Catecholamine Death Match "Part Two"


I believe that we move just as far in medicine by critiquing the work of others as we do by coming up with new ideas. This comment was so well thought out and salient that I had to include it in a follow up blog. I will admit that my view on the extent of coronary constriction with vasopressin as been refined with further research motivated by this comment. I believe comments like this help me refine my notes. There is conflicting data, and interpretation can lead to endless arguments on each side of the battle of which drug is ideal in cardiac arrest. If you would like to contribute to this shared note series, please email me foamfrat@gmail.com.

I have a few questions regarding this article. I really apologize for the length of this post (It has to be done in 3 separate comments). I am not familiar with this particular blog, or the background of the author. However, this is an area of particular interest for me, so naturally I had to read the link. First, I want to state that I do not necessarily disagree with the overall message the author is conveying. Yes epinephrine holds numerous harmful side effects that are in a large way caused by the increased beta stimulation. I also agree that beta blockade has shown benefit in cases of refractory VF. As far as norepinephrine is concerned, I also agree there is a theoretical benefit that needs further exploration. There has however, never been a solid publication that directly shows benefit of norepi over epi. That does not mean that a benefit doesn’t exist, it just hasn’t been shown yet. There have been quite a few publications comparing norepi and epi in cardiac arrest even in human trials, I will address this point later in my post. 

My concerns here stem from the evidence presented by the blog author. It seems that a very strong conclusion was drawn from the referenced literature citations. There appears to be some misinterpretations of the data referenced on the blog, data used to support the ending claim. I may be missing something, so I am seeking clarification regarding the data claims stated. I pulled the citations listed and I am only using these for my questions, as those were the authors stated sources for the data presented. 

1.

The blog was a shared note on thoughts I had comparing the use of norepinephrine vs epinephrine in arrest. It was stated multiple times that this was merely a shared note and not to be in anyway taken as medical advice. Even my conclusion began with “in my opinion.” This was the pre-frame in which I primed the blog.

#1: http://circ.ahajournals.org/content/circulationaha/30/2/180.full.pdf

The blog stated: “A paper published in Circulation by Peter M Yurchak, MD. showed improvement in MAP with no decrease in flow. While this does report an increase in resistance, it was overcome by an increase in diastolic pressure. This seems like the ideal agent in the setting of cardiac arrest.” 

In the referenced article it seems data that was left out of the blog. It is apparent that the publication cited shows a conclusion that opposes the information and interpretation stated in the blog. These are some quotes from the cited publication by Yurchak regarding the findings of how norepinephrine affected coronary vasculature.

“Average myocardial oxygen consumption increased 30 per cent, being met by both increased coronary flow and increased oxygen extraction.”

“Rise in flow was usually less than, or equal to, rise in perfusion pressure. In only one subject (L.B.) did flow increase more than pressure. In general, except for patient L.B., vascular resistance was unchanged or increased, despite progressively increasing myocardial oxygen and blood flow requirements. Coronary venous oxygen content fell progressively with increasing doses of catechol in five of six subjects”. 

“Despite an increase in cardiac oxygen consumption, coronary vascular resistance was unchanged, suggesting no vasodilatation in the coronary bed. On the contrary, oxygen extraction across the heart increased, implying that oxygen needs were inadequately met by rise in flow”. 

The final sentence of the referenced publication stated:

“it seems likely that norepinephrine induces a suboptimal rise in coronary flow that may set the stage for ultimate myocardial ischemia, particularly when coronary perfusion pressure is inadequate”.

It is very important to recognize that cardiac myocytes extract almost the maximum amount of O2 possible from coronary vasculature. What this means, is that the primary way to deliver more O2 to the myocardium is through vasodilation of the coronary vessels, to get more blood to the myocardium. This is a well-established principal that influences what medications a patient is prescribed or administered. If O2 delivery is less than demand, there may be a lower coronary sinus PO2 levels which can indicate increased O2 demand is not being adequately compensated for by increased O2 delivery. This study clearly indicated that norepinephrine raised O2 demand and did not cause compensatory dilation of coronary vasculature, this lead to increased O2 extraction from the heart, due to a lack of O2 delivery. 

My question here is that the blog stated, “This seems like the ideal agent in the setting of cardiac arrest”, however, the publication the author of the blog cited as evidence for this statement, seems to state the exact opposite. How was the conclusion of this being the ideal agent drawn from this publication? 

Reply 2

As mentioned in the study, in order for an agent to be considered a vasodilator it must increase flow disproportionate to increase in pressure. I don’t think anyone is saying that norepinephrine is a vasodilator. My interpretation of these experiments was that the expected increase in vascular tone was proportionally met by increase in pressure. The oxygen extraction was however disproportionate to delivery and a decrease in venous Po2 was noted. The article mentions that "this type of response is also seen in pitressin". Epinephrines beta properties do provide some coronary dilation,  but also can potentiate arrhythmias. Vasopressin has no beta properties and purely increases afterload (probably not a big deal till after ROSC).Norepinephrine has the same effect on coronary arteries as vasopressin, yet less beta properties than epinephrine. Thus I stated “in my opinion” norepinephrine seemed like a good choice. The VSE trial was tempting and in my opinion very well done. There was a slight disadvantage to the standard therapy group with systole being more common. Regardless, my blog momentum towards vasopressin being "useless" should be retracted.

