Hello, my name is Allie Marquez, and I am a pediatric intensivist and assistant professor at the University of Minnesota, as well as a resuscitation scientist based at the University Center for Resuscitation Medicine. I've been asked to talk about protocolized versus hemodynamic directed vasopressors during CPR. I have no conflicts, except a personal bias towards physiology. In this talk, we will go over the rationale for vasopressors, mostly focusing on epinephrine, the evidence for protocolized, which we're going to now refer to as scheduled epinephrine, and the evidence for hemodynamic directed vasopressors and how we might apply all this evidence to our clinical practice. Epinephrine is not just standard of care, it's the pharmacologic cornerstone of CPR used in resuscitations for over 100 years. So why are we talking about this now? First, there was a recent consensus and recommendations from Ilcor that identified major knowledge gaps about epinephrine in pediatric cardiac arrest. Second, recent adult trial data suggests that epinephrine may not be beneficial for long-term outcomes. And third, there's a new emphasis on monitoring our unique patient's physiologic response to our CPR efforts, and this includes how the patient is responding to vasopressors. Why do we give epinephrine? Of course, to get ROSC. Epinephrine increases aortic pressure during chest compressions via alpha-adrenergic constriction of arterioles. During the relaxation phase of CPR, a higher aortic diastolic blood pressure thereby leads to increased coronary perfusion pressure, and this augments the myocardial blood flow generated by chest compressions. The original animal experiments were performed more than a century ago by George Kreil and David Daly, two American surgeons trying to save their patients from the asphyxia and hemodynamic effects of ether and chloroform, the anesthetics du jour. They found the basic problem seems to be that of securing by means of some infusion a coronary pressure amounting to 30 to 40 millimeters of mercury. They also noted that it was impossible to raise the coronary pressure by cardiac massage alone. This is a tracing from one of their original experiments. Here they induce cardiac arrest and start CPR, then they give epinephrine. Look at that beautiful blood pressure. Epinephrine works. CPR, as we know, it starts to really take hold in the 1960s with Drs. Pearson and Redding, two founders of critical care medicine. This graph is showing that with a one milligram intracardiac dose of epinephrine, you can get raw skin nine out of 10 and 10 out of 10 times. Their experiments essentially define the one milligram dose of epinephrine. These are the studies that that comes from. The first American Heart Association guidelines came out in 1974, and this cover is actually fascinating if you have time to look later. These are images of the various ways to resuscitate humans throughout history. The AHA guidelines recommended 0.5 to one milligram of IV epinephrine every five minutes. And this recommendation, based on a little bit of animal data and a lot of consensus, has continued as dogma ever since. What are the current guidelines for pediatric patients? One is reasonable to administer epinephrine, two, it is reasonable to administer it within five minutes, and three, it is reasonable to give it every three to five minutes. These are moderate recommendations with limited data. Further appraisal of the evidence by ILCOR, they also recommended early epi for non-shockable rhythms but made no recommendation about shockable rhythms and no recommendation about intervals. Let's get more granular. When do you give your first dose? There are a series of time to epinephrine studies using the AHA's Get With The Guidelines registry. The pediatrics paper, this is in-hospital pediatric cardiac arrest with initially non-shockable rhythms, showed that earlier epinephrine within the first two minutes, time is on the x-axis here, was associated with higher survival to discharge. Earlier epinephrine was also associated with ROSC and neurologically favorable survival. Another way to say this, delays to first epinephrine decreased the chance of a good outcome. How often should you give epinephrine? The half-life of epi in animal studies shows that epi peaks pretty fast and only lasts a couple of minutes. Current recommendations of three to five minutes are based on this, plus a practical approach that allows providers to sync up epidosis with pulse checks, compressor changes, and defibs. There are no randomized controlled trials on intervals and observational data are conflicting. This is inherently hard to study. Most studies calculated the time interval simply by dividing the total CPR duration by the number of recorded epidosis, so we don't know the exact intervals, and we don't know why a clinician might veer off the guidelines. A study by Dr. Martha Kinsley and colleagues used documented epi times taken directly from code sheets. She