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Clinical and Experimental Study on Recruitment Maneuver in the Treatment of Pediatric Acute Lung Injury

Author: WangYu
Tutor: XuHong;LuZhuJin
School: Fudan University
Course: Pediatrics
Keywords: recruitment maneuver ventilation acute lung injury children Acute lung injury pulmonary surfactant
CLC: R725.8
Type: PhD thesis
Year: 2009
Downloads: 116
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Mechanical ventilation is an important supportive therapy for patients with ALI. But while it saved the lives of many people,it was found to result in ventilator-induced lung injury(VILI) and has side effects because of the cyclic opening and closing of alveoli in the operation.Recently the potential influence of VILI was reported by the trial performed by the ARDS Network.The results showed a significant reduction of mortality in patients ventilated with the low tidal volume.However,there have also been concems that this strategy with low tidal volume may result in progressive atelectasis and increasing in intrapulmonary shunting.In the last two decades,some investigators have advocated an "open-lung" approach to mechanical ventilation in ALI. Several experimental and clinical studies showed that RM can provide the most gas exchange and minimize the damage from VILI.However,the updated data were almost collected from adult patients,and there was little information as to the treatment of children.It is known that there exists difference pathophysiologically between children and adults.Children have higher chest wall compliance and lower pulmonary compliance than adults,which may therefore require the different level of airway pressures.It is also unclear that whether children are as susceptible to VILI as adults and whether they can benefit from RM.For these reasons,the objective of this clinical trial was to observe the effects of RM on gas exchange,lung mechanics and mortality in children with ALI,which may be helpful for the following study on the application of RM to the pediatrics.In order to get more from the alveolar recruitment mechanisms of RM,we performed an additional experiment of piglets. PartⅠClinical study on Recruitment Maneuver in the Treatment of Pediatric Acute Lung InjuryBackground:Acute lung injury(ALI) is one of the main death causes of critical ill patients.With the emphasis on VILI recently,the ventilation with low tidal volume as to reduce the side effect became to be a popular treatment for the patients with ALI.Seeing that this protective strategy resulted in atelectasis during the ventilation,RM (recruitment maneuver) was proposed for the management of it.In spite that RM is new and in dispute,some researchers have found its effect on improving oxygenation in ALI. Nowadays it was considered as an important supplemental part of lung protective strategy.However,there are too few reports on children in the previous work of RM and these trials have been limited by their small size,short duration and limited follow up. Therefore,we performed this study to gain more information of RM applied to pediatric patients with ALI,which may promote the development of ventilation in children.Objectives:1.To determine the effects and feasibility of RM on children with ALI2.To investigate the impact of RM on the prognosis of young patients3.To establish a more reasonable ventilation strategy in the treatment of pediatric ALIMethods:A prospective physiologic study was conducted in PICU(Pediatric Intensive Care Unit).Our local institution’s Health Research Ethics Board granted approval.We enrolled 30 consecutive eligible pediatric patients with ALI according to the 1994 AECC definition.Children were assigned to conventional ventilation group(CON group) or RM with low tidal volume group(RM group) with fifteen patients per group. All of them underwent pressure control ventilation(PCV).The patients in CON group were ventilated with tidal volume of 10-12ml/kg using a positive end-expiratory pressure(PEEP) of 2-5cmH2O.In contrast,the ventilation strategy in RM group included 6-8ml/kg tidal volume and optimal PEEP.The level of PEEP was set the minimal level at which PaO2 was higher than 60mmHg and FiO2 was below 60%.The clinician administered RM was performed by 30cmH2O continuous positive airway pressure(CPAP) for 30 seconds.We conducted RMs once every eight hours for five days.All the other managements were at the attending physician’s discretion.Data on gas exchange,lung mechanics and hemodynamics from pre-RM to post-RM(at 5、15、30 and 60min)was recorded at the first,third and fifth day.And blood samples were collected for the measurement of plasma levels of IL-6 and SP-A at the same day.To monitor the pathogenic conditions of children,the radiographic examination was rechecked for everyone within one week.At last,we documented the mortality and the length of ventilation of every patient.The data were summarized by descriptive statistics,and physiologic variables were compared between the two groups.Results:1.A total of 30 children with ALI was enrolled in our study,of which 15 were boys, 63.3%resulted from inflammation of lung,15(50%) were below one year.The length of ventilation was 11.04±4 days on the average.2.All the patients met the criteria for ALl at baseline,and there were no significant differences in the age,gender,heart rates(HR),blood pressure(BP),P/F radio and lung dynamic compliance(Cyn) between the two groups.