Clinical Studies Targeting Stroke and In-Hospital Cardiac Arrest

The use of therapeutic hypothermia and temperature management for targeting cerebral ischemic injury and stroke is an active area of preclinical and clinical work. This roundtable discussion, which was presented at the 2015 Therapeutic Hypothermia and Temperature Management Meeting in Miami, brought together several investigators interested in evaluating the beneficial effects of therapeutic hypothermia in clinical stroke. Dr. Justin Lundbye, Hospital Central Connecticut, provided a summary of an in-patient cardiac arrest therapeutic hypothermia program. Dr. Lundbye presented findings directed toward evaluating the impact of mild hypothermia (32–34°C) on short-term neurologic outcome in comatose survivors. In this study, therapeutic hypothermia was associated with improved neurological outcome and survival. Dr. Patrick Lyden, Cedars-Sinai Medical Center, presented new data and a clinical update on the use of hypothermia for the acute treatment of ischemic stroke. Dr. Lyden provided background information on the specific levels of hypothermia that are most optimal in protecting neurons from ischemic damage as a rationale for the use of moderate hypothermia in patients. Information from the ICTUS 2 clinical trial that will determine whether the combination of thrombolysis and hypothermia is superior to thrombolysis alone was also provided. The ICTUS 3 trial is now proposed to continue to test this interesting hypothesis. Together, these presentations help provide the framework for a very interesting discussion on this topic.

Question: Dr. Lyden, I ask you the same question every year: why not magnesium?

Dr. Patrick D. Lyden: Same answer as every year: magnesium does not have any preclinical or clinical data to support its efficacy in shivering management. We would add magnesium to the protocol if there were placebo control-blinded data showing that magnesium adds to shivering control. We are a little leery adding it to the protocol due to what might happen when we go to the FDA for approval.

Question: In one of your last sentences you mentioned that mechanical thrombectomy will be allowed in ICTUS 3. These patients usually, in at least my experience, get a full-scale anesthesia. Will you awake them before the 24 hours of hypothermia are over, or will you keep them ventilated on a tube for the 24 hours and then slowly awake them?

Dr. Patrick D. Lyden: The use of general anesthesia for interarterial embolectomy is controversial. At this moment many interventionalists in the United States prefer general anesthesia and conscious sedation. In the case of general anesthesia, the patient is extubated after the case. We will encourage our sites to follow their local protocol, which is very likely going to be extubation after the case is over.

Comment: I take your point of the FDA but the experience I have with awake patient cooling with the skin counter and magnesium treatment is that we need a minimal dose of sedation. The answer of whether we can cool awake patients without intubating them is very clearly yes. It looks to me that you guys are doing almost the same thing except for the magnesium and you need much more meperidine. I understand it is difficult when studies are ongoing, but that is something that I think for any study an awake patient will be extremely helpful.

Question: Didn't Kees previously talk about warming the surface and then cooling internally to produce therapeutic hypothermia in an awake patient?

Dr. Patrick D. Lyden: We use skin surface warming in all of our patients so that they get the endovascular cooling and then the skin surface warming, along with meperidine and busperone.

Question: For those of us who have been uninitiated, can you describe how you do skin surface warming and intravascular cooling? Logistically how do you do this?

Dr. Patrick D. Lyden: The catheter is an intravenous, femoral central venous catheter. We use the Innercool or Zoll products, and then once everything is tied down, put a warming blanket on the patient.

Question: I was intrigued by the in-hospital hypothermia for cardiac arrest patients. Are there other places that are doing similar types of studies and series to find out if this can be accomplished? I understand that the subjects are usually pretty sick.

Dr. Justin Lundbye: There are no prospective studies that are ongoing looking at this. The best that we are going to get out of this in my opinion, unless it comes out of Europe or something, is registries that will be looking at it. As far as I know, we have probably the largest data set right now.

Question: Can you also comment on how difficult that is to do in-house? At least in our experience, the decision in the emergency department is really quick.