#2: http://circres.ahajournals.org/content/circresaha/34/6/812.full.pdf

The blog stated: “In dog studies a dose of 1mcg/kg was compared with 0.1 mcg/kg given as a bolus. The effects showed an initial increase in coronary perfusion pressure and increase in flow, followed by an increase in coronary resistance. Once again this increase in resistance was overcome by an increase in diastolic pressure. This prevented an interruption in blood flow”. 

I think the interpretation of what this means is a little skewed in the blog. The increased resistance is a very undesirable effect. As you will see in the actual publication and in my quotes below, the increased resistance led to a decrease in coronary blood flow, even though MAP was increasing, in some of their models, this led to a reduction in coronary sinus PO2, meaning the heart was extracting more O2 from vessels. Which indicates that O2 demand is higher than O2 delivery, this is due to the increased resistance. What was observed was a state of sustained coronary vasoconstriction after norepi administration, which is certainly not desired in a cardiac arrest patient. Or most critical patients for that matter.

These are points made by the authors of the cited study.

“In some of the experiments in which the smaller bolus dose of norepinephrine (0.1 Mg/kg) was administered, coronary blood flow actually decreased below the control level during the later period of coronary vasoconstriction. Similarly, when the smaller dose of norepinephrine was administered as an infusion, coronary blood flow fell while arterial blood pressure remained at control levels”. 

“when norepinephrine was administered intravenously as a bolus in the conscious dog, a brief early period of coronary dilatation occurred and was followed by a sustained period of coronary vasoconstriction despite elevated left ventricular pressures, dimensions, and contractility. Arterial and Coronary Sinus Oxygen.—During the period of coronary vasoconstriction that occurred after the injection of norepinephrine at point B, arterial Po2 remained at control levels of, but in four conscious dogs coronary sinus Po2 fell”.

Essentially what this is saying is that the increased stress on the ventricular wall & increased inotropy caused by norepi produces increased O2 demand, to compensate for this there should be coronary vessel dilation to increase O2 delivery (remember that’s the primary way the heart can extract more O2). However, this did not occur, there was sustained coronary vasoconstriction which led to decreased flow & in some cases decreased coronary sinus PO2. 

My question on this point is; how did the blog author conclude that the effects seen in this cited publication are beneficial to a patient in cardiac arrest? 

Reply 3

I included this study because I felt it included some pertinent information regarding norepinephrine's effects on coronary artery constriction. This study kept coming up in my research and the information deserved to be listed.

#3: (https://www.ncbi.nlm.nih.gov/pubmed/20693888).

This cited publication confuses me a bit. I am not sure where it fits in to the blog post. Essentially this publication compared epinephrine’s harmful post-arrest effects in normothermic vs. hypothermic patients, it concluded the following:

“Epinephrine, when administered during normothermic cardiopulmonary resuscitation, significantly increases the severity of post resuscitation myocardial dysfunction and decreases the duration of survival. These detrimental effects of epinephrine, however, no longer exist when it is administered during therapeutic hypothermic cardiopulmonary resuscitation”. 

“Post resuscitation myocardial function was significantly better in animals treated with epinephrine during hypothermic cardiopulmonary resuscitation when compared with hypothermic controls. This was associated with significantly fewer post resuscitation ventricular arrhythmias, less ST-segment elevation, better post resuscitation neurologic deficit scores, and longer duration of survival.”

My question is, where does this fit in to the blog topic and what information was cited from it in the blog post? 

Reply 4

This study was cited regarding the dosing effects and duration of epinephrine quoted in the beginning of the blog. 

"Epinephrine was shown to increase coronary perfusion pressure by 30% for approximately three minutes in a study by Sun S, et al. This study is where we get our current recommendation to administer one milligram of epinephrine every three to five minutes. There are a few important points we need to keep in mind regarding epinephrine in cardiac arrest."

This is also quoted in the 4th edition (Current) of  "The ICU Book" by Paul Marino.

Link To That Study

The blog stated: “Besides showing no benefit over epinephrine, vasopressin is associated with significant coronary artery constriction and has been removed from the ACLS guidelines in 2015. This question has plagued me for awhile now. I am not able to find exactly why we would think its a good idea to trial a drug like vasopressin in cardiac arrest, however not study an agent such as norepinephrine”. 

This statement is incorrect on a few different levels. First, there have been several studies comparing epinephrine to norepinephrine in cardiac arrest treatment. Not only in animal models, but human trials as well, dating back to the 1980’s, including both hospital and prehospital trials. Im not sure if a proper literature search was done or if it was just assumed this has never been researched, but there are many publications on this. Some that would have even supported the blogs statements much more than the literature that was chosen to be cited. The publications show essentially inconclusive evidence. There were several done in the lab that showed some potential benefit, there is of course theoretical benefit. 