found that a quarter of patients received what she termed frequent epinephrine, given every two minutes or less, and these patients had higher rates of ROSC and favorable neurologic survival. Instead of controlling for CPR duration, she analyzed CPR duration as a mediator. As you can see by this figure, looking at cumulative probability of ROSC against time, the frequent epi group, the hatched line, had a much steeper slope, i.e. more likelihood to get ROSC in the early minutes of CPR. To say this another way, the effect of frequent epi was largely mediated by shortening the duration of CPR. What about the dose of epinephrine? Original animal studies used a greater weight per kilo of epi, one milligram for animals who were only about 20 to 30 kg. So it's a good question to ask, would epi work better if we used a bigger dose? There have been six adult and one pediatric RCT comparing standard versus high-dose epi, high-dose being anything more than a milligram, usually around 10 milligrams. The adult studies found that there was increased ROSC with high-dose epi, but no improvement in functional survival outcomes. In the year 2000, ILCOR formally recommended against high-dose epi. In the pediatric double-blinded RCT, high-dose epi, 0.1 mg per kilo, so 10 times more than a standard dose, when administered as a rescue after a single failed dose of standard epi, was of no benefit and caused possible harm. The nail is in the coffin on this one. What about no epinephrine? We should talk briefly about the PARAMEDIC-2 trial, a multicenter randomized double-blinded trial in the UK of pre-hospital epi versus placebo, an adult out-of-hospital cardiac arrest. For their primary outcome of survival at 30 days, they found a very small improvement with epinephrine. The number needed to treat here was 112. For their secondary outcome of favorable neurologic outcome at three months, they found no difference. Further, there were more patients in the epi group who survived with severe neurologic disability at discharge. That seems pretty concerning at first glance. However, there are a number of caveats to this study. First, the initial dose of drug, epi or placebo, was given at 21 minutes into the resuscitation. We know from animal and human data that epi may not be likely to work that far into a resuscitation. Second, there were very few survivors, so the study was not adequately powered to detect a difference in neurologic outcome. Nevertheless, it's food for thought. To recap, the evidence regarding scheduled epi suggests we should give standard dose epi as soon as possible if the initial rhythm is non-shockable. We may consider an earlier second dose of epi to achieve ROSC sooner. High dose epi is not better and may be harmful, and epi late in the game may not be effective. CPR guidelines were developed with a simplified one-size-fits-all strategy to serve both laypersons and professionals in any setting. However, as intensivists, we know from experience that our patients do not respond uniformly to resuscitation. New data suggests we may be able to save even more lives if we tailor and titrate our efforts to the patient's unique physiologic response. Since 2013, the AHA has recommended monitoring our efforts both on the provider end with feedback-enabled defibrillators and also on the patient end with physiologic monitoring. In-hospital pediatric cardiac arrests occur in monitored settings and almost exclusively in the intensive care unit. Close to half will have an arterial line, more in the cardiac ICU, and two-thirds will have end-tidal monitoring. Plus, we intensivists are skilled providers. What targets do we shoot for? The AHA consensus recommended a hierarchical and contextualized approach, but they didn't exactly say how to do this. So this chart shows four potential parameters, their targets, and the data backing them up. The most robust data is for coronary perfusion pressure, targeting more than 20 millimeters of mercury, and then its surrogate, diastolic blood pressure, targeting more than 25 to 30 millimeters of mercury, depending on the patient's age. We are going to focus on these two hemodynamic parameters. During chest compressions, we generate a coronary perfusion pressure, CPP, which determines myocardial blood flow. This study by Dr. Bobberg, echoed by the PALS and ACLS coursework, shows that pauses are detrimental to CPP. You must maintain CPP in order to achieve ROSC. A landmark study by Dr. Paradis was the first to evaluate the relationship between CPP and survival in humans. It showed that maximal CPP was the best predictor of ROSC compared to other hemodynamic variables, and no patient with a CPP less than 15 had ROSC. However, in practice, it is quite difficult to calculate and use coronary perfusion pressure as a target during resuscitation. Diastolic blood pressure, on the other hand, may be a readily available surrogate. The CAPCORN investigators prospectively evaluated the association of diastolic blood pressure