(p>0.05)3.There was a significant increase in P/F ratio(281.82±15mmHg) in RM group from the third day,while it was 256.87±18.7mmHg in CON group at that time.At the fifth day,the P/F ratio continued to increase into 309.87±20.6mmHg in RM group,which was much higher than CON group(273.6±24.8mmHg)(p<0.01).Significant improvements in oxygenation were demonstrated post-RM compared to pre-RM(p<0.01),P/F ratio increased by 23.3 per cent,18.3 per cent and 17.4 per cent respectively at the first,third,fifth day.Similar significant results were found in the changes of A-aDO2.At the third and fifth day,A-aDO2 decreased to 119±37.5mmHg and 92±33.8mmHg in RM group,while it changed into 148.5±39mmHg and 120.9±39.7mmHg in the controlled group.The difference was significant(p<0.05).4.Pulmonary mechanics have also been shown to increase in RM group.Cdyn of the group come to 0.928±0.12 ml/cmH2O.kg at the fifth day,which was higher than CON group(0.826±0.124 ml/cmH2O-kg)(p<0.05).Cdyn kept rising after RMs,and the largest rise was at 15min.There was a sustained significant decrease in PIP and RAW following the RM in one hour(p<0.01).5.Though there were some changes in blood pressure and heart rate following RM,both of the parameters soon returned to the pre-RM levels in an hour.No evidence of statistically significant changes were found during the course of RM(p>0.05). 6.No evidence of significant change in the level of IL-6 was found at study entry.When it come to the third day and the fifth day,the concentration of IL-6 in RM group were reduced into 304.3±58.6pg/ml and 223±60.6pg/ml,which were lower than that in CON group(374.9±105.7pg/ml,316.2±107.3pg/ml)(p<0.05).7.In RM group,the level of SP-A was 256±59.4ng/ml at the third day,and it decreased into 194.2±54.4ng/ml at the fifth day.Compared to it,the concentration of SP-A in the CON group was 293.5±48.6ng/ml and 252.1±71.5ng/ml respectively.Significant reduction of the concentration of SP-A at the third day and fifth day were observed in RM group(p<0.05).8.During the entire study of 5 days,one patient in CON group developed pneumothorax, eight out of twelve objects that appeared bilateral infiltration on X-ray relieved.In RM group,one patient suffered from emphysema,and all of eleven objects whose chest radiograph showed infiltration improved.There was significant difference between them(p<0.05).9.Though it seems that the length of ventilation in RM group(10.15±4.3d) is lower than CON group(12±3.6d),there was no significant change between them.And RM resulted in no significant difference in all-cause hospital mortality compared with CON group.Conclusions:1.RM can improve the oxygenation and attenuate the deterioration in pulmonary function in usual treatment for pediatric ALI.2.RM can alleviate the injury of the lung and may be helpful for improving the outcomes of the patients.3.RMs is safe and can be operated easily.PartⅡExperimental Study on Recruitment Maneuver in the Treatment of Young Piglets with ALIBackground:Among the treatments for ALI,RM can open collapsed alveoli,improve dramatic oxygenation and alleviate VILI by increasing PEEP to very high levels. However,whether it is feasible and effective in pediatric animals needs to be researched. And the mechanisms of underlying RM are still poorly understood.The aim of current study is to give further investigation to RM by analysis of pulmonary surfactant in ALI model of young piglet and to study whether there were any benefits in facilitating lung repair during recovery from ALI by RM.Objectives:1.Explore the feasibility and effects of RM on young animals with ALI.2.Investigate the effects of recruitment maneuver(RM) on pulmonary surfactant in young piglets with ALI and the possible underlining mechanisms of lung recruitment after RM.3.Investigate the effects of RM on lung repairMethods:The piglet model of ALI was established by lipopolysaccharide iv injection,ALI was defined as PaO2/FiO2≤300 mmHg,dynamic lung compliance(Cdyn) decreased by more than 30%of its baseline level.This moment was regarded as treatment time 0 h. And then two animals were immediately sacrificed.Their lungs showed that LPS induced