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The American Heart Association’s (AHA) cardiopulmonary resuscitation guidelines recommend against the routine administration of IV calcium during pediatric cardiopulmonary arrest because of its association with worse outcomes. However, IV calcium is routinely used in children with heart disease who have cardiopulmonary arrest. Maureen A. Madden, DNP, RN, CPNP-AC, CCRN, FCCM, is joined by Gurpreet S. Dhillon, MD, to discuss the article, “Calcium Administration During Cardiopulmonary Resuscitation for In-Hospital Cardiac Arrest in Children With Heart Disease is Associated With Worse Survival—A Report From the American Heart Association’s Get With the Guidelines-Resuscitation (GWTG-R) Registry," published in the November issue of Pediatric Critical Care Medicine (Dhillon G, et al. Pediatr Crit Care Med. 2022;23:860-871). Dr. Dhillon is a pediatric cardiac intensivist at Lucile Packard Children's Hospital at Stanford in Palo Alto, California.
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Transcript:
Dr. Madden: Hello and welcome to the Society of Critical Care Medicine Podcast. I’m your host, Maureen Madden. Today, I’ll be speaking with Dr. Gary Dhillon, MD. We’ll be talking about the article, “Calcium Administration During Cardiopulmonary Resuscitation for In-Hospital Cardiac Arrest in Children With Heart Disease Is Associated With Worse Survival—A Report from the American Heart Association’s Get With The Guidelines Resuscitation Registry,” published in the November 2022 issue of Pediatric Critical Care Medicine. To access the full article, visit pccmjournal.org. Dr. Dhillon is a pediatric cardiac intensivist at Lucile Packard Children’s Hospital at Stanford in Palo Alto, California. Welcome, Dr. Dhillon. Before we start, do you have any disclosures to report?
Dr. Dhillon: No, I have no disclosures to report for the purposes of this study and this podcast.
Dr. Madden: Excellent. I’m very excited to have the opportunity to talk with you about this article, and I want to congratulate you and your fellow authors on having this feature article published. I was very excited to receive it in the mail and have the opportunity to go through it in regards to our conversation. I wanted to ask if you could just tell us a little bit about yourself and your research interests and how you became involved in the American Heart Association resuscitation investigators.
Dr. Dhillon: Of course. Well, first of all, I’d like to say thank you for this opportunity to not only talk about my interest in resuscitation science, but to talk about this paper that our group recently published. It’s a very exciting opportunity. I’m very excited to be here. To start off, one of my big research interests is in resuscitation science, specifically focused more so on resuscitation in children with heart disease who suffer cardiac arrest. A lot of that’s because of my goal to treat children who are critically ill with heart disease in cardiac ICUs.
Also, I think a lot of this was, my current research interests were focused by the mentors I had along the way. I did my cardiology training at Texas Children’s, where I work a lot with Javier Lasa, who’s very prolific in resuscitation science research, who initially helped spark this interest. Then, doing my pediatric critical care medicine fellowship at Boston Children’s, I got the opportunity to work with Ravi Thiagarajan, who really helped spark my interest in resuscitation science, focusing more so on population of children with heart disease, where we started talking to each other about how we use calcium in this population, which spurred my involvement with this study.
Before I became involved with this study, I didn’t have as much knowledge about how to get engaged with American Heart Association’s Get With The Guidelines. I think a really important aspect is just knowing how things work and having mentors who support you and help guide you, especially mentors who have worked a lot with the Get With The Guidelines Resuscitation Registry. They helped me understand how the Get With The Guidelines teams receive open proposals every several months to evaluate how to get potentially Young Investigator Grant Awards, which wasn’t done for this study specifically, but I think having people who’ve worked with these registries before is really helpful in getting more engaged and involved with these registries as an early career faculty member or even as a fellow and a trainee as well.
