<International Circulation>:  Keep it simple and structured. From the INTERACT-2 study， should blood pressure be aggressively lowered acutely after intracerebral hemorrhage?

　　Dr. Anderson: Yes. I alluded to that in the first talk but went into much more detail in the afternoon session， which was devoted to intracerebral hemorrhage. I presented some further data， which was looked at， looking at the effects of treatment on hematoma growth and edema and there’s positive features there. It reinforces a positive mechanistic action of the treatment. It is modest; blood pressure lowering is not like tPA thrombolysis， it is a dosing like aspirin， it is a mild effect in controlling a physiological variable but what we emphasis in the study is that there is no harm in the protocol. We look very carefully for any serious adverse events in the patients and it is all very low and very well tolerated and there was a positive effect on outcome. We have really looked quite hard to see if there was any particular type of patients that did not respond at all or again， if there was any potential harm and we did not find anything. It is a very consistent treatment effect according to all patient characteristics and we believe that the data is fairly robust in indicating again， modest， but positive treatment effects of hematoma and edema. We think all these treatment types are very time dependent， so it took about 6 to 8 hours to get the blood pressure under control， at the time that was pretty aggressive treatment， and now we might think that it is a bit too slow but when we set it up 10 years ago it was pretty radical. The average time of randomization of the patients in INTERACT-2 was 4 hours. They get to hospital pretty quickly but then there was some time wasted in the emergency department， getting their assessment then randomizing their treatment and it took a couple hours to actually get the blood pressure under control， so I think now more intensive treatment would seem reasonable to recommend. Certainly target driven， more aggressively than the current guidelines which is 180， and we should be moving more aggressively towards 180. The earlier and speedier we do it and the more controlled we do， it is likely to provide the best outcomes for the patient.

　　《国际循环》：也就是说，研究的入选标准应尽量简单而又具有结构性。根据INTERACT-2研究结果，您认为急性脑出血后是否应进行积极降压治疗？

　　Anderson教授：我认为需要。在回答第一个问题时我已经提到这个问题，而在今天下午的有关脑出血专题讲座中，我会更详细就此进行探讨。我将会公布一些更进一步的数据，介绍治疗方案对血肿扩大及水肿的积极影响。需要强调的是降压治疗对脑出血具有积极作用，但降压需要温和，不能像溶栓那样，而是需要像应用阿司匹林那样缓慢控制生理改变。但需强调，降压治疗并无坏处。在降压治疗过程中，需要严密观察严重不良事件发生情况。我们的体会是，脑出血时进行积极降压治疗的不良事件发生率非常低，患者具有良好的耐受性，对患者结局有积极影响。我们在研究中非常仔细观察了是否有特定类型的患者对积极降压治疗无反应甚或有害，结果均未发现上述情况。积极降压治疗对不同特征的脑出血患者治疗疗效具有很好的一致性，故我们认为已有相对较强力的证据表明，适度积极降压治疗对血肿及水肿有积极治疗作用。而治疗的方式需随时间改变，原来推荐6~8小时内将血压控制住，现在看来这样的降压速度还是有些慢。INTERACT-2研究中采用的平均随机化时间为4小时。虽然现在患者达到医院的时间有所缩短，但急诊室耽搁时间相对较多，先评估再随机化治疗，可能需数小时才能将血压控制住。所以，我认为推荐进行更积极的强化降压治疗是合理的。这样一来，我治疗目标值会比现在指南推荐的180 mm Hg要更积极。如果能过越早越快做到这一点，将血压控制得更好，能为患者带来更好结局。

　　<International Circulation>:  That leads me to my next question about the mechanism we would use to do a rapid lowing of blood pressure.

　　Dr. Anderson: It is typical for us to look at what is the best drug. We are looking at that work at the moment but it is going to be extremely complicated statistically to be able to do with such a mixture of drugs being used and many people use dual treatments and everything. The most common regime is a bolus followed by an infusion. The trouble with that sort of regime is that most of the drugs have a half life of about half an hour. You always have the risk that you are overshooting or undershooting the target because you cannot get the titration so well. Nicardipine infusion is very attractive but expensive in China and most other countries but you could titrate that. There is a drug that is on the market in the US called clevidipine or Cleviprex， which is an ultra short acting calcium channel blocker and is very titratable， which is very appealing. You can set up an infusion and get the blood pressure under the control in 10 to 15 minutes and then the patient is pretty much under control and good to go. I think a bolus kickstart followed by infusion because an intracerebral hemorrhage is difference from ischemic stroke， there is a big mass of blood in your brain and the blood pressure is not going to come down quickly， it is going to come down over the next few days whereas in ischemic stroke there might be a bit of change once recanalization occurs and thrombolysis， so the blood pressure can drop down fairly quickly after tPA. I think for most of our patients， and we say that in INTERACT-2， that 2/3rds of our patients needed an infusion. You are looking at any of the drugs that are most appealing in infusion， which are probably not the nitrates because they cause headaches in patients.

