| Cardiac arrest(CA),which has a high incidence rate and a high mortality rate,has become one of the major issues of public health worldwide.The data from the Europe and USA has manifested that the initial rates of resuscitation success in non-traumatic and traumatic CA victims were 40% and 15.4%,and their survival to hospital discharge were 10.4% and 5.1%,respectively.The clinical prognosis of CA victims was worse in our country.It has been suggested that after experiencing one CA event,the key factors for improving the outcomes of CA victims are to effectively improve the techniques of basic life support during cardiopulmonary resuscitation(CPR)and also enhane the degree of organ protection during the post-CPR care.Currently,mild hypothermia(MH)has been confirmed to produce effective organ protection after resuscitation in non-traumatic CA victims and also strongly recommended by AHA and ERC CPR guidelines.However,the conventional methods of MH implementation might cause volume overload or have a slow cooling rate.Additionally,these methods have several defects such as uncomfortable body feeling,easily inducing shivering and unstablely maintaining the target cooling temperature.All of these problems would make an nfluence on its protective effects of vital organs after resuscitation.Considering that most traumatic cardiac arrest(TCA)victims has severe and uncontrolled hemorrhage,it's difficult to effectively control the hemorrhage and implement the CPR at the early stage,and also hard to maintain an adequate perfusion of body organs at the late stage,all of which would make it more difficult to resuscitate the victims successfully.Recently,some investigations have demonstrated that aortic balloon occlusion(ABO)might be effective to control the hemorrhage and also improve the efficacy of CPR;however,a longer duration of occlusion might aggravate the severity of ischemic reperfusion injury of body organs.In this study,we would investigate the effectiveness of two optimal strateties of MH implementation in post-resuscitation multiple organ protection after non-traumatic CA,and the optimal method of ABO implementation during TCA and resuscitation.Part 1 Rapid hypothermia induced by CRRT early after resuscitation and its effects on post-cardiac arrest syndromeObjective: To establish a porcine model of CA and resuscitation,and then investigate the effectiveness and safety of MH induced by continuous renal replacement therapy(CRRT)early after resuscitation and its effects on post-cardiac arrest syndrome.Methods: Thirty-two male domestic pigs weighing 36±2 kg were utilized.The animals were then randomized with the Sealed Envelope Method into 1 of the 4 groups: sham(S,n=5),normothermia(NT,n=9),surface cooling(SC,n=9),and CRRT cooling(CRRT-C,n=9).The animals in the S group only finished the animal preparation without experiencing the procedure of CA and resuscitation.In the NT,SC and CRRT-C groups,ventricular fibrillation was induced by 1-m A alternating current via the pacing catheter and untreated for 8 min,and then CPR was performed for 5 min;both of which was used to establish the pig model of CA and resuscitation.In the S and NT groups,a normal temperature of 38.0±0.5? was maintained with the aid of surface blanket throughout the experiment.At 5 min after successful resuscitation,the cooling in the CRRT-C group was implemented by withdrawing the blood via the extracorporeal circuit to exchange the heat with 4? of cold water in vitro.After body temperature was decreased to 33?,a target temperature of 33±0.5? was maintained by CRRT-C until 8 h post-resuscitation,and followed by surface blanket cooling to maintain the target temperature until 24 h post-resuscitation.In the meanwhile,the cooling in the SC group was performed by circulating 4? of cold water into surface blanket to extract the heat from the body.The same target temperature was achieved and then maintained by SC until 24 h post-resuscitation.After that,the animals in the two hypothermic groups were rewarmed by SC at a rate of 1?/h until body temperature reached the normal level.The ollowing measurements were carried out in the experiment:(1)Baseline heart rate(HR),mean arterial pressure(MAP),pressure of end-tidal carbon dioxide(PETCO2),arterial blood gas and lactate were measured prior to the induction of CA.(2)The outcomes of CPR including coronary perfusion pressure(CPP),rate of resuscitation success,duration of CPR,number of defibrillations and dosage of epinephrine were recorded during CPR.(3)The temperautres in blood,tympanum and rectum,and hemodynamics including HR and MAP were continuously measured during 30 h post-resuscitation.