Dr. Madden: I think it’s wonderful, your work in this. I have to say I was not familiar with the American Heart Association’s Get With The Guidelines Registry, but I love the title of it. One of my focuses in my work is, I help with the development of guidelines in various aspects related to critical care. So, I just love that title and I applaud the people who are really pushing the concept of getting with the guidelines. You talked about how Ravi focused you on thinking about calcium in resuscitation, particularly in heart disease patients. Can you talk a little bit more about what those conversations were like and what you thought about before you got to this publication?
Dr. Dhillon: Of course. We know a lot of things about in-hospital cardiac arrest in children with heart disease. We know that they suffer arrests at higher rates than children without heart disease. We also know that outcomes in children with heart disease who suffer in-hospital cardiac arrest are better than in noncardiac populations. Another interesting concept is, over the last several decades, we’ve actually had data that show us that calcium use in pediatric populations during cardiac arrest may be associated with worse outcomes. The most recent large study was in pediatrics in 2008 by Srinivasan and colleagues out of CHOP that also used an earlier version of the Get With The Guidelines Registry at that time as well. What’s interesting is, if you ask an intensivist or any clinician who cares for children with heart disease in a critically ill setting, you’ll find that we generally tend to use calcium more commonly and more frequently in this population. There are multiple reasons for that, I think.
First of all, in cardiac ICU populations, a larger proportion of those populations tend to be younger—neonates and infants. We know in those groups that they have immature sarcoplasmic reticulum, they’re not as able to utilize calcium-dependent calcium release mechanisms or sequester calcium in their sarcoplasmic reticulum and rely more on extracellular calcium stores to perform calcium-dependent cellular mechanisms. We also know that surgical populations specifically have increased blood product exposure during and after bypass, which can lend itself to citrate-mediated ionized hypocalcemia, for which we know that calcium can be administered to normalize those levels and to allow for normal calcium-dependent cellular mechanisms as well.
Additionally, we have quite a few studies that interestingly look at physiologic waveform data and physiologic effects of calcium, and we’ve found that intravenous calcium salts and infusions, even in pediatric populations, they do potentiate, they support myocardial contractility, they mediate vascular tone. They’ve been shown to increase cardiac index, stroke volume, blood pressure, mean arterial pressure, all of which, as you can imagine, and for example, post-cardiac surgical patients who have low cardiac output states, is going to be really beneficial for us. You will find intensivists do commonly try, especially in certain centers, to use calcium more frequently to help get those responses in early postoperative periods to maintain basically DO2, or oxygen delivery, to the tissues of the body.
We also know that our populations are more at risk for cardiac dysrhythmias, either postoperatively or if you have medical cardiac populations who have myocardial dysfunction, myocarditis, etc. You can imagine that, in those populations, we try to maintain normal electrolyte ranges. Here at Stanford we’ll try to maintain potassiums greater than 4, magnesiums greater than 2, i-cal greater than 1.2. We’ll commonly give ionized calcium if needed, if we’re not within those ranges and have risk of cardiac dysrhythmias. So, it’s not surprising to imagine that we use that frame of reference that anybody who cares for critically ill children with heart disease in the increased utility of calcium, that frame of reference will probably carry over to when we care for these patients in the arrest period. But that’s going to be despite some of the recommendations that we have.
Calcium, I feel, is a double-edged sword. During states of perfusion, there are a lot of benefits to it. However, when tissues and cells become ischemic, things change. Especially when you get depletion in ATP, you get a loss of calcium homeostasis. With ATP-dependent calcium ion channel mechanisms gone, you can get a rapid influx of calcium, and cytosolic calcium increases in the cell, especially in neonates and infants who may have immature sarcoplasmic reticulum and can’t sequester that calcium, that increased calcium can accumulate in mitochondria, further depleting ATP production. You can lose calcium hemostasis mechanisms that cause a significant influx and lead to cell lysis and death. Studies have shown that to occur in myocardial and neurologic tissues.
