Hypothermia induces Cardioprotective Effects in Resuscitation
Date Issued
2006
Date
2006
Author(s)
Hsu, Chiung-Yuan
DOI
zh-TW
Abstract
Introduction
To restart spontaneous heart beat and restore spontaneous circulation are the very goals in the modern Resuscitation Medicine for decays. We have focused on how to improve the rate of Return Spontaneous Circulation (ROSC rate) so much, and the goal of successful resuscitation has been achieved after much effort on the resuscitation education and technique training. However, clinically the doctors, families and patients still face the tragedy that post-resuscitation multi-organs failure still exist and strongly threaten patient’s survival even initial successfully resuscitated. The discharge rate of these out-of-hospital cardiac arrest patients is still very unsatisfactory as decays ago, 2-5% on average, and the patients with good cortical function are still very rare. The in-hospital-cardiac-arrest （IHCA）patients have higher discharge rate but it is still limited to 16-18% only no matter in Taiwan or the west. Post-Resuscitation Syndrome is the most important reason which results in multiple organs failure because reperfusion is absolute necessary for life saving in the cardiac arrest patients, but global and large scaled ischemic reperfusion injury also starts when resuscitation begins. Numerous published researches had found even the patient is successfully resuscitated but the systemic ischemic reperfusion injury may induce severe organ dysfunction, including post-resuscitation myocardium dysfunction and unstable hemodynamic, and 50-70% patients died in the pos-resuscitation acute stages due to cardiac dysfunction fails to maintain homodynamic. Most of the survived patients need long tern nursing care due to sever brain injury and results in many complications. Therefore, to develop new managements or even medicines, which can attenuate post-resuscitation syndrome, is as important as to achieve ROSC when resuscitation starts, so that we could really help these patients to prolong their meaningful life but not waste medical resources or produce more vegetative only.
The pos-resuscitated patients not only experience the ischemic injury but also, the most important, the large scaled Ischemia/Reperfusion injury between cardiac arrest and circulation restore. Cell apoptosis is the central hypotheses but in fact there are many mechanisms like oxidant injury, pro-inflammatory cytokines, complex and cross-talked signal transduction pathways involved in the tissue response to Ischemic/Reperfusion injury. Many evidences from animal studies of myocardium infarction or brain stroke disclose the Ischemic – Reperfusion injury would augment the area and severity of initial ischemic injury and extend organ dysfunction. In the heart, they all result in global, both systolic and diastolic, cardiac dysfunctions and it is termed “post-resuscitation myocardium stunning” if it developed after cardiac arrest and resuscitation.
Clinically, organ protection is feasible. More and more evidences find the myocardium have protective windows when ischemic reperfusion injury attacks, the pre-conditioning、delayed - preconditioning and post-condition. There are many physiological protective responses against ischemic reperfusion injury under some strategies like brief and transient ischemia、exercise、Angiotensin Conversion Enzyme Inhibitors、angiotensin II type 1 receptor antagonist are all the examples and well known in these protective effects. The mechanisms of these protective effects are complex and including many proteins in different signal pathways but finally all leads to cell survival or decrease cell apoptotic response. For example, Interleukin-10 is the anti-proinflammatory cytokine which suppress the inflammatory cytokines. Other proteins attenuate Ischemic/Reperfusion injury related cell apoptosis process by modulate the key proteins like Bcl-2, Bax or caspases in the apoptosis pathways. Mitogen Activation Protein Kinase Family ( MAPK Family), including ERK、p38、JNK, could bring signals like oxidant pressure, cytokines stimulation, or signals from growth hormone and environment change from the receptors to the nucleus and then modulate cell function by activate or suppress gene transcription. ERK 1/2 participate in the signal transcription of Reperfusion Injury Salvage Kinase Pathway (RISK pathway) and have strong protective effects against cell apoptosis which is induced by ischemic reperfusion injury. JNK and p38 are the major stress signal transduction pathways and cell response to the outside depends on their effective work.
Today, hypothermic resuscitation has been proved by prospective multi-centers randomized clinical trials to have strong protective effects in the post-resuscitated patients. It can improve long term survival and brain recovery in the cardiogenic originated cardiac arrest or even the severe to moderate traumatic brain injury patients. Many animal studies also revealed localized or systemic hypothermia have good protective effects against local ischemic reperfusion injury related cell apoptosis in the brain and myocardium which improve organ dysfunction significantly. However, severe hypothermia also has controversial negative inotropic effects. It has not been studied and well understood whether systemic hypothermia also has protective effect in the pot-resuscitation myocardium dysfunction. If the hypothermia has post-resuscitation cardioprotective effects, it would be the very powerful strategy to reduce multi-organs failure in post-resuscitation care.