However, the only randomized human studies done on this that I have seen have showed no benefit of norepi over epi, and some even showed better outcomes with epi and vasopressin compared to norepi. From a theoretical standpoint norepi holds some validity, there have been a couple recent case studies where norepinephrine was administered to a patient and they had success. One was done after 45mg of epinephrine was administered, but that’s a different story. 

My point here is there have been publications on this, the claim that the healthcare community has not studied this is incredibly false. There just has not been any study that showed a clear enough benefit to justify a change in practice. Is it possible that future studies could reveal norepi is more beneficial? Of course, but as of right now the only evidence supporting it is conflicting animal lab data, some theoretical benefits, and anecdote that has some serious limitations, and that will not stand against human trials that showed no significant benefit and counter lab data that has shown no benefit or even displayed theoretical harm. The truth is, no one really knows yet, there is too much confliction in the data. It is incredibly premature and borderline irresponsible to make a solid conclusion right now. 

Second, could you please cite what source you are looking at that indicates vasopressin causes “significant coronary vasoconstriction during cardiac arrest”? 

Circulation. 1991 Jun;83(6):2111-21

Also The ICU Book By Paul Marino

This is a bit misleading. Yes, vasopressin can cause coronary vasoconstriction. However, in every publication I have seen on this topic, vasopressin significantly improved coronary blood flow compared to epinephrine during CPR. This has been a question for some time. Why does vasopressin cause coronary constriction in healthy hearts, but in cardiac arrest patients we see significantly increased flow, indicating more dilation when compared to epinephrine? The research stating vasopressin is a potent vasoconstrictor is very controversial. The effects vasopressin has on coronary vasculature appear to be dependent on numerous variables from endothelial status, dose, and stress level of the heart. There are studies showing very mixed results, however generally what has been displayed is that the vasoconstriction is mostly seen in normal hearts. In hearts undergoing hypoxia or states of shock, vasopressin shows increased dilation, particularly in cardiac arrest states. The improved coronary blood flow with vasopressin has been well documented when compared to epinephrine in cardiac arrest. As to why this happens, well that’s still up for debate.

One well known publication looked directly at this question by measuring varying doses of vasopressin and epinephrine’s effects on coronary perfusion, 

Linder KH, et al Circulation 1995 “Total cerebral blood flow was significantly higher after high-dose vasopressin than after epinephrine. Vasopressin leads to a significantly higher coronary perfusion pressure and myocardial blood flow than epinephrine during closed-chest CPR in a pig model of ventricular fibrillation”. 

There is publication after publication showing increased coronary perfusion, better rates of ROSC, etc in patients who received vasopressin. Vasopressin was not removed from ACLS due to coronary vasoconstrictive concerns, it was removed due to it showing no clear long-term benefit over epinephrine in VF/VT arrests even though it is associated with increased ROSC rates in nearly every clinical trial done on the subject. 

There is certainly a place for vasopressin and we are seeing it coming back in tertiary centers or had never ceased complete use in some centers. It has a particular role in certain shock states. This is due to its mechanism of action. In shock states we see dysfunctional adrenergic receptors that can inhibit the effectiveness of catecholamines. We can also see interruptions in signal transduction and metabolic factors that help inhibit catecholamine effectiveness. This is why we sometimes need steroids in persistent hypotensive states, steroids upregulate vascular a1 receptors helping catecholamines become more effective and also have other beneficial effects. Vasopressin can in a way bypass this adrenergic receptor dysregulation due to its binding to V class receptors as opposed to adrenergic. 

There has been more than one RCT done that shows greater survival in non-shockable arrest states with vasopressin being used. Mentzelopoulos 2009 & 2013 conducted separate RCT’s over different centers and showed nearly identical results, vasopressin used in non-shockable cardiac arrest states had a much higher ROSC and survival with positive neurological outcome compared to epinephrine (19% vs. 4%). This was randomized and reproduced using around 400 patients in total. 

One publication by Prosen in 2010 showed improved ROSC rates in pseudo PEA when vasopressin was administered. They were able to achieve ROSC in 94% of the patients studied and survival with a good neurological outcome in 50% of their pseudo-PEA patients, when normally we would see around 10%. That’s impressive by any standard. What did they do different? Stopped CPR and gave vasopressin. I am happy to provide proper citations on my statements, I just didn’t have the time to pull them all tonight. 

Is vasopressin some magical medication? Of course not. It has its uses though for sure! And is being used in tertiary level ICU’s and ER’s all over the country in cases where it may be beneficial. To say that its essentially useless is just a gross misunderstanding of pharmacologic principals and the literature on the topic. 

Reply 5

I think the studies you bring up are very interesting and have caused me to dig a little further into the dead vs alive pharmacologic effects of vasopressin.