using arterial line data with survival outcomes in order to identify optimal targets for CPR in children. Among 164 patients across 11 sites, they found that a mean DBP of at least 25 in infants and more than 30 in children older than a year was associated with 70% greater likelihood of survival and 60% greater favorable neurologic survival. With an art line in place, these are your targets. A number of swine studies from CHOP, Dr. Suttenberg, Morgan, Kilbaugh, to name a few, demonstrated that vasopressors can be titrated to patient hemodynamics. This is their hemodynamic-directed HD-CPR protocol. During CPR, if the coronary perfusion pressure is less than 20, vasopressors are given in this dosing order, epinephrine every one minute for up to two doses, followed by a vasopressin rescue dose, then repeat. If CPP is more than 20, no vasopressors are given. The chest compression depth is titrated to achieve the systolic pressure of more than 90. They found that coronary perfusion pressure was significantly higher in the HD-CPR approach as you can see in the solid line. This pretty busy slide summarizes all the animal research using the HD-CPR approach. They have found that comparing HD-CPR to standard depth-guided CPR, there were improvements in hemodynamic and survival outcomes with sustained ROSC and 24-hour survival, as well as improved neurobehavioral outcomes at 24 hours. Further, this was backed up with improved cerebral hemodynamic data and improved brain mitochondrial bioenergetics in the HD group. There are certain limitations to hemodynamic-directed CPR. For one, invasive monitors are needed. Two, there is a theoretical potential for epinephrine toxicity if your patient simply isn't responding to epi and you are giving it every 1-2 minutes during a long resuscitation. However, on the flip side, your patient may not require as much epinephrine if their hemodynamics are adequate with CPR alone. There is so much more to study here. What about clinical data? Very recently, Dr. Sutton with the Capcorn Network conducted a hybrid cluster-randomized interventional trial across 18 PICUs in the U.S. evaluating the effectiveness of a bundled intervention comprising of physiologic-focused point-of-care training and structured debriefing. It found that post-intervention, DBP targets were more likely to be achieved and frequent epi was associated with improved outcomes. Although there was no observed difference in survival outcome between groups, this was a high-performing control group with excellent CPR and good overall outcomes. Please stay tuned for their publication. How might we apply a physiology-directed hemodynamic approach to CPR and vasopressor administration? I will show you two examples of protocols. First, this protocol is Dr. Bob Neumar's adult protocol from the University of Michigan. It is currently being used as an alternative to standard ECLS in their ED. It has N-tidal CO2 as an initial physiologic monitor, titrating chest compressions to that, and then it moves to arterial monitoring with diastolic blood pressure if goals are not met. Here, the goal DBP is greater or equal to 35. This protocol, as you can see, uses epinephrine infusion in addition to bolus epi and bolus vaso with a rationale of using a vasopressor infusion to maintain a more steady cerebral blood flow. This is a CHOP Resuscitation Science Center PALS card, more in development, not actively being used in clinical practice just yet. In the gray box on the right, you see the targets for both CPR mechanics and patient hemodynamics as well as dosing for epi and vaso. Then the algorithm, Minute 1, focuses on ensuring high-quality chest compressions, planning next steps. Minute 2 to 6 brings in the patient's hemodynamics, CVP, DBP, and SVP, and it makes specific recommendations how to titrate depth and vasopressors to these goals. Finally, it adds early activation of eCPR if conventional CPR is not effective. Here are my take-home points. Give epinephrine as soon as possible in non-shockable rhythms. Monitor your patient's response, ideally the arterial blood pressure waveform. Your goals should be a diastolic blood pressure greater than 25 in infants and greater than 30 in children. Consider an earlier second dose of epi a priori, or if you have hemodynamic monitoring and your diastolic blood pressure is below goal, then give it, or don't if you have met these hemodynamic targets with CPR alone. There are many questions regarding other vasopressors that might be effective, how epinephrine should be used in an eCPR situation, the complex relationship of epinephrine and neurologic outcomes, and whether an even lower dose of epi might be effective for some patients. Thank you very much for tuning into my presentation, and please feel free to reach out to me by email. Thank you to the organizers for this opportunity to present at SCCM 2022.

epinephrine

cardiopulmonary resuscitation

pediatric patients

hemodynamic-directed CPR

clinical practice