Study On Drug Delivery Method Of Pulmonary Surfactant For Treating Respiratory Distress Syndrome

BackgroundRespiratory distress syndrome, including neonatal respiratory distress syndrome (NRDS) and acute respiratory distress syndrome (ARDS), has a high mortality rate of 34%-64%. It's one of the leading causes of death in the patients who suffered from respiratory diseases, no matter in the peace period or wartime. So lots of budgets have been invested to study the pathophysiological process and treatment of RDS. The application of efficient medication, however, has arised great interests of the researchers and clinicians.There's a history of more than 30 years since the exogenous pulmonary surfactant adopted to treat RDS in clinic. Until now, pulmonary surfactant is commonly used in preterm infants as a life-saving treatment and has become a standard of care in neonatal intensive care unit, but there still no similar effective therapy exists for patients with acute respiratory distress syndrome. Drug delivery method is important consideration. Instillation of bolus exogenous surfactant into the airway through endotracheal intubation or bronchoscopy is the conventional way of administering surfactant, but the methods require the operator skilled and always associated with many complications, such as bradycardias, changes in blood pressure, drug reflux, and need for re-intubation. Aerosolized surfactant by a jet nebulizer or ultrasonic which was connected to ventilator has been adopted by foreigners in recent years. Although these approaches have been proved to be efficient and safe in animal models, the therapeutic effects of aerosolized surfactant in clinical trials are not convincing. Moreover most ultrasonic or jet nebulizers require mechanical ventilation to deliver aerosolized surfactants. No matther which method, the purpose of administration is to send exogenous pulmonary surfactant to distal alveolus uniformly. However, the methods used now still have some defects, so how to improve inhaled system of exogenous pulmonary surfactant still an important issue to be solved in hospital. Noninvasive surfactant administration without the need for intubation and instillation of surfactant into the airway is a highly appealing option for clinicians. In China, instilling pulmonary surfactant into the lung is the main method used in clinic. However, the pain and complications associated with this method always aggravate the illness of patients, and bring conflicts between patients and medical workers. So an efficient, convenient, noninvasive method will be crucial for introducing exogenous pulmonary surfactant to distal alveolus. Considering that the oxygen-driven aerosol treatment is a feasible, safe, efficient method used clinically, especially for respiratory diseases. So it will be studied for introducing exogenous pulmonary surfactant to the lung, which not only can alleviate the pains the patients suffered and decrease the workload of medical workers, but also be good for the exogenous pulmonary replacement therapy developing to base course hospitals, military medicine and preventive medicine.In this study, animal experiment was used to measure the safety and efficacy of aerosolized exogenous pulmonary surfactant by oxygen-driven aerosol treatment. At the condition of analyzing the experiment results and observation in clinic, we also make a suggestion of the operation procedure. We hope that this method can be generalized for surfactant replacement therapy in hospital and pre-hospital care, no matter in peace period or wartime.ObjectivesOptimize the parameters of oxygen-driven aerosol system for pulmonary surfactant, such as oxygen flow, concentration and volume of pulmonary surfactant, temperature of the aerosolized chamber, in order to make it convenient, safe, and feasible. Compare the therapeutic effects of oxygen driven group and air driven group, discussing whether air can replace oxygen as the power source. Make a suggestion of operation procedure for nurses, and measure the efficacy of introducing exogenous surfactant by this method through analyzing the experiment results. In order to instruct nurses operate correctly and provide an alternative of surfactant adminiatration system, furthermore, make it an established method for surfactant administration in the future.Methods1. Analysis of surfactant administration system On the basis of literature researches and investigation, compare the methods for introducing surfactant which used clinically in China. Identify the factors influencing the therapeutic response and made a suggestion of introducing exogenous surfactant by oxygen-driven aerosol treatment. 2. Experiment study(1) Use the laser particle counter to detect velocity of oxygen flow at the condition of aerosolized optimum particle size. In order to assure that the particle which aerosolized can reach distal alveolus.(2) Animal experiment: To testify the optimum concentration and volume of pulmonary surfactant aerosolized. Furthermore, measure the efficacy, safety and operability of adminiatering surfactant by oxygen-driven aerosol treatment through administering surfactant to the Sprague-Dawley rats with acute lung injury induced by olice acid.The experimental animals were randomly divided into five groups.1) Group 1: model group, n=10, after operation, the animals were injected oleic acid (0.20ml/kg) through jugular vein to establish models of acute lung injury.2) Group 2: aerosolized normal saline driven by air, n=10, after establishing models of acute lung injury, aerosolized normal saline through oxygen-driven aerosol treatment except that used air replace oxygen as the power source.3) Group 3: aerosolized pulmonary surfactant driven by air, n=13, after establishing models of acute lung injury, aerosolized pulmonary surfactant through oxygen-driven aerosol treatment except that used air replace oxygen as the power source.4) Group 4: aerosolized normal saline driven by oxygen, n=10, after establishing models of acute lung injury, aerosolized normal saline through oxygen-driven aerosol treatment.5) Group 5: aerosolized pulmonary surfactant driven by oxygen, n=13, after establishing models of acute lung injury, aerosolized pulmonary surfactant through oxygen-driven aerosol treatment.The parameters measured including①time between aerosolization and having effect;②survival rate;③respiratory condition: including PaO2, PaCO2, pH and BR;④lung inflammation: including lung index, the concentration of total protein, TNF-α, IL-1β, IL-6 in the bronchoalveolar lavage fluid;⑤degree of the lung injury: including appearance of the lung, histological examination of the lung and lung injury score;⑥the differences of the parameters between group 3 and group 5. And the differences were compared.Results1. Optimize the oxygen-driven aerosol system.①At the velocity of 4.5L/min of oxygen flow, the aerosolized partical size which was smaller than 2μm account for 99.9%.②The aerosolized volume and concentration of aerosolized surfactant were 4ml and 20mg/ml respectively.③Some measures shoud be adopted to keep animals'body warm under the consideration of ethics.2. Evaluation of the efficacy of delivering surfactant by this method.①The administration is convenient for introducing PS.②The adminiatration can alleviate dyspena of ALI rats quickly: it decreased respiratory rate from 140-150 per minute to 90-100 per minute; improved PaO2 of ALI rats from 62-64mmHg to 100mmHg.③The administration can reduce inflammatory reactions of the lung: decrease the concentration of total protein, TNF-α, IL-1β, IL-6 in the BALF.④Ameliorate the lung injury of ALI rats: the lung appearance, histological examination and lung injury score represented that hemorrhage and odema were reduced in the groups that were treated with aerosolized pulmonary surfactant.⑤It's safe, and satisfied physiological requirement of the experimental objects.⑥One nurse is competent, it can save time and manpower in the emergency conditions.3. Compare the therapeutic effect of oxygen-driven and air-driven on ALI. It showed no statistical difference in improving PaO2 and survival rate, lessening lung inflammatory and degree of lung injury, except decreasing BR.4. Make a suggestion of operation procedure for clinic usage.ConclusionsThe newly optimized oxygen-driven aerosol system can introduce exogenous pulmonary surfactant into the lungs and alleviate dyspena conditions. Compare with instillation through tracheal cannula and bronchoscopes, it's non-invasive and make the patients suffer less pain. It can also save time, apparatus and manpower for the emergency. And in the conditions without oxygen, air canbe used as power source.