Effect Of Airway Obstruction And Carotid Body Changes On Respiratory Regulation Function

RationalThe rational of this research project was to study the correlation between the changes of carotid body morphology or its sensitivity and the stability of respiratory regulation function in patients with chronic obstructive pulmonary disease（COPD）,obstructive sleep apnea hypopnea syndrome（OSAHS）and overlap syndrome（OS）,so as to explore a possible pathophysiological mechanism of chronic airway obstructive disease,and to early identify high-risk complications such as respiratory failure.MethodThe first study was a control study of animal experiment.The rats in COPD group were treated with smoking and lipopolysaccharide（LPS）intratracheal injection.Rats in the smoking box were smoked twice a day for 8 weeks,and LPS was injected intratracheally once every 2 weeks in the 8 weeks.However,the rats of control group were treated without smoking,and same amount of normal saline was injected into trachea oncely per 2 weeks.Pulmonary function test,HRCT and pathology examination were used to verify whether or not the COPD model was established successfully 8 weeks later.In order to study the effect of carotid body（CB）hypofunction（CBHF）on respiratory rhythm and arterial blood gas,the CB of rats were chemical injuried by 3%H₂O₂,then the effects of CBHF were studied by low O₂ventilation reaction and high CO₂ ventilation reaction in the two groups.In the second study,an airway obstruction device was developed according to my authorized patent.The device was composed of a control host and several airway control modules,and a wireless communication between host and terminal module is realized,which can simultaneously control several animals.The usability,stability and safety of the device were tested by the Testchest system of active lung simulator.The airway control terminal was connected to the tracheotomy cannula of the rabbits,and parameters were preset in the airway control host to simulate various severity of OSAHS.Polysomnography（PSG）and pleural manometry were performed simultaneously,and compared with the data recorded by the airway obstruction device itself.It was verified that the synchronous of intermittent airway obstruction,intermittent thoracic pressure fluctuation and intermittent hypoxia could be realized OSAHS model.The third study was a randomized controlled trial（RCT）.COPD,OSAHS and OS groups were enrollment ccording to the inclusion and exclusion criteria.All patients underwent carotid artery doppler ultrasound to measure the peak systolic velocity（PSV）,intima-media thickness（IMT）,carotid plaque crouse score,presence or absence of bifurcation plaque,CB shape,size and calculated volume of bilaterial CB;PSG was used to monitor respiratory rhythm,and the Breath Drive Instability Index（BDISI）was obtained by an algorithm with apnea-hypopnea index（AHI）,central sleep apnea index（CSAI）and mixed sleep apnea index（MSAI）.BDISI were combined with arterial blood gas values and other indicators to analyze its correlation,and to explore the role of carotid body changes in pathophysiological mechanism of breath drive stability and respiratory failure,as well as the predictive value of respiratory failure.Result1.Establishment of COPD rats model and carotid body injury operation in rats.When the model was established successfully,rats in COPD group showed higher respiratory rate,lower activity,dimmer hair color,and lower body weight than the rats in control group.HRCT of COPD rats showed more air content in lung than control rats,with degenerated alveolar structure,occured lung air sac,and increased lung volume.COPD rats showed decreased of FVC,FEV_0.3,FEV_0.3/FVC,with decreased PaO₂ and increased PaCO₂of arterial blood.Lung biopsy of COPD rats showed pathological bronchial mucosa thickening,destruction of airway epithelial cells,alveolar enlargement and fusion,elastic fiber rupture,and inflammatory cell infiltration.Biopsy of CB showed enlargement apperance,and histopathology showed increased proportion of type I cells,increased cell volume,and capillary hyperplasia.When the CBs were injuried（CBI）by 3%H₂O₂,an decrease of respiratory rate（RR）,inspiratory time（Ti）,expiratory time（Te）and PaO₂ was observed,and increase of PaCO₂ were observed in COPD rats.While CB sham injury（sham-CBI）had no significant effect on respiratory rhythm and arterial blood gas.The hypoxic ventilation reaction of COPD rats was weakened or disappeared after CBI,and more severe hypoxemia was observed in the hypoxic condition than that in the control group and sham-CBI rats.The hypercapnia reaction of COPD rats was weakened or disappeared,and more severe hypercapnia with type-II respiratory failure was observed in the COPD rats than in the control group and sham-CBI group,while the respiratory function of control group and sham-CBI group was stable.2.A wireless airway control device based on Zig Bee network topology was developed and connected with the upper airway of rabbits.An animal model of OSAHS with intermittent airway obstruction was established.The apnea events,AHI and ODI monitored by PSG were consistent with the setting of airway control device.The pleural pressure was monitored by direct manometric tube.The waveform showed that when the airway control module narrowed or obstructed the airway,intermittent hypopnea/apnea,oxygen desaturation and fluctuated intrapleural pressure would occur simultaneously.It was proved that the airway obstruction device developed in this project can achieve accurate controllable and synchronous intermittent airway obstruction,intermittent hypoxia,intermittent intrapleural pressure fluctuations and other clinical pathophysiological characteristics of OSAHS diseases,and make up for the shortcomings of the existing experimental animal model of OSAHS.3.Results of the clinical patients RCT study suggested the following aspects.（1）CB volume of all three groups patients were increased,with significant difference among three groups;CB positive rate were difference among groups（P<0.01）,the positive rate of OS group was the lowest,and CB could not be founded by ultrasound in some patients,which might caused by fibrosis or atrophy of CB.（2）There was significant difference in average Tc CO₂,variation rangeΔTc CO₂,total time of Tc CO₂>45mm Hg among the three groups.（3）There was significant differences in AHI,MSAI,CSAI and BDISI among the three groups,and the OS patients with the highest value（P<0.01）.（4）Correlation analysis and multiple logistic regression analysis showed that PSV,IMT and V_BCB were independent risk factors of BDISI（P<0.05）,and PSV had better predictive value for BDISI（AUC=0.640,95%CI 0.540～0.740,P<0.05）.（5）the total volume of bilateral carotid body V_BCB was correlated with PSV,IMT,Crouse score（P<0.05）,and negatively correlated with plaque area at bifurcation（P<0.05）;multivariate logistic regression analysis showed that Crouse score was an independent risk factor for V_BCB and PaCO₂ respectively（P<0.05）.Conclusions1.Smoking and intratracheal injection of LPS is an effective method to develop COPD rat model.In COPD rats,volume and sensitivity of CB increased compensably.Chemical injury of CB can lead to CBHF and decrease of respiratory regulation.2.The self-developed intermittent airway obstruction device can achieve accurate controllable synchronous intermittent upper airway obstruction,intermittent hypoxia,intermittent intrapleural pressure fluctuations and other clinical characteristics of OSAHS,which make up for the deficiency of existing OSAHS models and can be used to study pathogenesis of OSAHS.3.In COPD,OSAHS and OS patients,various change of CB morphology and respiratory regulation function was abserved,and their BDISI increased to a certain extent.CB couldnot been found in some patients,which may be related to fiberosis or atrophy of CB.PSV can be used as a marker to predict BDISI.Crouse scores and CB atrophy can be used to predict respiratory failure.