatory changes in adult rabbits with meconium aspiration.

BACKGROUND: Pulmonary inflammation and vasoconstriction are important pathogenetic factors in neonatal meconium aspiration syndrome (MAS). OBJECTIVES: Study was performed to evaluate cardiopulmonary and inflammatory changes in adult rabbits after meconium administration. METHODS: Animals were anesthetized and ventilated with room air. Initial values of cardiopulmonary parameters were recorded and blood samples taken. Three animals were then sacrifice and used as controls. The others were administered saline (4 ml/kg, n = 4) or meconium (25 mg/ml, 4 ml/kg, n = 5) and were further ventilated with 100% oxygen. When respiratory failure developed, parameters were recorded and animals were ventilated for additional 5 hours. Rabbits were then sacrifice and lungs excised. Right lungs were dried to determine wet/dry weight ratio and left lungs were lavaged with saline. Differential leukocyte count in the blood and lavage fluid sediment, and total blood leukocyte count were evaluated. RESULTS: Instillation of meconium significantly decreased lung compliance, ventilation efficiency index and gas exchange, and increased right-to-left pulmonary shunts in comparison with saline group. No significant differences between groups were observed in mean blood pressure, heart rate, and central venous pressure. Meconium caused higher fluid and polymorphonuclear accumulation in the lungs, linked with decreased neutrophil and increased eosinophil counts in the blood. CONCLUSIONS: Adult rabbits may be used for experimental testing of drugs influencing lung inflammation and vasoconstriction in MAS (Tab. 1, Fig. 4, Ref. 16).

Lung lavage using high-frequency jet ventilation in rabbits with meconium aspiration.

AIM: To determine the efficacy of the expulsion effect of high-frequency jet ventilation (HFJV) on meconium clearance from the airways in comparison with conventional suctioning in adult rabbits with meconium aspiration. METHODS: Experiments were carried out on tracheotomized, anaesthetized and paralysed adult rabbits. A suspension of human meconium in saline (25 mg ml(-1), 4 ml kg(-1)) was instilled into the tracheal cannula. When respiratory failure developed, saline lavage (10 ml kg(-1) in 3 portions) was performed during conventional ventilation or by means of the inpulsion and expulsion regime of HFJV. Animals were further ventilated for 2 h with either conventional ventilation or HFJV. RESULTS: There was no significant difference between groups in the amount of meconium recovered by lavage. Compared to conventional ventilation, the application of HFJV enhanced the elimination of carbon dioxide, increased lung compliance and diminished right-to-left shunts after 30 min of ventilatory treatment. Oxygenation also improved during HFJV, although this was not a consistent finding during the ventilation period. CONCLUSION: HFJV improved gas exchange, lung compliance and reduced right-to-left pulmonary shunts, but saline lung lavage by HFJV was not found to be more efficient than lavage during conventional ventilation in rabbits with meconium aspiration.

Heart rate variability and cardiovascular tests in young patients with diabetes mellitus type 1.

The aim of this study was to obtain information about parameters of heart rate variability (HRV) in three frequency bands (high frequency - HF, low frequency - LF and very low frequency - VLF), the sensitivity of cardiovascular tests, and subjective feelings depending on autonomic nervous system balance in a group of young patients with diabetes mellitus type 1 (IDDM). Sixty-four subjects were examined: 32 patients with diabetes with a mean age of 16.1 +/- 0.7 years and a mean duration of IDDM of 6.3 +/- 0.8 years, and 32 healthy controls matched for age, sex and BMI. Shorter R-R intervals and abnormal values reflecting HRV were found in the diabetic group. In particular, parameters of total power, and HF and LF bands were reduced. The ratio VLF/HF power revealed predominance of sympathetic tone in the diabetic subjects. Although relative power VLF was increased in the supine position, the reactive rise of the VLF band activity in orthostasis was lower in the IDDM group. Using cardiovascular tests (deep breathing, Valsalva, orthostasis), significant differences in reactions were found only in the deep breathing test. Evaluation of sympathetic:parasympathetic:indifferent subjective feelings by questionnaire did not reveal any differences between the diabetic and healthy groups.