I think it’s important to remember that calcium homeostasis being thrown out, especially in periods of ischemia, especially when you’re administering additional extracellular calcium through intravenous formulations, could potentially be detrimental. I think a lot of this over time, in the last two decades, these studies have borne this out, have led to the recommendations that both the American Heart Association, even the European Resuscitation Council, the ERC, have made regarding calcium use during arrest.
Currently, and most recently, in the last updates both of those large organizations made in the last several years, they’ve recommended that calcium use during arrest be limited to four specific indications; those are hyperkalemia, hypermagnesemia, ionized hypocalcemia, and calcium channel blockade intoxication. It’s gone even further to say that the routine use of calcium during pediatric arrest outside of those four indications is recommended against, as a class E recommendation, due to observational studies showing a potential association with worse outcomes.
I think you can imagine, and what we’ve seen and what this study also shows, is that we still tend to use calcium at higher rates in children with heart disease, even with those guidelines in place. That was really the impetus of this study, to know why we use calcium more, and should we be doing that in cardiac arrest as opposed to outside of cardiac arrest?
Dr. Madden: You’ve just raised so many questions that I want to ask you, but we’re going to focus first on the article. I’d love for you to talk about it a little bit and tell us what your findings are.
Dr. Dhillon: Yeah, absolutely. I’m happy to. In order to ask this question of calcium use in children with heart disease suffering in-hospital cardiac arrest, we aim to use the American Heart Association’s Get With The Guidelines Resuscitation Registry, which we use to evaluate children with heart disease less than 18 years of age, who suffered an index in-hospital cardiac arrest event between January of 2000 to January of 2019.
Inclusion criteria were less than 18 years of age, only index events. We looked at medical and surgical illness categories, which are basically two illness categories that are categories of children who have underlying heart disease of some sort. We looked at events where compressions were done, which was our identifying factor for an arrest event. We included cases where ECMO was deployed to achieve return of circulation or ECPR. We excluded out-of-hospital arrest events and events where calcium data during arrest were missing.
After application of all those criteria, we arrived at a total cohort of 4556 children, of which 2229 were medical cardiac and 2327 were surgical cardiac. In order to compare groups where calcium was or was not given, we aimed to used propensity score matching. In doing so, we selected certain a priori variables on which we matched patients based on the propensity of receiving calcium. These variables have been known to be associated, not just with calcium administration, but also with outcomes in children with heart disease who suffer in-hospital cardiac arrest.
Those variables that we used for propensity score matching were age; event location; the presence of metabolic and electronic derangements preceding arrest; hypotension preceding arrest; initial pulseless rhythm; CPR duration, which we divided into quartiles of variable distribution; and illness category, with the categories being surgical and medical cardiac illness categories. After we matched on those variables, we arrived at matched pairs of 678, which were evaluated. Then, we also did a propensity score matching on the individual subgroups of surgical, medical, cardiac. Using the same a priori variables, we had 322 matched medical cardiac pairs and 339 matched surgical cardiac pairs as part of a subgroup evaluation.
Understanding that our propensity score matching only looks at a smaller cohort or specific part of our population, in order to assess the generalizability of our propensity outcomes without elimination of large portions of our cohort, we also performed sensitivity analyses on the entire unmatched group using multivariable logistic regression, adjusting for the propensity score as well. With regards to our main results, I think one really interesting finding that I think we all felt, as cardiac intensivists who care for these populations of children with heart disease that, actually you can visually see now is figure 2 in our paper, where we looked at the proportion of calcium use during CPR during in-hospital cardiac arrest among four major illness categories or two cardiac groups or surgical and medical cardiac and our noncardiac surgical and medical groups as well from 2000 to 2019.
