Clinical Epidemiology And Experimental Lung Protective Ventilation In Pediatric Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a rare but intractable disease in intensive care unit (ICU) leading to a high mortality in patients with pulmonary and extrapulmonary causes. There is an uniform criteria for diagnosis of ARDS in 1994 by American-European Consensus Conference (AECC) definition, but no conmvincing therapeutic guideline has ever been established except for small tidal volume ventilation strategy. Derangements of respiration, circulation, metabolism, coagulation, and inflammation are all present in this syndrome, which is then a perfect paradigm to study the underlying physiology, the complex interations between organ systems, and their interaction with treatment especially mechanical ventilation. ARDS is the main death cause of severe acute respiratory syndrome and avian influenza. It is also one of the most troublesome diseases in pediatric ICU (PICU).In 1994 AECC, ARDS was defined as co-existance of acute onset of bilateral infiltrates on chest radiograph without evidence of left atrial hypertension, and PaO₂/ FiO₂ ≤200 mmHg, irrespective of ventilatory support, type and settings. In recent years, investigations of various interventions through randomized, controlled clinical trial tend to include patient response towards mandatory mechanical ventilation, so that only most severe cases are eligible for the trial study, and those with transient respiratory difficulty and insufficiency may be eliminated.In PICU, ARDS should be classified as rare disease. Multicenter collaboration is essential to obtain enough pediatric ARDS samples to achieve sufficient statistical power. Large population in China determines a sufficient cases available to the study endpoint. To this purpose, we established a collaborative study group of pediatric respiratory disease in 25 PICUs in China and exerted a 12-month prospective, multicenter study in ARDS. Furthermore, based on a new, disputable lung protectiveventilation strategy, that is, open lung concept (OLC), we conducted an experimental study in an oleic acid-induced model of severe ALI in young piglets and compared the effects of OLC with different ventilatory modes. The first study provided clinical epidemiologic data in pediatric ARDS in China, which may promote interventional investigation as multicenter, randomized, controlled trials in pediatric severe hypoxic respiratory failure. The second study should enable a comprehensible experiment for testing of effects and safety of an extraordinary ventilatory means in combating intractable respiratory failure such as ARDS in children.Part I Prospective, Multicenter Clinical Study of Pediatric Acute Respiratory distress in 25 Pediatric Intensive Care Units in ChinaBackground Acute respiratory distress syndrome is a serious clinical problem associated with low incidence, high mortality, morbidity, and cost in PICU. In 1994, the AECC on ARDS was convened to bring clarity and uniformity to the definition of ALI and ARDS. The conference defined ARDS as acute onset of bilateral infiltrates on chest radiograph without evidence of left atrial hypertension and with a PaO₂/FiO₂ ≤200 mmHg. Clinical epidemiologic studies may provide incidence, clinical course and risk factors of underlying diseases leading to pediatric ARDS. This information is essential for planning research, allocating resources, promoting quality improvement of medical care for pediatric critical patients. The published incidence of ARDS in PICU varies from 0.7% to 4.2%, and the mortality of ARDS in PICU varies from 40% to as high as 80%, most of whcih come from single center and/or retrospective studies. No prospective multicenter studies specifically investigated the incidence and outcomes of ARDS in PICU patients since AECC definition was published and before we initiated this study.Objective To determine incidence, management, mortality, risk factors, diagnostic feature, disease burden of pediatric patients who developed ARDS while in PICU.Methods Chinese collaborative study group for pediatric respiratory failure consisted of 25 PICU located in 20 cities of 17 provinces/municipals, we prospectively investigated all the patients between 29 days to 14 years old admitted to these PICU, and entry criteria were used with a Chinese