缺氧性肺血管收缩 z-bo 2020-12-08 303

　　Background: Heart failure and subsequent circulatory shock are usually attributed to the left ventricle and systemic circulation. In recent years, acute right ventricular failure (ARVF) and its effects on circulatory shock have received extensive attention, especially in intensive care medicine. ARVF is usually caused by an increase in right ventricular (RV) afterload caused by chronic or acute pulmonary hypertension (PH), combined with a decrease in local or overall RV contractility, although ARVF is possible without PH. The pulmonary circulation is a low pressure, low resistance system. The increase in lung resistance will instantly increase the systolic blood pressure and volume of the RV. This prolongs isovolumic contraction, shortens the ejection phase, and creates a pumping mechanism similar to that of the left ventricle. The result is an increase in oxygen consumption and a decrease in oxygen supply, because increased intramyocardial pressure will reduce coronary perfusion. A normal RV can adapt to a certain degree of chronic and acute afterload increased by hypertrophy at the same time. However, when RV cannot compensate for the increased afterload, destructive progressive ARVF and total circulatory failure eventually develop. Of course, it is necessary to conduct more research on the mechanism that causes ARVF and how to treat this disease. Due to its complex nature and because it is caused by relatively small pressure changes, it is very important to use a good complete animal model to study this phenomenon. Several previous large animal models have adopted the open-chest method. We believe that keeping the thorax closed and keeping the pericardium intact is important because these surgical operations change the pressure-flow relationship between the RV and the pulmonary circulation, which interferes with the ARVF model. Therefore, our goal is to establish a new viable large animal model that is preferably reversible, with minimal invasiveness and a closed chest. In this model, the effect of increasing afterload on the hemodynamics of RV can be studied in detail, and the method can be applied to different RV failure models. In the pulmonary vasculature, vasoconstriction is a response to hypoxia, called hypoxic pulmonary vasoconstriction (hpv). This mechanism responds to low alveolar PO2 and is an important physiological function of guiding blood to the ventilated alveoli, thereby greatly reducing pulmonary shunt. This mechanism responds to low alveolar PO2 and is an important physiological function of guiding blood to the ventilated alveoli, thereby greatly reducing pulmonary shunt. As the alveolar PO2 decreases, hpv will drop within a few seconds, and it will increase rapidly and gradually. The contraction is mainly confined to the small resistance pulmonary artery (pas,<200μm), which can be reversed and restores alveolar normoxia. Hypoxia can cause HPV in all lung segments, leading to an increase in pulmonary vascular resistance (PVR), which is estimated to be between 50% and 300%. In animal experiments, hpv has been used as a means to increase acute and chronic PVR. There is no systematic description in the literature on how to use hpv to induce acute RV afterload increase in pigs. In this study, we explored the use of hpv as a method to increase the RV pressure load, aiming to determine the fraction of inhaled oxygen (FiO2) levels to produce the desired effect without causing severe hypoxia. We use standard-defined ph as the target level, and mean pulmonary artery pressure (mPAP) ≥25 mmHg at rest.

　　Methods: Animals, handling, anesthesia, surgery and euthanasia: Animals were pre-injected with 10 mg of diazepam and 400 mg of azaperone intramuscularly. Anesthesia was induced by intravenous injection of atropine 1.0 mg, fentanyl 8.0 μg/kg, thiopental sodium 4.0 mg/kg and ketamine 8.0 mg/kg through the external ear. Before intubation, apply 5ml, 40mg/ml lidocaine to the throat. The animal was ventilated with a ventilator in PRVC mode. The initial value of FiO2 was 0.30, the tidal volume was 10 ml/kg, and the minute ventilation was adjusted at 6cmH2O to maintain Paco2 at 4.5-5.5 kpa. Anesthesia was maintained by infusion of fentanyl 20μg/(kg h) and midazolam 0.40 mg/(kg h). According to clinical response, 50μg/ml fentanyl can be added as needed. Throughout the experiment, the intravascular volume was maintained by injecting 10 ml/kg of Grignard solution, and then 10 ml/(kg h) was infused continuously. Inject 5000 international units of heparin intravenously to prevent thrombosis. Before intubation, we prepared the left carotid artery, right internal jugular vein and left internal jugular vein through surgery. Two single-lumen catheters were inserted into the left carotid artery and left internal jugular vein for monitoring invasive blood pressure, arterial blood gas and intravenous injection. Insert a guiding pulmonary artery catheter into the right internal jugular vein, and guide and verify the entry into the pulmonary artery through classical pressure observation and fluoroscope. PAC provides central venous pressure (CVP) and pulmonary artery pressure (PAP). At the end of the experiment, the animals were euthanized with 100 mg/kg pentobarbital. In order to induce hpv, FiO2 must be reduced to a level below the physiological range. In order to reduce FiO2 below normal, insert nitrogen into the air inlet of the respirator, and then ventilate the animal with a mixture of oxygen and nitrogen. The actual FiO2 is monitored by a sidestream multi-gas analyzer. After the operation, the animal was stable for 30 minutes before recording the baseline measurement. Then, while monitoring the mPAP response, pH was induced by slowly lowering FiO2 on the respirator. When the mPAP level exceeds 25 mmHg, the animal rests for 30 minutes, and then records the new measurement. The main variables [mean pulmonary artery pressure (mPAP), pulmonary wedge pressure (pwp), central venous pressure (cvp), heart rate (hr), cardiac output (co)] and arterial and mixed venous blood gases are measured at baseline and after establishing pH . This study only uses simple descriptive medical statistics and paired-sample t-test.

　　 Results: Although the age, weight and treatment methods are similar, the baseline mPAP values of individual animals are very different, with an average (SD) 18.3 (4.2) mmHg (range 14-27 mmHg). The level of FiO2 required to raise mPAP above 25 mmHg also varies greatly, 0.15 (0.026) [mean (SD)], ranging from 0.13-0.21. (In an animal with a baseline mPAP higher than 25 mmHg, FiO2 decreased to 0.15.) This significantly increased mPAP from 18.3 (4.2) to 28.4 (4.6) mmHg. Since co did not change, the PVR changes of all animals were also consistent: from 254 (76) dyns/cm5 to 504 (191) dyns/cm5. Blood gases collected at baseline and after reducing FiO2 showed a slight decrease in oxygen delivery (DO2), from 409 (92) ml/min to 354 (52) ml/min. The oxygen consumption (VO2) from 195 (35) ml/min to 200 (41) ml/min is not affected, and the oxygen consumption remains unchanged. This is due to the increase in oxygen extraction after the induction of pH, and the mixed venous blood oxygen saturation (svo2) was significantly reduced from 0.51 (0.076) to 0.36 (0.070). In addition, from baseline to after FiO2 decreased, there was no change in lactic acid, pH or alkalinity.

　　 Conclusion: Studies have shown that by reducing FiO2 from 0.30 to 0.15 (0.024), the mPAP and PVR of research animals can be increased by approximately 100%. The response is individual, as is the baseline mPAP. This decrease in FiO2 caused a decrease in Sao2 and Do2 in some animals, but VO2 did not decrease after the stabilization period. In the initial stage, the animal seemed unstable and the clinical symptom was hypoxia, but after a few minutes, normal oxygenation was restored. In addition, this method should be used with caution, because reducing FiO2 too quickly may lead to sympathetic nerve activation, accompanied by tachycardia and high CO. Although the mPAP is high, it still leads to the secondary normalization of PVR. The method should be reversible in principle, although we did not study it in this work. Therefore, we propose a new minimally invasive (closed chest) RV afterload operation method for future ARVF research.