From the early 2000s, in 2000, we had recommendations that limited the indications for calcium. At that time, our noncardiac population, about 40% to 45% of that population received calcium during arrest. From the cardiac group, that was about 55% to 60% of that population received calcium. And as you go from 2000 to the end of 2018, what you’ll see is that the rates of calcium use in all four groups do decrease significantly. By the end of this 19-year period in noncardiac populations, only 20% to 25% received calcium during arrest. In our medical cardiac group, about 30%. But in our surgical population, that number’s still quite high, with almost 50% of that group still receiving calcium during arrest. It goes to show that, yes, even in our population of children with heart disease, we do use calcium a bit more often than noncardiac populations, with those guidelines having been in place over the 19-year period of study.
Out of our 4556 patients, about 44% received calcium during CPR. We found that intravenous calcium administration during in-hospital cardiac arrest was more common in ICU event locations in younger populations, in surgical cardiac groups, and for longer-duration CPR events. The patients who received calcium were likely to have vasoactive infusions in place, more epi drip, more epi given during arrest, which would be colinear with CPR duration, and had longer CPR durations for arrest where calcium was used, 27 versus five minutes.
When we looked at our propensity score matched cohort of 678, those receiving calcium during arrest had lower rates of survival to hospital discharge, lower rates of discharge from the hospital with a favorable neurologic outcome, and higher rates of ECPR deployment to achieve return of circulation. When we also looked at our subgroups of medical cardiac and surgical cardiac, we found that, in the surgical cardiac matched cohort, we still found that we had lower rates of survival to hospital discharge and lower rates of survival with a favorable neurologic outcome. However, in the medical cardiac propensity score matched cohort of 322 patients, there were no significant differences seen in outcome based on calcium use during CPR.
We found this to be interesting. We proposed this maybe because, first of all, we know that outcomes are generally poorer in the medical cardiac population. There are a lot of reasons for that and that medical cardiac populations may have more irreversible causes of cardiac arrest or more comorbid conditions coming into the hospital and then suffering cardiac arrest that may preclude successful CPR, and that this increased mortality may have dulled the adverse effects of calcium administration during CPR. We’re also looking at our sensitivity analysis. We also showed, through multivariable regression analysis of our entire unmatched cohort, that there was lower odds of survival when calcium was used during CPR, and this finding was still seen in the surgical cardiac group as well. We also looked at unadjusted outcomes in children less than one year of age, where we’re more likely to give calcium in those populations, and still found that there was a decreased likelihood of survival in cases where calcium was used during CPR.
Looking at all those results and looking at it in different ways for propensity score matching of specific subgroups to evaluate the entire unmatched cohort and having these findings, we did conclude that intravenous calcium administration during CPR occurs at higher rates in children with heart disease. Calcium is used more frequently during arrest in younger populations and surgical cardiac groups with longer CPR duration events and those receiving other nonadrenergic pharmacologic interventions during arrest, and that intravenous calcium administration during arrest was associated with decreased survival to hospital discharge in children with heart disease using propensity score matched analysis.
Dr. Madden: Based on all of that, your study now has an important subgroup that was looked at, and it confirms the results of previous reports that also looked at calcium, where it was administered in all disease processes, and it led to longer CPR duration events. It had shown that it still had decreased survival or, if there was survival, had poor neurologic outcome. So, these guidelines exist and yet we, as practitioners, are still not adhering to them. I know that we definitely have art and science, and we have our own perspectives on the individual patient that we’re facing at that moment in time. But what do you think? How can we improve our clinicians’ adherence to the guidelines and the recognition that there is strong evidence that supports the use of calcium in hospital cardiac arrests, that it should not be used unless it’s for those situations that you’ve already previously described?
Dr. Dhillon: Right. Absolutely. No, it’s tough. You’re absolutely right. We have to come to a place where our clinical care meets the guidelines and understand that the data we do have, there’s quite a bit of it in the literature, but there are some shortcomings and some limitations based off of how that data was collected. For example, using Get With The Guidelines, we’re doing a retrospective observational study. The Get With The Guidelines has fantastic CPR data, but there are some limitations in granularity. For example, calcium is a binary variable, so we don’t really have an understanding based off of this study, or most other studies out there, about the time- and dose-dependent nature of calcium administration during arrest. Does it matter how you give it, when you give it, how much you give it?