(4)Myocardial function including stroke volume(SV)and global ejection fraction(GEF)were evaluated with the Pi CCO system at 1,3,6,12,24,and 30 h post-resuscitation.Arterial and venous blood samples were collected at the same time points.Arterial blood samples were used for the measurements of blood gas,lactate,and electrolyte.Venous blood samples were used to measure coagulation parameters including prothrombin time(PT)and activated partial thromboplastin time(APTT),systemic inflammatory cytokines including tumor necrosis factor-a(TNF-a)and interleukin-6(IL-6),the injury biomarkers of heart and brain including cardiac troponin I(c Tn I),neuron-specific enolase(NSE)and S100 B protein(S100B).(5)For the evaluation of inflammation,oxidative stress and cell apoptosis in the heart and brain,left ventricular myocardium and cerebral cortex were harvested immediately after animal euthanasia at 30 h post resuscitation.Subsequently,the levels of TNF-a,IL-6 and malondialdehyde(MDA),the activities of superoxide dismutase(SOD),apoptotic index(AI)and cleaved-caspase 3 expression in the heart and brain were measured.Results: 1.Before CA,body weight,HR,MAP,PETCO2,lactate and body temperature did not differ among the four groups(all P>0.05).2.During CPR,CPP was maintained at an even level in the NT,SC and CRRT-C groups.Eight animals were successfully resuscitated in each group.Additionally,the differences in the duration of CPR,number of defibrillations and dosage of epinephrine ere not significant among the three groups(all P>0.05).3.After resuscitation,blood,tympanic and rectal temperatures were maintained at a normal level in the S and NT groups.However,these temperatures were gradually decreased to 33?,then stably maintained until 24 h post-resuscitation,and finally rewarmed at the same speed to normal temperature in the SC and CRRT-C groups.During the induction phase,the cooling rates of 9.8?,3.9? and 3.3?/h in blood,tympanum,and rectum were achieved in the CRRT-C group,and their times to target temperature were 28,77 and 91 min,respectively.However,the cooling rates were 1.5?,1.6? and 1.7?/h in these sites in the SC group,and their times to target temperature were 185,169 and 169 min,respectively.The cooling rates were significantly faster and the times to target temperature were significantly shorter in the CRRT-C group compared to the SC group(all P<0.05).4.After resuscitation,HR was increased and MAP was decreased in the NT,SC and CRRT-C groups.However,HR returned to near-baseline level during hypothermic treatment in the SC and CRRT-C groups,which was significantly lower than that in the NT group(all P<0.05).In addition,post-resuscitation MAP was decreased but maintained at a normal physiological level of more than 98 mm Hg in the two hypothermic groups.5.After resuscitation,p H was significantly decreased and lactate was significantly increased at 1 and 3 h in the NT,SC and CRRT-C groups compared with the S group(all P<0.05).However,the values of p H and lactate gradually returned to near-baseline level starting 6 h after resuscitation.After resuscitation,the decrease in PO2 was observed in the NT,SC and CRRT-C groups.However,the values of PO2 starting 6 h after resuscitation were significantly higher in the two hypothermic groups than in the NT group(all P<0.05).In addition,the values of PO2 starting 12 h after resuscitation were significantly higher in the CRRT-C group compared to the SC group(all P<0.05).The values of arterial PCO2,potassium,sodium and calcium were maintained at a normal level throughout the experiment,and no differences were observed among the our groups(all P>0.05).6.After resuscitation,abnormal blood coagulation was observed in the NT,SC and CRRT-C groups,in which PT and APTT were firstly decreased and then increased in the NT group,and they were firstly increased and then decreased in the SC and CRRT-C groups.Further analysis showed that the values of PT were always maintained at a normal level in the three groups;however,the values of APTT at 6 and 12 h post resuscitation were significantly greater in the SC group than in the S and NT groups,and its values at 1,3,6 and 12 h post resuscitation were significantly greater in the CRRT-C group compared to the S,NT and SC groups(all P<0.05).7.Post-resuscitation systemic inflammation,which was indicated by the increase of serum TNF-a and IL-6,was observed in the NT,SC and CRRT-C groups.However,the serum levels of TNF-a and IL-6 starting 6 h after resuscitation were significantly reduced in the two hypothermic groups than in the NT group(all P<0.05).The levels of inflammatory cytokines in serum were significantly decreased starting 12 h after resuscitation in the CRRT-C group compared to the SC group(all P<0.05).8.Post-resuscitation myocardial dysfunction and damage,which were indicated by the decrease of SV and GEF and the increase of serum c Tn I,were observed in the NT,SC and CRRT-C groups.However,the values of SV and GEF were significantly increased starting 1 h after resuscitation in the CRRT-C group and starting 6 h after resuscitation in the SC group when compared with the NT group(all P<0.05).The values of GEF starting 12 h after resuscitation and the values of SV starting 24 h after resuscitation were significantly increased in the CRRT-C group when compared to the SC group(all P<0.05).The serum