The Effect Of Venovenous Extracorporeal Membrane Oxygenation And Combined With Continous Renal Replacement Therapy On The Heart And Associated Mechanism

Acute respiratory distress syndrome(ARDS)is a main cause of death in critically ill patients.Venovenous extracorporeal membrane oxygenation(VV ECMO)is an efficient therapy for severe respiratory failure patient refractory to conventional therapy.It provides extracorporeal gas-exchange,maintaining sufficient tissue oxygenation and carbon dioxide elimination,and provides time for lung to rest and recovery.Patients with severe ARDS have a high prevalence of cardiac injury and dysfunction.While VV ECMO does not provide direct cardiac support,it is significant to clarify the condition of cardiac function during VV ECMO treatment.Theoretically,VV ECMO plays paradoxical effect on the heart,and the effect of VV ECMO on the heart in adult ARDS patients has not ever been studied.As an invasive therapy,VV ECMO is associated with several adverse effects and potential risks,among which the most common is the activation of the inflammatory response and exacerbation of the inflammatory cascade,with massive production of proinflammatory cytokines,inducing organ dysfunction.Continuous renal replacement therapy(CRRT)operates with the ability of inflammatory mediator elimination,preserving organ function.Therefore,we speculate that combine CRRT with VV ECMO has benefit on the heart.Nevertheless,there is no associated research.The object of this project is to systemically study the effect of VV ECMO and VV ECMO combine with CRRT on the heart through animal experiment and clinical research,and to explore the associated mechanism,providing reference for clinical protocol improvement,to improve the treatment effect and overall survival.PART?Effect of WV ECMO and combined with CRRT on the heart in a healthy piglet modelStudy ? Effect of VV ECMO on the heart in a healthy piglet modelObjectives:To study the effect of VV ECMO treatment itself on the heart in multi-aspects including hemodynamics,myocardial morphology,and myocardial energy metabolism;and to explore the associated mechanism.Methods:Twelve healthy piglets were randomly assigned into two groups:the control group and the ECMO group(n=6/each).All the animals received the same animal preparation procedures;in the ECMO group,heparin was intravenous injected for anticoagulation,ECMO cannulaes were placed and ECMO circulation was instituted.Hemodynamics was recorded at baseline,2 hour after induction,and every 4 hours thereafter,to assess the cardiac performance.Blood was collected at baseline,2h,6h,12h,and 24h after induction to measure the serum level of cardiac injury markers cTnI and CK-MB.All animals were monitored for 24 hours and were euthanized and myocardium was harvested.Myocardial histology,ultrastructure of cardiomyocyte and mitochondria were observed,and activities of mitochondrial complexes ?-? were measured,to assess the effect on cardiomyocyte and mitochondria.Myocardial inflammatory and oxidative stress was observed to explore the associated mechanism.Results:Hemodynamics was stable in each group of animals throughout the experiment,and no significance was presented between groups.Serum level of cTnI and CK-MB lies within the normal range and no significance was showed.Myocardium from ECMO group can be observed interstitial edema under optical microscope,and myofilament was mildly disorderd with focal myofilament dissolved under transmission electron microscope.Mitochondrion from ECMO group was also with obvious swollen,and the activities of complex ?-? decreased,with complex I and IV reached significance(p<0.05).Myocardial inflammatory was activated in the ECMO group,with significantly increased of activity of MPO,concentration and mRNA expression of inflammatory cytokines TNF-a,IL-1b and IL-6(p<0.01).Myocardial oxidative damage products of lipid and protein--MDA and protein carbonyl were increased significantly in the ECMO group(p<0.01).Conclusions:VV ECMO treatment itself will induce myocardium swollen,focal myofilament dissolution,and myocardial energy metabolism impaired mildly;nevertheless,the injury is within the cardiac compensated ability for a healthy heart.The activation of myocardial inflammation and oxidative stress is an important mechanism for the VV ECMO-associated cardiac injury.Study ? Effect of combining CRRT on the heart in healthy piglet treated by VV ECMOObjectives:To study the effect of combining CRRT on the myocardial inflammation and oxidative stress in healthy piglet treated by VV ECMO.Methods:Twelve healthy piglets were randomly assigned into two groups:the ECMO group and the ECMO+CRRT group(n=6/each).After ECMO cannulation,VV ECMO was instituted in the ECMO group,and VV ECMO and CRRT was instituted simultaneously in the ECMO+CRRT group.All animals were monitored for 24 hours and were euthanized and myocardium was harvested.Myocardial inflammatory and oxidative stress was detected;myocardial histology,ultrastructure of cardiomyocyte and mitochondrion were observed;and activities of mitochondrial complexes ?