Get With The Guidelines will give you illness categories, but we don’t really know, in surgical cardiac groups, should we be treating a neonate who had a Norwood-Sano or a truncus repair similarly to help you treating an adolescent ASD repair? With regards to how we manage the population, how we treat the population during CPR, I think there are some differences that still need to be borne out, some additional studies and more granular studies to identify some more specific factors around calcium use. I think a large part of what we have, and the data would support and our guidelines do state, that we should somewhat limit to specific indications that we give calcium.
A lot of it’s appropriate training. Things like simulation, practicing for those who work in our CVICUs, from our fellow trainees and our residents to our APPs to our attendings as well, on focusing on things like CPR quality, which we know is associated with outcomes. Good CPR quality, limiting the duration of an arrest, potentially even early deployment of ECMO for resuscitation, are going to be equally, if not more, important as well. I think ongoing education, ongoing training, potentially even simulation to help with adherence to the guidelines is going to be a start to what you’re describing as just having to change the culture of practice in cardiac ICUs, specifically around arrest events.
Dr. Madden: Exactly. I know, when we all find ourselves in the situation at the bedside, in particular with children, that there are these driving forces that we have, particularly the immediate postop patient and other disease populations that we really want to give the best opportunity for survival. But sometimes I think we also collectively may lose track of what is occurring in duration, etc., and not adhering to the guidelines. It may potentially be to the detriment of our patient population’s survival as well as neurologic outcome. But I think your piece on education, and it always comes back to education and it’s the changing of the culture, and this evidence that you are providing is really a key element to helping change the culture. So, I applaud the publication of this article. I think it’s incredibly timely as well as very important information.
Along those lines, we talked about, there’s an editorial that accompanied the publication of this article. I just wanted to briefly get your take on that from Dr. Savorgnan and Dr. Acosta. In particular, when they talked about, that we already know that using calcium during the CPR events is associated with sicker patients who need more interventions, they make the statement, “. . . are bound to have a worse outcome with decreased survival to hospital discharge.” One of the things that they were talking about that I’d like you to touch upon is, not just only the patients that we choose to administer calcium to, but the concept of a prospective randomized controlled study to match the severity of illness and adequately settle the question on the impact of calcium on survival to hospital discharge. I think we always want to go in that direction, but I want your take on it.
Dr. Dhillon: Of course. Having read the article, I agree on most all the points that we state. Regarding the sicker population, there was a really interesting great use of a statement that I recall from Dr. Tia Raymond’s publication in Resuscitation, 2015, looking at another nonadrenergic pharmacologic intervention during arrest in peds patients, which was bicarb, describing, similar to where we share in one of our figures increased calcium use with longer CPR duration, we find a similar thing with bicarb. It’s that unnerving standpoint from a person who’s running an arrest, when you’re getting toward the end of that and not achieving ROSC, wanting to perform last-ditch efforts, you’re throwing the kitchen sink at a patient, which would include certain nonadrenergic interventions, like calcium, for example.
It is a potential possibility that we are looking at sicker populations. One of our hopes was to balance for that in our propensities cohort by picking factors that would also identify sicker populations, like CPR duration, hypotension preceding arrest, and ICU event location, which are some things we match for. But obviously, in a retrospective study, you can’t match for all things. And the more you try to match for, you tend to potentially overfit your model and limit your ability to calculate a difference or have enough of a sample size to even do an analysis. I think that is a balance we did. You have to walk and kind of figure out with this propensity score match analysis as well. I still think it’s hard to say for sure that we’re only using calcium in sicker populations. I think that could be a possibility. Additional studies will definitely be needed.