levels of c Tn I were significantly lower starting 6 h after resuscitation in the SC group than in the NT group,and meanwhile its levels were significantly decreaed in the CRRT-C group compared to the NT and SC groups(all P<0.05).9.Post-resuscitation brain damage,which were indicated by the increase of serum NSE and S100 B,were observed in the NT,SC and CRRT-C groups.However,the erum levels of NSE and S100 B were significantly decreased starting 6 h after resuscitation in the CRRT-C group and starting 12 h after resuscitation in the SC group when compared with the NT group(all P<0.05).The levels of biomarkers of brain damage were further significantly decreased starting 24 h after resuscitation in the CRRT-C group when compared to the SC group(all P<0.05).10.At 30 h post resuscitation,tissue inflammation,oxidative stress and cell apoptosis in the heart and brain were observed in the the NT,SC and CRRT-C groups,which were indicated by the increased levels of TNF-a,IL-6 and MDA,the decreased activities of SOD and the increase of AI and cleaved-caspase 3 expression.However,the levels of TNF-a,IL-6 and MDA were significantly decreased,the activities of SOD were significantly increased,and both of AI and cleaved-caspase 3 expression were significantly reduced in the two hypothermic groups than in the NT group(all P<0.05).Additionally,tissue inflammation,oxidative stress and cell apoptosis in the heart and brain were further significantly decreased in the CRRT-C group compared to the SC group(all P<0.05).Conclusion: In a porcine model of CA and resuscitation,MH could be rapidly induced by CRRT early after resuscitation,in which the cooling was significantly faster than conventional SC and its safety was equal to SC.Consequently,CRRT-C further significantly alleviated the severity of post-cardiac arrest syndrome compared with SC,in which CRRT-C produced significantly greater myocardial and cerebral protection through the inhibition of tissue inflammation,oxidative stress,and cell apoptosis compared to SC.Part 2 The effects of esophageal cooling on cardiac and cerebral injuries after cardiac arrest and resuscitationObjective: To establish a porcine model of CA and resuscitation,and then investigate the effects of esophageal cooling(EC)on post-resuscitation cardiac and cerebral injuries and its potential mechanisms.Methods: Thirty-two male domestic pigs weighing 36±2 kg were used.The animals were randomized with the Sealed Envelope Method into the following 4 groups: S(n=5),NT(n=9),SC(n=9),and EC(n=9).The animals in the S group experienced the animal preparation only,and the animal model was established by inducing 8 min of ventricular fibrillation and performing 5 min of CPR in the other three groups.In the S and NT groups,a normal temperature of 38.0±0.5? was maintained by surface blanket throughout the experiment.At 5 min after resuscitation,MH was implemented via EC catheter or surface blanket to reach a target temperature of 33?,and then maintained until 24 h post-resuscitation,and followed by a rewarming rate of 1?/h for 5 h.The following measurements were carried out in the experiment:(1)Baseline hemodynamics,arterial blood gas and lactate were measured prior to the induction of CA.(2)The outcomes of CPR including CPP,rate of resuscitation success,duration of CPR,number of defibrillations and dosage of epinephrine were recorded during CPR.(3)Blood,tympanic and rectal temperatures,HR and MAP were continuously measured during 30 h post-resuscitation.(4)Arterial blood samples were collected for the measurements of blood gas and lactate at 1,3,6,12,24,and 30 h post resuscitation.(5)GEF were evaluated with the Pi CCO system at 1,6,12,24,and 30 h post resuscitation.In the meanwhile,venous blood samples were collected to measure the serum levels of TnI,NSE and S100 B.(6)At 30 h post resuscitation,the animals were euthanized,and then left ventricular myocardium and cerebral cortex were rapidly harvested to measure the levels of TNF-a,IL-6 and MDA,the activities of SOD,AI and cleaved-caspase 3 expression.In the meanwhile,the tissue of lower esophagus was harvested for pathological analysis.results: 1.Before CA,baseline body weight,hemodynamics,tissue perfusion and body temperature did not differ among the four groups(all P>0.05).2.During CPR,the same levels of CPP were achieved in the NT,SC and EC groups.The outcomes of CPR including the rate of resuscitation success,duration of CPR,number of defibrillations and dosage of epinephrine were not significant among the three groups(all P>0.05).3.In the experiment,surface blanket was used to maintain body temperature at a normal level in the S and NT groups.At 5 min after resuscitation,the animals in the SC and EC groups were cooled until blood,tympanic and rectal temperatures were gradually decreased to 33?.The cooling rates in these temperatures were significantly faster and their times to target temperature were significantly shorter in the EC group than in the SC group(all P<0.05).During the