Changes in parameters of mechanics of breathing during high-frequency jet ventilation: what is the cause?

In experiments on 51 healthy anaesthetized and paralyzed rabbits the changes in parameters of mechanics of breathing during high frequency jet ventilation (HFJV) were determined and the mechanisms responsible for these changes were investigated. In the first series of experiments with two groups of animals ventilated by HFJV with relative inspiratory time ti=0.5 and ti=0.7 airway resistance (Raw) after 5 h of HFJV in the ti=0.5 group increased from 1.14+/-0.05 to 2.31+/-0.09 kPal(-1) x s (P < or = 0.001), in the ti=0.7 group from 1.22+/-0.04 to 1.78+/-0.08 kPal(-1) x s (P < or = 0.01). Dynamic compliance (Cdyn) decreased in the ti=0.5 group from 0.041+/-0.004 to 0.017+/-0.001 l x kPa(-1) (P < or = 0.01) and in the ti=0.7 group from 0.034+/-0.003 to 0.022+/-0.002 l x kPa(-1) (P < or = 0.01). In the second series of experiments a group of animals was ventilated by HFJV after cervical vagotomy. The deterioration of Raw and Cdyn was significantly reduced in vagotomized rabbits in comparison to the controls without vagotomy. Finally, the study of phospholipid content in bronchoalveolar lavage fluid revealed no significant differences after 5 h of artificial ventilation or spontaneous breathing. These data indicate that HFJV results in changes in the parameters of mechanics of breathing in healthy lungs, which may be attenuated, but not fully eliminated, by bilateral cervical vagotomy. The decrease in Cdyn and increase in Raw are probably not due to changes in the pulmonary surfactant content.

Cardiorespiratory parameters and respiratory reflexes in rabbits during hyperthermia.

The effects of different body temperature (BT) on the respiratory and cardiovascular parameters and respiratory reflexes were studied in 33 anaesthetized adult rabbits. Hyperthermia elicited panting with mean panting respiratory rate 199 +/- 14 x min-1 in all anaesthetized rabbits. Significant correlations between BT and frequency of breathing (positive), heart rate (positive) or tidal volume (negative) were found. Cooling was accompanied by considerable arterial hypotension. Duration of the Hering-Breuer reflex (HB) was reduced by the rise of BT. Intensity of the reflex (assessed as the ratio of the apnoeic pause to the mean duration of the previous 5 breaths) was unchanged up to the body temperature eliciting panting (41.15 +/- 0.08 degrees C) when it was greatly diminished. Defensive airway reflexes were also changed in hyperthermia. The duration as well as the intensity of nasal apnoea (Kratschmer's reflex) and laryngeal chemoreflex apnoea were decreased. The intensities of respiratory efforts in sneezing and laryngeal coughing were reduced. The expulsive reactions evoked by mechanical stimulation of the larynx were replaced by very shortlasting inhibition of breathing during panting. The results indicate that reflex control of breathing via the Hering-Breuer reflex and the ability to eliminate irritants from the airways are diminished during hyperthermia and panting in anaesthetized rabbits.

[Changes in the parameters of respiratory mechanics after the aspiration reflex and asphyxia]. / Zmeny parametrov mechaniky dýchania po aspiracnom reflexe a asfyxii.

Parameters of respiration mechanics (dynamic compliance--Cdyn and total lung resistance--RL), ventilation, blood gases, and right-to-left pulmonary shunts were studied after aspiration reflex in experiments on 29 anesthetized cats. Attacks of aspiration reflex were induced without asphyxia (8 cats) and during two-minute asphyxia (9 cats). The control group consisted of 12 animals. A series of aspiration reflex attacks resulted in short-term improvement of the parameters of respiration mechanics with an increase in Cdyn and reduction of RL. A simultaneous elevation of PaO2 and a decrease of PaCO2 were recorded. In combination with asphyxia (hypoxemia and hyperkapnia), the aspiration reflex induced a reversed reaction, i.e. decreased Cdyn lasting till the end of experiment (3 hours) and an increase of functional alveolar right-to-left shunts. The results indicate that in cats impairment of respiration mechanics parameters is brought on only when deep inspiration is combined with asphyxia.