diffuse alveolar damage represented by alveolar atelectasis and leukocyte sequestration.Twelve male piglets were randomly divided into two groups: conventional ventilation group(CON group) and RM with low tidal volume group(RM group).They all received pressure controlled ventilation(PCV).A tidal volume of 10-15ml/kg and a PEEP of 2-5cmH2O were used in the CON group.And the ventilator settings in RM group were set at follows:tidal volume 6-8ml/kg,PEEP 6-8cmH2O. RMs were conducted by regulating FiO2 to 100%,applying 30cmH2O of continuing positive airway pressure(CPAP) for 30s,then presumed to previous settings,and regulated PEEP to 2 cmH2O above LIP(low inflection point),the modality was repeated once every an hour for total eight times.Arterial blood gas,dynamic lung compliance(Cdyn),systematic hemodynamics were monitored at the baseline,establishment of ALI,and each hour during the treatment.Blood samples were collected at the end of the treatment.After eight hours of ventilation,animals were sacrificed and lung tissues and bronchoalveolar lavage fluid (BALF) were collected.The mRNA expression of surfactant protein-A(SP-A)、SP-B、 SP-C、SP-D and TGF-β1 and distribution of SP-A protein in the piglet lungs were assessed by real time PCR and immunohistochemistry.The biochemical analyses of TP, total phospholipids(TPL),DSPC and white cell count were proceeded.Lung tissue was also determined in morphology by the distensibility and injury score.And the lungs were processed for SP-A and TGF-β1 levels in BALF and plasma,which were measured by enzyme-linked immunosorbent assay(ELISA).Results:1.ALI model:Piglets appeared transient purple plague,poor response,the increase of blood temperature and heart rate,tachypnea,and the decrease of systemic blood pressure at 0.5-1 hour since LPS infused.It took 4-8 h to result in ALI.The lung pathology showed that LPS induced diffuse alveolar damage represented by alveolar bleeding,atelectasis,leukocyte sequestration.2.Hemodynamics during treatment:No significant difference was observed in heart rate(HR)、cardiac output(CO) and mean arterial blood pressure(MBAP) between the two groups.But extravascular lung water index(ELWI) and Pulmonary vascular permeability index(PVPI) in RM group all decreased compared to CON group.3.Lung mechanics during treatment:Cdyn in RM group increased quickly at T1,and there is a significant difference between two groups during treatment(p<0.05).But there was no significant differences in ventilation index(Ⅳ)(P>0.05).4.Gas exchange during treatment:P/F(ratio of PaO2 to FiO2) of RM group was significantly higher than that of CON groups from T2(p<0.05).A-aDO2 (Alveolar-to-arterial oxygen difference) and Qs/Qt of RM group were obviously lower in comparison to that of CON group(p<0.05),and there was a reducing trend of them in RM group.In the first and third RM,P/F increased more notably after RM than that before RM(p<0.05),and they went up to the most at 15 min and 30 min.5.Phospholipids,white cell counts(WCC),and TP in BALF:RM group had higher DSPC and TPL than that of CON group(p<0.05),and had lower WCC and TP level in BALF than that of CON group(p<0.05).6.Lung histopathology:There was prominent neutrophil infiltration in CON group and RM group had moderate pathological changes.Volume density of alveolar aeration in RM group was significantly higher than in CON group(p<0.05).7.The rnRNA expression ofSP-A、SP-B、SP-C、SP-D and TGF-β1 in the lung tissue: Compared with CON group,RM group had higher expression of SP-A、SP-B、SP-C、SP-D.But the expression of TGF-β1 is lower than CON group(p<0.05).8.The protein expression of SP-A in lung tissue:The average grey value of SP-A in RM group was 97.8±6.4,which was lower than that in CON group(106.3±8.5)(p<0.05).9.SP-A concentration in plasma and BALF:The concentration of SP-A in RM group BALF(741.3±92 ng/ml) was higher than CON group(659±74 ng/ml),while the level of SP-A in plasma(119.6±31 ng/ml) was lower than CON group (283.9±77.4ng/ml).10.TGF-β1 concentration in plasma and BALF:The levels of TGF-β1 in plasma and BALF in RM group were 3104.7±521.5ng/ml and 54.5±24.6ng/ml respectively,but they were all raised to 3884.3±695.9ng/ml and 78.3±28ng/ml in CON group.The difference was significant(p<0.05).Conclusions:1.RM is feasible and results in superior gas exchange and Cdy compared with conventional PPV,while there is no significant change in hemodynamics.RM is a safe and effective approach to alveolar recruitment.2.RM can promote the synthesis and expression of surfactant protein,reduce dysfunction of PS,which may improve alveolar recruitment.3.RM can alleviate VILI and suppress the expression of TGF-βmRNA in the lung, which may postpone the profibrogenetic process and contribute to the prognosis of ALI.

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