pediatric critical illness severity score and American guidelines for admission and discharge policies for PICU provided by American college of critical care medicine of the society of critical caremedicine and American academy of pediatrics. ARDS was diagnosed according to the 1994 AECC definition. Information of ARDS patients admitted to all participating PICUs was prospectively collected by trained staffs using a standard case report form. In the first 5 days after study entry, data were collected twice daily, and then once daily in the subsequent days until death or discharge. If the survival period was longer than 21 days, data should be collected at least twice a week until discharge or death. The data included demographics, ventilator settings, hemodynamics and lung mechanics, arterial blood gas, liver, renal function test, prognosis, etc. Children's Hospital of Fudan University coordinated the study. We eastablished a standard central database and the web site for the collaborative study group. With a network assisted by internet techniques, some data were electronically submitted to the center in a timely and convenient way. Data management was conducted using software SPSS version 11.0.Results A total of 7,269 of ICU admissions was enrolled in a 12-month period, of which 105 (1.44%) developed ARDS. Mortality of all the admissions in these ICUs was 6.7% (485/7 269), and overall mortality for ARDS was 61.0% (64/105), which accounts for 13.2% of ICU deaths (64/485) and approximately 9.1 times as high as the average death rate of PICU. The constitutive ratio of deaths in the first 24-h period of the onset of ARDS was 35.9% (23/64). The mean (SD) time course between the disorders as predisposing factor (s) and onset of ARDS was 77.8 + 55.7 h, the 25th, 50th, 75th, 90th, 95th percentile were 24, 72, 120, 144, 168 h respectively. During the treatment period of ARDS in PICU, 97 patients received mechanical ventilation. The most commonly used ventilatory mode was pressure control (60, 61.9%). The mean (SD) values of initial peak inspiratory pressure, positive end-expiratory pressure, mean airway pressure and tidal volume in ARDS during invasive mechanical ventilation were 27.5 ± 6.1 cmH₂O, 13.9±4.1 cmH₂O, 7.1±3.4 cmH₂O, and 8.0± 3.7 ml/kg, respectively. The mean length of stay for ARDS survivors was 18.8 days which was 2.8 times as high as the average level for those of PICU stay. Costs of clinical care for ARDS survivors were 4.3 times as high as average level for PICU stay.Conclusion The results provided a preliminary profile of pediatric ARDS in China, with low incidence, high mortality and cost, and the mortality was higher than the published data in developed country. These results suggest an importance ofimplementation of advanced respiratory care concept and protocols as well as clinical epidemiology. This also calls for attention in improvement of service quality, resource and staff competence as well as welfare policies for pediatric intensive care. It also serves as a basis for further multicenter, prospective clinical studies of pediatric ARDS.Part II Experimental Study on Open Lung Concept in Rescuing Treatment of Young Piglets with ARDS Induced by Oleic AcidBackground Mechanical ventilation remains the most important treatment for pediatric ARDS. About 30% adult patients died of ARDS even though lung protective ventilation strategy by lower tidal volume was executed. A new, disputable lung protective ventilation strategy which mainly targets to ARDS, that is, open lung concept (OLC) has currently been the focus of clinical and experimental investigation of the field. Anecdotal reports revealed that it may achieve dramatic oxygenation target by increasing PIP and PEEP to very high levels to open unstable alveoli completely. Whether it is feasible in pediatric ARDS remains unknown. The aim of current study is to investigate efficacy and safety of OLC in severe experimental ALLObjective To establish an ARDS model in young piglets induced by oleic acid. To explore the feasibility of OLC on ARDS piglet and compare effects of mandatory and assist ventilatory modes after OLC was established in the ARDS piglets.Methods The study was performed in 25 male piglets (body weight 8-10 kg). Anesthesia was induced by ketamine. A tracheotomy was performed with placement of an endotracheal