-? were measured.Results:Compared with ECMO group,myocardial inflammation was attenuated in the ECMO+CRRT group,with significantly decreased activity of MPO(p<0.05),decreased concentration of myocardial IL-1? and IL-6(p<0.01),decreased myocardial mRNA expression of IL-6(p<0.05).Myocardial oxidative damage products were also decreased in the ECMO+CRRT group,with MDA reached significance.Myocardial and mitochondrion swollen attenuated,myofilament dissolution ameliorated,and the activities of complexes increased in the ECMO+CRRT group.Conclusions:Combining CRRT attenuates myocardial inflammation and oxidative stress induced by VV ECMO,preserving the cardiac function.Combining CRRT with VV ECMO is a more optimized therapy.PART ?Effect of VV ECMO combining CRRT on the heart in a traumatic ARDS piglet modelStudy I Establishment of traumatic ARDS modelObjectives:To establish a traumatic severe ARDS model with good reproducibility,high fidelity,low cost,and easy to perform,for further study.Methods:Four healthy piglets were applicated.Diffused chest contusion and followed ischemia-reperfusion was used:object weighting 40%of the pig's weight was used,and fell on the chest of the pig from 1 meter high;immediately,the pigs underwent the systemic ischemia for 2 hours,and then reperfusion for 2 hours;and then observed for 24 hours.The survival was observed;changing of oxygen index was detected;CT score and histopathological changes of the lung were assessed to evaluate the degree of lung injury;general and microstructure of the heart is also assessed to evaluate the cardiac injury.Results:There were 2 animals died in the model establishment process,and no animal died in the observation duration,with mortality of 50%,and the average living time is 1417 hours.After the model established,the oxygen index was remarkably decreased,and continue to decrease to less than 200 during the observation.CT score(CTVI)was 52.0 ± 7.1%.After dissected,diffused injury of the lung can be seen,while no physical injury was presented on the heart.Both the histopathological change of the lung and the heart consist with the pathophysiology of ARDS.Conclusions:Diffused chest contusion and followed ischemia-reperfusion under this condition can be used to establish traumatic ARDS model,without physical damage to the heart,and the histopathological change of the heart consists with the pathophysiology of ARDS.The traumatic severity satisfies the demand of further study.Study ? Effect of VV ECMO combining CRRT on the heart in a traumatic ARDS piglet modelObjectives:VV ECMO is an important treatment for patients with severe ARDS,and result of former studies indicate that VV ECMO combines CRRT is a more optimized therapy.The objective of this part is to simulate the clinical pathophysiology of ARDS,and to study the effect of VV ECMO combines CRRT on the original injured heart,and explore the associated mechanism.Methods:Eighteen healthy piglets were applicated.Traumatic ARDS model was established according to the method described in the study I of part II.Then the animals were randomly assigned into three groups:the ARDS-model group,the ARDS-ECMO group and the ARDS-ECMO+CRRT group(n=6/each).Hemodynamics was recorded at baseline,immediately and 2 hours after the ARDS model established,and every 4 hours thereafter.Blood was collected at baseline,immediately,2h,6h,12h,and 24h after the ARDS model established to measure the serum level of cardiac injury markers cTnI and CK-MB.All animals were monitored for 24 hours and were euthanized and myocardium was harvested.Myocardial histology,ultrastructure of cardiomyocyte and mitochondria were observed,and activities of mitochondrial complexes ?-? were measured.Myocardial inflammatory and oxidative stress was detected.Results:During the observation,hemodynamics was stable in the ARDS-ECMO group and the ARDS-ECMO+CRRT group,while HR gradually increased and MAP gradually decreased in the ARDS-model group,and reached significance after 14 hours(p<0.01).Remarkably myofilament fragmentation can be seen under both optical microscope and transmission electron microscope;while myofilament fragmentation decreased and level of serum cardiac injury markers cTnI and CK-MB reduced in the ARDS-ECMO group and ARDS-ECMO+CRRT group.Mitochondrial structure was improved,and activities of complexes increased in the ARDS-ECMO+CRRT group.Myocardial inflammation increased midly and oxidative stress attenuated in the ARDS-ECMO group;Myocardial inflammation and oxidative stress decreased significantly in the ARDS-ECMO+CRRT group.Conclusions:Myocardium was injured under ARDS condition,and therapy of VV ECMO combines CRRT could reduce myocardial inflammation and oxidative stress.and attenuate cardiac injury,preserving cardiac function.PART ?Effect of VV ECMO combining CRRT on the heart in ARDS patientsObjectives:To study the effect of VV ECMO combines CRRT on the hemodynamics and myocardium in severe ARDS patients,and the association with outcome.Methods:Patients who treated by VV ECMO combines CRRT for severe ARDS in the surgical intensive care unit of Jinling Hospital from January 2011 to November 2013 were included,and patients who younger than 18 years old,or treated by ECMO less than 24 hours were excluded.Hemodynamics of the first 24 hours,and changing of serum level of cardiac injury markers cTnI and CK-MB were analyzed,and association between changing of cardiac injury and outcome was evaluated.Results:A total 14 patients who met criteria were identified.The ECMO survival was 64.3%,and overall survival was 57.1%.After ECMO and CRRT were instituted,HR gradually decreased;for patients vasoactive-independent before ECMO,MAP gradually increased;for patients vasoactive-dependent before ECMO,dose of vasoactive decreased while MAP maintained.During the treatment,serum level of cTnI and CK-MB was decreasing,without significance presented.Dividing the patients into survivors and nonsurvivors according to the outcome,serum level of cTnI and CK-MB was decreasing in survivors and increasing in nonsurvivors,and difference between survivors and nonsurvivors reached significance(p<0.01).Conclusions:Treatment of VV ECMO combines CRRT could improve hemodynamics and attenuate cardiac injury,with some potential cardiac protection;moreover,changing of cardiac injury during treatment is an important influence on outcome.