maintenance phase,these temperatures were maintained at 32-34? in the SC and EC groups,and no differences in maximum,mean and minimum temperatures and temperature variability were observed between the two hypothermic groups(all P>0.05).During the rewarming phase,the same rate of rewarming of 0.9-1.0? was achieved in these temperatures in the SC and EC groups.4.After resuscitation,HR was significantly increased during the induction and rewarming phases in the SC and EC groups compared with the S group(all P<0.05).However,HR returned to near-baseline level during the maintenance phase in the two hypothermic groups,in which the differences were not significant compared to the S roup(all P>0.05).MAP was significantly decreased during the induction and maintenance phases in the SC and EC groups compared with the S group(all P<0.05).However,MAP was maintained at a normal physiological level in the two hypothermic groups.5.Post-resuscitation tissue hypoperfusion and hypoxia,which were indicated by the decrease of p H and PO2 and the increase of lactate,were observed in the NT,SC and EC groups compared to the S group.The values of p H and lactate were gradually improved starting 6 h after resuscitation in the three groups,and meanwhile the values of PO2 were significantly greater in the two hypothermic groups than in the NT group(all P<0.05).In addition,the values of PO2 were significantly greater starting 12 h after resuscitation in the EC group compared to the NT and SC groups(all P<0.05).Post-resuscitation PCO2 was maintained at a normal physiological level,and no difference was observed among the four groups(all P>0.05).6.Post-resuscitation myocardial dysfunction and damage,which were indicated by decreased GEF and increased c Tn I,were observed in the NT,SC and EC groups compared to the S group.However,the values of GEF were significantly increased and the serum levels of c Tn I were significantly decreased starting 6 h after resuscitation in the SC and EC groups than in the NT group(all P<0.05).The values of GEF starting 12 h after resuscitation and the serum levels of c Tn I starting 6 h after resuscitation were significantly improved in the EC group than in the SC group(all P<0.05).7.Post-resuscitation brain damage,which were indicated by significantly increased NSE and S100 B,were observed in the NT,SC and EC groups compared to the S group(all P<0.05).However,the serum levels of NSE and S100 B were significantly decreased starting 6 h after resuscitation in the EC group and starting 12 h after resuscitation in the SC group compared with the NT group(all P<0.05).The severity of brain damage was further significantly alleviated starting 24 h after resuscitation in the EC group compared to the SC group(all P<0.05).8.At 30 h post-resuscitation,cardiac and cerebral inflammation,oxidative stress,cell apoptosis were observed in the the NT,SC and EC groups compared to the S group(all P<0.05),which were indicated by the increase of TNF-a,IL-6 and MDA contents,the decrease of SOD activities and the increase of AI and cleaved-caspase 3 expression.However,cardiac and cerebral inflammation,oxidative stress,cell apoptosis were significantly alleviated in the SC and EC groups than in the NT group(all P<0.05).Additionally,all these pathological injuries were further significantly improved in the EC group than in the SC group(all P<0.05).9.Pathological analysis indicated that the tissue of lower esophagus was normal in the S group and had mild inflammatory infiltrates in the NT,SC and EC groups.Conclusion: In a porcine model of CA and resuscitation,EC was significantly faster in the induction of hypothermia and equally effective for its maintenance and rewarming when compared with SC.Consequently,EC further significantly alleviated post-resuscitation cardiac and cerebral injuries when compared to SC,in which the protective mechanisms were related with the inhibition of tissue inflammation,oxidative stress,and cell apoptosis.Part 3 The effects of different durations of ABO on the outcomes of resuscitation after TCAObjective: To establish a porcine model of TCA,and then investigate the effects of different durations of ABO on the efficacy of CPR and post-resuscitation multiple organ injury.Methods: Twenty-seven male domestic pigs weighing 33±4 kg were utilized.The animals were then randomized with the Sealed Envelope Method into the following groups: Control(n=12),30-min ABO(n=7),and 60-min ABO(n=8).After animal preparation was completed,forty percent of estimated blood volume was removed with the aid of a pump during an internal of 20 min.The animals were then subjected to 5 min of untreated ventricular fibrillation and 5 min of CPR.Coincident with the start of CPR,aortic balloon was inflated to stop the blood flow of aortic zone I for 30 min in the 30-min ABO group or 60 min in the 60-min ABO group.In the meanwhile,fluid resuscitation was initiated by the infusion of normal saline with 1.5 times of hemorrhage volume in 1 h,and finished by the reinfusion of 50% of the shed blood in another 1 h.The following measurements were carried out in the experiment:(1)Baseline HR,MAP,PETCO2 and lactate were measured prior to the induction of TCA.