tube connected to the ventilator circuit, followed by mechanical ventilation with a standard tidal volume of 10 ml/kg. Following instrumentation and a 30-min stabilization period, severe lung injury was produced by oleic acid. After establishment of ARDS model, PIP and PEEP were increased step by step every 5 minutes until PaO₂/FiO₂ ≥ 400 mmHg in 21 piglets. Then PIP and PEEP were decreased and titrated step by step every 5 minutes until an optimal level of oxygenation was achieved. In 18 piglets when OLC was established successfully, they then were randomly allocated to three groups (n=6) receiving PCV, PSV and APRV,respectively for another 6 h. The variables for gas exchange, lung mechanics, hemodynamics were measured at baseline (B), establishment of ALI (M), accomplishment of OLC (R), and every 1 h during post-OLC period. Blood cytology was measured at B, M, R, and the 6 h of the post-OLC period. Values for total proteins (TP), total phospholipids (TPL), disaturated phosphatidylcholine (DSPC) were measured with biochemical methods, and values of minimum and maximum surface tension ( γ _min, γ _max) of TPL in bronchoalveolar lavage fluid (BALF) were measured using pulsating bubble surfactometer. Wet-to-dry lung weight ratio (W/D), lung morphology, myeloperoxidase (MPO) and malondialdehyde (MDA) in lung tissue were determined at the end of the experiment.Results1. Twenty-five piglets developed ARDS in 3 to 5 hours after oleic acid injection as evidenced by marked decrease of PaO₂/FiO₂< 200 mmHg, and reduction of Cdyn by 50% compared to the corresponding time B levels. Four piglets were sacrificed at once for evaluation of lung pathological changes. The pathologic changes in these piglets revealed significant protenaceous alveolar edema and atelactasis, alternative with markedly interstitial hemorrhage.2. OLC was achieved successfully in 18 piglets with ARDS as evidenced by marked increase of PaO₂/FiO₂>400 mmHg, and Cdyn significantly increased compared to that at time M (P<0.01). No pneumothorax was found in these animals.3. Gas exchange. No significant difference was observed in all gas exchange variables among the three groups at the time R. At time 06 h in the APRV group, PaO₂/FiO₂ increased significantly as compared with that at R (P<0.01), or compare with PCV (P<0.05) and PSV (P<0.05) at the same time point. The same is true for the difference of other oxygenation variables compared to PaO₂/FiO₂.4. Lung mechanics. No significant difference was observed in all lung mechanics variables among the three groups at the time R. At 06 in the APRV, PIP (P<0.01) decreased and Cdyn (P<0.01) increased significantly as compared with those at R, but no significant difference in PIP and Cdyn was found among the three groups. No significant difference of other lung mechanic variables was observed.5. Hemodynamics. No significant difference was observed in all hemodynamic variables at the time R. No significant difference was found in cardiac output (CO) between 06 and R or M. CO in the APRV (P<0.01) and the PCV (P<0.01) at R and following all time point decreased significantly as compared with that at timeB. CO in the APRV (P<0.01) and the PCV (P<0.05) was lower than that in the PSV. The difference of other hemodynamic variables was similar to CO, whcih was inversely correlated to PIP (r=-0.500, P=0.000) and MAP(r=-0.571, P=0.000).6. Inflammation. No significant difference was found in white blood cell counts (WCC) among three groups at time B, R and 06. WCC of the APRV was lower than that of the PCV (P<0.05) and the PSV (P<0.05) at R. There was no significant difference in W/D, MPO among the three groups. MDA in the APRV increased significantly as compared with the PCV (P<0.05) and the PSV (P<0.01). No difference was observed in WCC in BALF among the three groups.7. Phospholipid assay. Significant increase was seen in TPL and DSPC in the APRV and the PSV as compared to the PCV, but no significant difference in DSPC/TPL, TP and DSPC/TP.ConclusionThe achievement of OLC on piglets with ARDS is feasible. To maintain the oxygenation effects of OLC, APRV is superior to PCV and PSV. In contrast, PSV had advantage of hemodynamic stability as compared to APRV and PCV when OLC was performed. These results warrant a design of clinical investigation to assess efficacy of OLC in ARDS in pediatric patients.