I think one thing we could consider doing that may be potentially beneficial is things like linkage analyses. Every registry has areas where their variables are very granular and other areas where they’re not. A lot of our registries, we work so often in silos with limited communication. Something like a linkage registry, which can link certain registries with very specific cardiac disease-specific variables and illness category variables or severity-of-illness category variables with something that provides great CPR registry data, like Get With The Guidelines, could potentially be beneficial.
I think single-center studies, which look at very granular data, we can potentially even go through code sheets and look at specific illness factors that Get With The Guidelines might not be able to give you. Looking at the time- and dose-dependent nature of something like calcium would be really beneficial. I think prospective and randomized control trials in something that is as infrequent as cardiac arrest and emergent situations as cardiac arrest can be very difficult to do, which is probably why we haven’t seen very many randomized studies in cardiac arrest in pediatric populations.
Dr. Madden: Exactly.
Dr. Dhillon: That’s definitely going to be a limiting factor, for sure, for a lot of people being able to get something like this off the ground.
Dr. Madden: Yeah, I thoroughly agree, and I appreciate your commenting upon the editorial. We’re almost out of time, but I just wanted to ask if there’s anything else that you wanted to discuss or bring up about your publication that maybe we haven’t touched upon yet?
Dr. Dhillon: No, I think what I really wanted to focus on was to hopefully stir some conversation, maybe even some controversy, to have people look into this a little bit more. We’ll be doing more evaluations, specifically from our group, looking at calcium, not necessarily even during arrest, but how we use it in cardiac populations in general and how we should and should not be using it, if it’s beneficial or if it’s not. Really, I think my biggest goal was to bring up the concept or the idea of the fact that we use calcium very differently in children with heart disease, and there are many reasons for that. We may just need to have a change of frame of reference and divide it based off of not arresting or arresting. How we should use calcium may need to differ.
Once again, I think the most important point is that current guidelines do have certain recommendations on restricting calcium use that I think a lot of us just need to remind ourselves about and focus on certain things that we know are associated with outcomes, CPR quality metrics. There have been a lot of data coming out of Get With The Guidelines. CHOP has done a lot of patient-centric CPR quality metric information that we should be abiding by. Doing studies to look at modifiable risk factors associated with cardiac arrest and focusing on those modifiable risk factors. You can’t do anything about the age of a child during arrest, especially when we have surgical cardiac populations, of which a reasonable portion need to undergo surgical interventions during the neonatal period. But folks’ modifiable risk factors are important.
I think there’s been a lot of excitement recently from Jeffrey Alten and the PC4 group looking at how to prevent arrest. The only thing that’s better than good cardiopulmonary resuscitation is not having to perform cardiopulmonary resuscitation. This group, with the institution of their CAP bundle, cardiac arrest prevention bundle, has been able to show a relative risk reduction in cardiac arrest by about 30% in institutions that deploy and utilize the CAP bundles. I think that’s a really exciting area of further research for anyone from trainees who are interested and anybody who’s been interested in resuscitation science. I think we’re on a frontier of being able to expand how we look at resuscitation in pediatrics, what aspects we focus on, because we’ve started to hit a little bit of a plateau in our success rates and survival rates, and I think we need to open up other avenues, which we’re starting to, how we look at resuscitation in children and children with heart disease.
Dr. Madden: It’s been wonderful to have the opportunity to chat with you on this podcast. I have to say, hopefully we get to meet in person. I too support the appropriate use of calcium in normalizing ionized calciums because I don’t necessarily want to study resuscitative science. I’m more on the preventative capacity, so I’ll help you stir the pot. Thank you again for your time. This concludes another edition of the Society of Critical Care Medicine Podcast. For the Society of Critical Care Medicine Podcast, I’m Maureen Madden.
Maureen A. Madden, DNP, RN, CPNP-AC, CCRN, FCCM, is a professor of pediatrics at Rutgers Robert Wood Johnson Medical School and a pediatric critical care nurse practitioner in the pediatric intensive care unit at Bristol-Myers Squibb Children’s Hospital in New Brunswick, New Jersey.
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