Hypothesis and Study Designs
Therefore, we purposed that adequate systemic hypothermia may provide cardioprotective effect and attenuate post-resuscitation myocardium dysfunction by reduce ischemic reperfusion injury. We designed and set up the first temperature controlled asphyxia induced cardiac arrest and resuscitation model in the rat. Serial animal studies are designed to further observe if the hypothermia improved the short term survival and decline post-resuscitation myocardium dysfunction. The others are designed to evaluate the temperature effects in different Ischemia/Reperfusion injury related signals transduction especially focused on cytokines, MAPK family and cell apoptosis.
The Preliminary Results
1. Short-term Survival Rate:
Post-resuscitation hypothermia therapy would significantly improve 4 hours short term survival then Normothermia. (Hypothermia survival rate 92.9%; Normothermia 32.3%, p< 0.001)
2. Post-Resuscitation Myocardium Dysfunction:
In the study of LV fraction shortening, post-resuscitation hypothermia can significantly stabilize post -resuscitation systolic dysfunction and maintain hemodynamic if compared with Normothermia especially in post-resuscitation 30-60 minutes. The Normothermia individuals would results in early death if heart sunning ongoing deteriorate after post-resuscitation 30 minutes. However, in the study of positive dp/dt(max), the hypothermia therapy only results in trends of better systolic function but statistically not achieved significant level.
Besides, systemic hypothermia therapy has trends toward improving diastolic dysfunction in the negative dp/dt(max), but the statistics results neither do not achieve significant level in our studies and need more investigations.
3. Ischemia/Reperfusion injury related cytokines:
Global ischemic and resuscitation would lower myocardium protective IL-10 levels immediately in the post-resuscitation period. The individuals who developed post-resuscitation myocardium dysfunction under Normothermia would significantly develop more rapid attenuation in myocardium IL-10 level then Hypothermia or those without myocardium dysfunction. The hypothermia therapy would provide significant protective effect then normothermia therapy in the post-resuscitation 1 hours.
In the study of myocardium TNF-α, post-resuscitation hypothermia can effectively repress the elevation of myocardial TNF-α level after ischemia/reperfusion injury from global cardiac arrest and resuscitation then post-resuscitation Normothermia therapy. The results of TNF-α would achieve significant level in the post-resuscitation 2 hours
4. MAPK Family:
Hypothermia would increase pERK activations no matter ischemic reperfusion injury developed or not. The Hypothermia would persistently and significantly augment pERK activation after resuscitation if compared with Normothermia which maintains activated but stable level in the myocardium. The difference waxes and wanes especially at post-resuscitation 2 hours.
On the other way, pP38 activation is significantly found in the Normothermia after resuscitation. Post-resuscitation Hypothermia has trends toward suppress pP38 activation after ROSC and achieve significant difference level in post-resuscitation 1hr.
However, pJNK activation is only observed transiently and immediately after resuscitation. It is not detectable after post-resuscitation periods and the moderate hypothermia would not influence its effect.
5. Cell apoptosis
We detect myocardium Caspase 3 activity and found caspase 3 activities would increase much after ROSC under Normothermia. Hypothermia would decrease caspase 3 activities even before ischemic reperfusion injury, and post-resuscitation hypothermia would further maintain slower increase rate of caspase 3 then Normothermia after resuscitation and achieved significant difference in the first 1 hour.
Conclusion:
To summarize the results of this study, we could conclude that the Post-resuscitation Hypothermia would increase short term survival rate for stabilized post-resuscitation myocardium dysfunction. The mechanism of its cardioprotective effect may be related to:
1. Hypothermia could effectively decrease pro- inflammatory cytokine TNF-α, and attenuate the rapid deterioration of protective cytokine, IL-10, in the post-resuscitation periods.
2. Hypothermia could persistently induce pERK activation and suppress stress signal pP38 transduction in the post-resuscitation periods. The total effects of the MAPK lead the myocardium to survive under ischemia/Reperfusion injury.
Subjects
低體溫
心跳停止
急救
心臟保護
後處理
Hypothermia
cardiac arrest
resuscitation
cardioprotection
post-conditioning
Type
text
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