Dr. Justin Lundbye: It is and it isn't if you have a rapid response team approach. If you have a group of people who manage those patients in the prearrest and the periarrest period, you have sort of hard-wired the process of contacting the right people to get them into the cooling process. It can work. I see your point. You have staff at two in the morning who is running a code, patient ends up in an ICU who doesn't cool, maybe a surgical ICU or something that doesn't have that infrastructure. You lose some of those patients and that is where the challenge is. You need the process in place for it to work.

Question: How do you handle all the consultants that have to weigh in when you decide that this person is undergoing this protocol and you have to make sure all the people taking care of this person agree that it is ok to go?

Dr. Justin Lundbye: I think we have been lucky enough that a large part of our medical community endorses therapeutic hypothermia and they have bought into it. In the beginning when we started this journey back in 2005, 2006, everybody was skeptical. I think now it is more accepted as part of the standard at least where we are.

Comment: We work at a community hospital here in Florida and we've had protocols for 3 years. I manage the 22 ICU beds and run the code team and the rapid response team. We only have 50 codes in a year, and out of those 50, cardiac arrests are from the oncology floor that didn't have code status addressed in the first place. We get them back and we bring them to the ICU. Within 12 hours we have had the appropriate conversations with the family, and we move forward in the right direction. We don't even talk about putting them on Arctic Sun because it is not ethical from our standpoint. The rest of the codes, and you have spoken of this, is pain management. They have gotten too much drugs, and after have we reversed them, they are up and talking in a few hours. I know we are a very small hospital with a small population, but I think that speaks to generally what is happening with codes in the building. Our rapid responses are stopping codes before they get to that point.

Dr. Justin Lundbye: I agree. I think there is certainly a good proportion of patients who get rescued now with the EMRs that trigger certain criteria. You get a warning by a page that says this patient is in trouble. Those things are in place but there are still a lot of patients that you don't get to the naloxone quickly enough and by the time you get to them they are arresting or something like that. That is still happening and then of course the CO₂ retainers that come in go into respiratory arrest. These are all anecdotes but your point is very well taken on the oncology population and the end-stage patients. We have to do a better job of talking to the patients and families about the care options we are going to try. I am not sure if I answered or I just commented along with you here.

Question: Dr. Lyden presented us with information about what is going on in the United States in terms of our current hypothermia and stroke trial. I am wondering if Dr. Schwab can let us know about what is going on in Europe and stroke and therapeutic hypothermia.

Dr. Stefan Schwab: I think we are in the same stage as Pat. We started just last year, and so we are about 30 patients; otherwise, it is sort of a companion trial. The idea that we have now is to speed up the enrollment with shorter time of hypothermia, which may overcome some of the problems that you obviously showed us here for 36 hours' cooling. It is a very time-consuming and a difficult procedure even for experienced nurses on the stroke unit.

Dr. Patrick D. Lyden: I would like to point out that the European authors have met and we have tried to coordinate our case report forms, and our data collection and protocols to the extent possible so that we can facilitate a meta-analysis when we are done.

Question: Dr. Lundbye, in your patients with in-hospital cardiac arrest, were these patients monitored before they entered this cardiac arrest by pulse oximetry? How was the PCO₂ when they were resuscitated or before they were resuscitated? Very briefly, is doing pulse oximetry in a normal ward harmful?

Dr. Justin Lundbye: It is a great question. I don't have all the analysis done for our study, but what you are asking is my speculation, should there be a universal protocol for those patients that meet certain criteria and get simple pulse oximetry that may avoid some of these events from happening. It is obviously hugely resourceful, but it is something to keep in mind. I don't have the results yet; we are still sort of going through all of the data.

Dr. Justin Lundbye: I brought up the hypothermia mafia a little bit earlier. If you remember my slide about the shockable in-hospital cardiac arrest patient population, our survival with good outcome was in the 50s. My early speculation for that is that relates to the same thing that happened in the TTM trial, where it was very rapid rescue CPR in that specific patient population. This situation falls into the mild injury that are going to do well regardless of what you do to them or how you manage them. I just wanted to throw that out.