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[资料]小儿急性肺损伤的治疗（来自上海国际呼吸研讨会Heidi R. Flori MD的讲座）
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小儿急性肺损伤的治疗，来自上海国际呼吸研讨会Heidi R. Flori MD的讲座。主要讨论了Liquid ventilation、Surfactant administration、Prone positioning三方面的问题 。Treatment of pediatric ALI： Trials with liquid ventilation, surfactant administration and prone positioning Heidi R. Flori MD Director; Pediatric Critical Care Clinical Research， Children’s Hospital and Research Center at Oakland, Oakland, California, USA (Tel: 510, 428-3885 x 5016. Email: hflori@mail.cho.org) Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS) affects both adults and children. In fact, in Ashbaugh's landmark article on ARDS published in Lancet in 1967, 5 of the 12 patients described were less than 20 years of age. ALI is associated with a variety of disease states that either effect the lung directly or indirectly. The most common direct causes of ALI in pediatric patients are pneumonia, aspiration of gastric contents and near drowning. The most common indirect cause is sepsis followed by many other processes that may be underestimated and include cardiopulmonary bypass, transfusion related lung injury, hemorrhage associated with autoimmune disease and trauma. Not only is the outcome of the patient with ALI affected by the disease process itself, but the susceptibility to injury is likely affected by the gene profile and age of the patient at the onset of ALI. Understandably, the heterogeneous nature of ALI, both in terms of patient profile and disease process associated with it, have made identifying therapeutic targets and testing these treatment possibilities a formidable task over the last 40 years in adult medicine and over tile last 20 years in a much younger subspecialty, pediatric intensive care. Further, although the process of ALI is the result of several activated and inactivated inflammatory, coagulation and fibrotic cascades, current clinical trial design allows for rigorous evaluation of only I or 2 therapeutic targets to be tested in any given clinical trial. Additionally, the clinical outcomes of most importance, mortality and duration of mechanical ventilation, are impacted by many factors not directly related to the therapy in question. Therefore, in order to least bias critical care research studies to the null, strict adherence of each center to the protocolized management of non-randomized procedures, like management of the fluid and sedation requirements, is needed. As mortalities decrease in ALI patient populations with time, trial sizes must increase in order to test the effects of new therapies with adequate power. Surrogate outcomes for mortality and duration of mechanical ventilation, such as deadspace measurement, arc not fully validated at this point but the future is hopeful that fills will decrease needed trial size and Allow for more therapies to be tested ill a timely fashion. The issue of patient numbers and accurate trial design has particularly plagued pediatric ALI trials as studies with incomplete enrollment patterns have resulted in unequal patient distributions across groups that has confounded analysis of the therapies ill question. With this preface in mind, this article will review the recent pediatric clinical trials in three areas of ALI research: liquid ventilation, surfactant administration and prone positioning. Liquid ventilation Liquid ventilation was first described as a concept ill 1966 by Clark and Gollan. First attempts at liquid ventilation involved "total" ventilation of the lung and thus required the use of a liquid ventilator. More recent trials, and ALI human trials, have involved partial liquid ventilation using gas ventilation and either conventional or high frequency mechanical ventilators. Liquid ventilation is achieved by administering liquid phase perflourcarbons (PFCs) into the lung. PFCs are colorless, odorless, inert to the human body and are eliminated by evaporation from the lungs or ingestion by macrophages. Clinically, PFCs have high respiratory gas solubility, low surface tension, a high spreading coefficient, high density and are incompressible. These properties Allow for exchange of oxygen and carbon dioxide under lung injury conditions, improved lung recruitment by filling dependent areas of the lung and decreasing atelectasis, decreased lung heterogeneity by decreasing lung surface tension, and improved pulmonary toilet as the highly dense liquid Allows fur "lighter" debris to float "ontop" and become more easily evacuated upon endotracheal suctioning. Because PFC's distribute to non-dependent and dependent areas of the lung, its use has been extended to include improving drug delivery to distal lung units including delivery of nitric oxide, surfactant, antibiotics, prostaglandins and even genes. In vitro and animal studies have been very promising and have indicated that PFC's improve lung injury by decreasing neutrophil sequestration, attenuating oxidant damage to both biological and nonbiological systems independent of its anti-inflammatory properties, improving lung histology when administered in a uniform way, and inhibiting chemokine expression and nuclear factor-kB activation. Alliance Pharmaceuticals has produced the compound used in ALI human trials to date. It is called PerFlubron, brand name LiquiVent. It has a density of 1.9 g/mi, a surface tension of 19 dyne/cm and is immiscible in aqueus solution. It carries 50 mi of oxygen per dl of perfluorocarbon and 210 ml of CO2 per dl of perfluorocarbon. Human investigations began in 1990 and involved instillation to total lung volume in 3 moribund premature infants. Since then, most investigations have limited dosing to about 30cc/kg, or functional residual capacity. With this technique, a meniscus of liquid is visible at the level of the chest when positive pressure is transiently removed. As PFC's evaporate rapidly (1-2 ml/kg per hour), losses must be replaced at regular intervals. At the termination of use, PFC's are cleared by evaporation over a 24-48 hour period. Most recently, several investigators have tested single dose instillations or instillations in doses less than FRC in various experimental models. In 1996, 13 premature infants received PFC's as a rescue measure for their severe respiratory distress. Eight of the 13 survived to 36 weeks corrected gestational age. ALI exhibited improved oxygenation, dynamic compliance, tidal volume and mean airway pressures and did not sustain any adverse event related to the treatment. Gauger and colleagues successfully used PFC's to treat six children on ECMO for severe ARDS in an uncontrolled, Phase I/II study in 1996. Patients were dosed daily for 3-7 days and a cumulative dose of 45 mg/kg. ALI six patients survived but 2 of the 6 sustained pneumothoraces that were considered possibly associated with the treatment. Average A-a gradient improved from 635 +/- 10 to 499 +/- 77 torr over the treatment period and static compliance improved from 0.12 +/- 0.02 to 0.28 +/- 0.08 ml/cmH20/kg (P=0.01). In another study of 6 children with severe acute respiratory failure unable to be treated with ECMO, Fedora and colleagues instilled 1 FRC of PFC's and redosed hourly for 3 hours. Average pH improved from 7.22 to 7.34, PaO2/FiO2 improved from 72 to 100 and FiO2 was decreased from 82% to 64% (ALI P <0.05). The largest pediatric trial to date enrolled 120-200 subjects from 1996-1998 in a multi-center, Phase II/III study. Patients were included if they had acute onset of bilateral infiltrates on chest radiograph within 72 hours of screening and required an FiO2 of at least 50% and a PEEP of > 6 for more than 12 hours prior to screening. Patients were excluded if they had chronic lung disease, active air leak or hemodynamic instability, intracardiac shunting of blood, a high risk of death within 3 months of screening or presence of 2 |
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