　　《国际循环》：接下来我想请教的是，我们应如何实现快速降压？

　　Anderson教授：通常我们非常想知道哪种药物最好。我们现在正在开展这方面工作，但鉴于很多患者应用多种药物，可能统计分析上存在一定困难。目前，最常用的制剂是先推注应用然后输注。目前存在的问题是，大多数药物半衰期较短，仅半小时左右，不能很好地进行剂量滴定，故容易出现降压不足或过度问题。尼卡地平的剂量能进行滴定，是一种非常好的输注治疗选择，但在中国及其他国家其价格相对较贵。目前美国有一种名为氯维地平或Cleviprex的药物，是超短效钙离子拮抗剂，非常易于滴定，具有很好的应用前景，在输注后10~15分钟即可将血压控制住，然后患者可一直保持较好的控制水平。鉴于脑出血与缺血性脑卒中的区别在于前者大脑中存在大量血液，因此血压难以快速下降，在发病几天内会不断下降；而缺血性脑卒中一旦溶栓实现了再通，在应用tPA后血压会快速降低。因此，我推荐脑出血患者应用降压药时采用先推注再输注的方式。INTERACT-2研究中有2/3患者需持续输注降压药。就最佳输注用药选择而言，可能硝酸酯类药物并不是最好的选择，因为其会导致头痛。

　　<International Circulation>:  We do not want to give them a big dose of nitro. What is the best way to obtain， deal， and evaluate how we are dealing with that mechanistic effect? What do you do to keep an eye on the efficiency with that rapid lowering of the blood pressure?

　　Dr. Anderson: We are still refining those guidelines and everything. We did some secondary analysis in INTERACT-2 and it is published in Lancet Neurology in April where we showed that blood pressure variability was a very strong predictor of outcome and the key blood pressure parameter that was of prognostic significance was the maximum， the peaks. I think when you are looking at the blood pressure charts， and the nurses were recording and everything， it is just as important to look at where you are tracking on average， but you have to take a lot of note of the peaks. Probably also the troughs， obvious you do not want the troughs getting too low， not below 110 or 120 but you have to get those peaks under control because it is probably the peaks of systolic blood pressure which are the most damaging in terms of stress on the endothelium and small vessels in your brain. Clearly serial CT scans， so clearly people who come in with a diagnostic CT and then according to clinical severity， patients will probably get another CT scan in the next 8 to 12 hours and certainly by the first 24 hours， just monitoring the amount of growth in the bleeding and we know now that there is going to be more bleeding if the patient arrives early compared to arriving late. I think with the INTERACT-2 datasets and other large datasets that are emerging to intracerebral hemorrhage， we are going to be able to refine those recommendations in terms of prognostic variables and refinement of the blood pressure parameters and have a much clearer guideline set around the management of that condition.

　　《国际循环》：我们一般不会用太大剂量的硝酸酯类药物。判断治疗有效的措施是什么？如何对血压的快速下降进行监测？

　　Anderson教授：我们仍正在完善相关指南。我们对INTERACT-2进行了再次分析，并将其结果发表在了《柳叶刀神经内科学杂志》上。其结果显示，血压变异性是患者临床结局的强力预测因素；最具显著预测价值的关键性血压参数是血压峰值。在阅读血压记录表时，除了要看血压平均值还要关注血压峰值及最低值。我们肯定不希望血压最低值过低，希望其不低于110或120 mm Hg，但又希望能控制血压峰值，因为收缩压峰值对大脑内皮及小血管危害最大。为了检测脑出血患者出血量变化，我们需要进行系列CT扫描，对CT确诊的脑出血患者，要根据其临床严重程度在发病8~12小时及24小时后分别行CT检查。与就诊较晚者相比，就诊较早的患者可能出血会更多。我认为，INTERACT-2研究及其他大型研究数据正在为我们制订更明确的脑缺血管理指南以确定患者预后指标及血压控制目标提供更多依据。