(2)The outcomes of CPR including CPP,rate of resuscitation success,duration of CPR,number of defibrillations,dosage of epinephrine were recorded during CPR.(3)Myocardial function including cardiac output(CO)and ejection fraction(EF)were evaluated with the Mindray ultrasound system at 1,3 and 6 h post resuscitation.Arterial blood samples were collected at the same time points to measure blood gas,lactate and electrolyte.(4)Venous blood samples were collected at 1,3,6 and 24 h post resuscitation to measure systemic inflammatory cytokines including TNF-? and IL-6,and the injury biomarkers of heart,brain,kidney and intestine including c Tn I,NSE,Cr,BUN,IFABP and DAO.(5)Neurological deficit score(NDS)was evaluated at 24 h post resuscitation.After that,the animals were euthanized,and then left ventricular myocardium,cerebral cortex,left kidney and distal ileum were harvested to measure AI and cleaved-caspase 3 expression.Results: 1.Before TCA,body weight,HR,MAP,PETCO2 and lactate did not differ among the three groups(all P>0.05).2.During CPR,CPP was significantly increased in the 30-min and 60-min ABO groups compared with the control group(all P<0.05).Consequently,a 100% of resuscitation success was achieved in the two ABO groups(7/7 vs.8/8);however,only 75% of resuscitation success was obtained in the control group(9/12).The rate of resuscitation success was increased and the duration of CPR,number of defibrillation and dosage of epinephrine were decreased in the two ABO groups compared to the control group although statistically insignificantly different(all P>0.05).3.After resuscitation,HR was increased and MAP was decreased in the three groups.However,both of them were improved faster in the 30-min ABO group,in which the values of MAP at all time points were significantly greater than that in the control group,and its values at 3 and 6 h were significantly greater than that in the 60-min ABO group(all P<0.05).After resuscitation,arterial p H and base excess were decreased and lactate was increased in the three groups.Similarly,these indexes were improved faster in the 30-min ABO group,in which the values of lactate at 3 and 6 h were significantly lower than that in the control and 60-min ABO groups(all P<0.05).After resuscitation,no differences in arterial PCO2,PO2,potassium and sodium were observed among the three groups(all P>0.05).4.After resuscitation,the serum levels of inflammatory cytokines including TNF-a nd IL-6 were gradually increased in the three groups.However,the increases in them were slower in the 30-min ABO group,in which their levels at 6 and 24 h were significantly lower than that in the control and 60-min ABO groups(all P<0.05).5.After resuscitation,the values of CO and EF were decreased and the serum levels of c Tn I were increased in the three groups.However,a faster improvement in post-resuscitation myocardial dysfunction was observed in the 30-min ABO group,in which the values of EF at 3 and 6 h were significantly greater than that in the control and 60-min ABO groups(all P<0.05).In addition,the serum levels of c Tn I starting 1 h after resuscitation were significantly lower in the 30-min ABO group compared to the control and 60-min ABO groups(all P<0.05).6.After resuscitation,the serum levels of NSE were increased in the three groups.However,the serum levels of NSE were lower in the 30-min ABO group than in the control and 60-min ABO groups,in which the differences were significant at 6 and 24 h post-resuscitation(all P<0.05).In addition,NDS was significantly lower at 24 h after resuscitation in the 30-min ABO group compared to the control and 60-min ABO groups(both P<0.05).7.After resuscitation,serum Cr,BUN,IFABP and DAO were increased in the three groups.However,all of them were lower in the 30-min ABO group than in the control and 60-min ABO groups although statistically insignificantly different(all P>0.05).8.At 24 h post-resuscitation,cell apoptosis and cleaved-caspase 3 positive staining were observed in the heart,brain,kidney and intestine in the three groups.However,AI was significantly reduced and the expression of cleaved-caspase 3 were significantly decreased in the heart and brain in the 30-min ABO group compared with the control and 60-min ABO groups(all P<0.05).Additionally,AI and cleaved-caspase 3 expression in the kidney and intestine were lower in the 30-min ABO group than in the control and 60-min ABO groups(all P>0.05).Conclusion: During CPR,ABO increased CPP and therefore improved the efficacy of CPR in a porcine model of TCA.After resuscitation,a 30-min ABO alleviated cardiac and cerebral injuries without exacerbating the injuries of kidney and intestine;however,a 60-min ABO would exacerbate the severity of all the above-mentioned vital organs. |
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